Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

• the invention relates to the use of cilansetron and, more particularly, to a method for treating diarrhea-predominant irritable bowel syndrome in a subject.
• IBS Irritable bowel syndrome
• This invention provides a method of treatment of diarrhea-predominant
• IBS in a subject comprising administering a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to achieve a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject, comprising administering a sufficient amount of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to reach a mean plasma cilansetron concentration across a statistically significant population of subjects of between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject, comprising administering a daily dose of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof in an amount sufficient to substantially maintain a plasma cilansetron concentration of between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising administering a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to achieve a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising administering a sufficient amount of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to reach a mean plasma cilansetron concentration across a statistically significant population of subjects of between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising administering a daily dose of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof in an amount sufficient to substantially maintain a plasma cilansetron concentration of between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising administering a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to achieve a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising administering a sufficient amount of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to reach a mean plasma cilansetron concentration across a statistically significant population of subjects of between about 0.1 ng/mL and about 25 ng/mL.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising administering a daily dose of a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof in an amount sufficient to substantially maintain a plasma cilansetron concentration of between about 0.1 ng/niL and about 25 ng/mL.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject receiving selective serotonin reuptake inhibitor
• SSRI SSRI therapy
• a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof to achieve a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL.
• FIGS. 1 (a) - (d) show dissolution profile plots for cilansetron 4 mg capsules.
• FIG. 2 (a) - (d) show dissolution profile plots for cilansetron 8 mg capsules.
• FIG. 3 is a comparative dissolution profile plot of cilansetron 8 mg tablet and 8 mg capsule formulations
• FIG. 4 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations for tablet and oral solutions.
• FIG. 5 is a Linear and Semi-Logarithmic Geometric Mean plot of (4R)- hydroxy cilansetron mean plasma concentrations for tablet and oral solutions.
• FIG. 6 is a Linear and Semi-Logarithmic Geometric Mean plot of (4S)- hydroxy cilansetron mean plasma concentrations for tablet and oral solutions.
• FIG. 7 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations under fasted and high-fat conditions.
• FIG. 8 is a Linear and Semi-Logarithmic Geometric Mean plot of (4R)- hydroxy cilansetron mean plasma concentrations under fasted and high-fat conditions.
• FIG. 9 is a Linear and Semi-Logarithmic Geometric Mean plot of (4S)- hydroxy cilansetron mean plasma concentrations under fasted and high-fat conditions.
• FIG. 10 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations following a single dose or at steady state.
• FIG. 11 is a Linear and Semi-Logarithmic Geometric Mean plot of (4R)- hydroxy cilansetron mean plasma concentrations following a single dose or at steady state.
• FIG. 12 is a Linear and Semi-Logarithmic Geometric Mean plot of (4S)- hydroxy cilansetron mean plasma concentrations following a single dose or at steady state.
• FIG. 13 (a) - (d) shows plots of plasma trough concentrations of cilansetron and its 4-hydroxy metabolites following oral treatment.
• FIG. 14 is a box plot of cilansetron AUC(O-inf) following 4 mg to 16 mg administration.
• FIG. 15 is a box plot of cilansetron dose-normalized AUC(O-inf) following
• FIG. 16 is a box plot of cilansetron AUC(O-inf) following 2 mg to 64 mg administration.
• FIG. 17 is a box plot of cilansetron Cmax following 2 mg to 64 mg administration.
• FIG. 18 is a box plot of cilansetron dose-normalized AUC (0-inf) following 2 mg to 64 mg administration.
• FIG. 19 is a box plot of cilansetron dose-normalized Cmax following 2 mg to 64 mg administration.
• FIG. 20 is a box plot of cilansetron AUC (0- ⁇ ) following 2 mg to 32 mg
• FIG. 21 is box plot of cilansetron Cmax following 2 mg to 32 mg TID administration.
• FIG. 22 is a box plot of cilansetron dose-normalized AUC (0- ⁇ ) following
• FIG. 23 is a box plot of cilansetron dose-normalized Cmax following 2 mg to 32 mg TID administration.
• FIG. 24 is a plot of mean 14 C-radioactivity and unchanged cilansetron plasma concentration following a single IV dose of 14 C-labeled cilansetron.
• FIG. 25 is a plot of mean w C-radioactivity and unchanged cilansetron plasma concentration following a single oral dose of ⁇ C-labeled cilansetron.
• FIG. 26 shows a metabolic scheme for cilansetron in humans and other animal species.
• FIG. 27 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations in young and elderly male and female subjects following 8 mg administration.
• FIG. 28 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations in young and elderly male and female subjects following 8 mg TED administration.
• FIG. 29 (a) - (b) show pharmacokinetic values for cilansetron in healthy and renally-impaired subjects following 2 mg TDD administration.
• FIG. 30 (a) - (b) show pharmacokinetic values for (4R)-hydroxy cilansetron in healthy and renally-impaired subjects following 2 mg TDD administration.
• FIG. 31 (a) - (b) show pharmacokinetic values for (4S)-hydroxy cilansetron in healthy and renally-impaired subjects following 2 mg TID administration.
• FIG. 32 is regression analysis plot for individual cilansetron AUC(O- ⁇ ) values versus creatinine clearance.
• FIG. 33 is regression analysis plot for individual (4R)-hydroxy cilansetron
• FIG. 34 is regression analysis plot for individual (4S)-hydroxy cilansetron
• FIG. 35 is a Linear and Semi-Logarithmic Geometric Mean plot of cilansetron mean plasma concentrations in hepatically impaired and healthy subjects.
• FIG. 36 is a Linear and Semi-Logarithmic Geometric Mean plot of (4R)- hydroxy cilansetron and (4S)-hydroxy cilansetron mean plasma concentrations in hepatically impaired and healthy subjects.
• FIG. 37 is a plot of mean plasma cilansetron concentrations following administration of cilansetron alone or in combination with Maalox liquid.
• FIG. 38 is a plot of mean plasma ethinyl estradiol concentrations following administration of Ortho Tri-Cyclen alone or in combination with cilansetron.
• FIG. 39 is a plot of mean plasma norgestrel concentrations following administration of Ortho Tri-Cyclen alone or in combination with cilansetron.
• FIG. 40 is a plot of mean plasma 17-deacetyl-norgestimate concentrations following administration of Ortho Tri-Cyclen alone or in combination with cilansetron.
• FIG. 41 (a) - (c) shows plots of mean serum concentrations or follicle stimulating hormone, luteinizing hormone and progesterone following administration of
• FIG. 42 is a plot of mean plasma cilansetron concentrations following administration of cilansetron alone or in combination with fluvoxamine.
• FIG. 43 is a plot of mean plasma (4R)-hydroxy cilansetron concentrations following administration of cilansetron alone or in combination with fluvoxamine.
• FIG. 44 is a plot of mean plasma (4S)-hydroxy cilansetron concentrations following administration of cilansetron alone or in combination with fluvoxamine.
• FIG. 45 is a box plot of AUC(O- ⁇ ) values for cilansetron and its 4-hydroxy metabolites following administration of cilansetron alone or in combination with fluvoxamine.
• FIG. 46 is a plot of mean cilansetron concentration following administration of cilansetron alone or in combination with ketoconazole.
• FIG. 47 is a plot of mean (4R)-hydroxy cilansetron concentration following administration of cilansetron alone or in combination with ketoconazole.
• FIG. 48 is a plot of mean (4S)-hydroxy cilansetron concentration following administration of cilansetron alone or in combination with ketoconazole.
• FIG. 49 (a) - (c) show box plots of AUC(O- ⁇ ) values for cilansetron and its
• FIG. 50 is a plot of mean cilansetron concentration following administration of cilansetron alone or in combination with paroxetine.
• FIG. 51 is a plot of mean (4R)-hydroxy cilansetron concentration following administration of cilansetron alone or in combination with paroxetine.
• FIG. 52 is a plot of mean (4S)-hydroxy cilansetron concentration following administration of cilansetron alone or in combination with paroxetine.
• FIG. 53 (a) - (c) show box plots of AUC(O- ⁇ ) values for cilansetron and its
• FIG. 54 is a scatter plot of observed plasma cilansetron concentration versus post-dose time for 1, 2, 8, and 16 mg cilansetron treatments.
• FIG. 55 is a scatter plot of observed plasma (4R)-hydroxy cilansetron concentration versus post-dose time for 1, 2, 8, and 16 mg cilansetron treatments.
• FIG. 56 is a scatter plot of observed plasma (4S)-hydroxy cilansetron concentration versus post-dose time for 1, 2, 8, and 16 mg cilansetron treatments.
• FIG. 57 is a scatter plot of individual placebo-corrected QTc intervals versus cilansetron concentrations following 16 mg cilansetron administration.
• FIG. 58 is a plot summary of adequate relief of IBS symptoms by week for the intent-to-treat (ITT) population of subjects.
• FIG. 59 is a plot summary of adequate relief of abdominal pain/ and/or discomfort by week for the ITT population of subjects.
• FIG. 60 is a plot summary of adequate relief of abnormal bowel habits by week for the ITT population of subjects.
• FIG. 61 is a plot of the percentage of subjects with adequate relief of IBS symptoms by week during a four-month treatment period.
• FIG. 62 is a plot of the percentage of subjects with adequate relief of abdominal pain and/or discomfort by week during a four-month treatment period.
• FIG. 63 is a plot of the percentage of subjects with adequate relief of abnormal bowel habits by week during a four-month treatment period.
• FIG. 64 is a plot of change in mean adequate relief of IBS symptoms with cilansetron or placebo treatment.
• FIG. 65 is a plot of change in mean adequate relief of abdominal pain and/or discomfort with cilansetron or placebo treatment.
• FIG. 66 is a plot of change in mean adequate relief of abnormal bowel habits with cilansetron or placebo treatment.
• FIG. 67 is a plot of change in mean daily abdominal pain and/or discomfort with cilansetron or placebo treatment.
• FIG. 68 is a plot of change in mean daily abdominal pain and/or discomfort with cilansetron or placebo treatment.
• FIG. 69 is a plot of change in mean daily abdominal pain and/or discomfort with cilansetron or placebo treatment.
• FIG. 70 is a plot of change in mean daily stool consistency with cilansetron or placebo treatment.
• FIG. 71 is a plot of change in mean daily stool consistency with cilansetron or placebo treatment.
• FIG. 72 is a plot of change in mean daily stool consistency with cilansetron or placebo treatment.
• FIG. 73 is a plot of change in mean daily stool frequency with cilansetron or placebo treatment.
• FIG. 74 is a plot of change in mean daily stool frequency with cilansetron or placebo treatment.
• FIG. 75 is a plot of change in mean daily stool frequency with cilansetron or placebo treatment.
• FIG. 76 is a plot of change in daily urgency with cilansetron or placebo treatment.
• FIG. 77 is a plot of change in mean urgency with cilansetron or placebo treatment.
• FIG. 78 is a plot of change in mean urgency with cilansetron or placebo treatment.
• FIG. 79 is a plot of change in mean bloating or abdominal distention with cilansetron or placebo treatment.
• FIG. 80 is a plot of change in mean bloating or abdominal distention with cilansetron or placebo treatment.
• FIG. 81 is a plot of change in mean bloating or abdominal distention with cilansetron or placebo treatment.
• FIG. 82 is a plot of mean change in overall quality of life from baseline to endpoint of treatment with cilansetron or placebo.
• FIG. 83 is a plot of mean change in overall quality of life from baseline to endpoint of treatment with cilansetron or placebo.
• FIG. 84 is a plot of mean change in overall quality of life from baseline to endpoint of treatment with cilansetron or placebo.
• FIG. 85 is a plot of mean interruption of activities from baseline to endpoint of treatment with cilansetron or placebo.
• FIG. 86 is a plot of mean interruption of activities from baseline to endpoint of treatment with cilansetron or placebo.
• FIG. 87 is a plot of mean interruption of activities from baseline to endpoint of treatment with cilansetron or placebo.
• any ranges, ratios and ranges of ratios that can be formed by any of the numbers or data present herein represent further embodiments of the present invention. This includes ranges that can be formed that do or do not include a finite upper and/or lower boundary. For example, by way of illustration and not limitation, referring to FIG. 38, wherein it is illustrated that the difference in mean plasma concentration of EE between OC + cilansetron and OC administration alone is less than about 10 pg/mL or even less than about 1 pg/mL. Accordingly, the skilled person will appreciate that such ratios, ranges and values are unambiguously derivable from the data presented herein.
• AAG Alpha- 1 acid glycoprotein
• ANOVA Analysis of variance
• AUC Area under curve
• AUC(O-inf) Area under curve from time zero to infinity
• AUC (0-t) Area under curve from time zero to the concentration time point t
• AUC O-last
• AUC Area under curve over the dosing interval
• AUC (0- ⁇ ) Area under curve over the dosing interval
• AUC(0-8) Area under curve over the dosing interval for a three times a daily dosing regimen
• BA Biovailability
• BID Twice daily
• CI Confidential interval
• CL Systemic clearance
• CL/F Apparent oral clearance
• Cm Centimeter
• Cmax Maximum concentration observed
• Cmin Minimum concentration observed
• CLcr Cratinine concentration observed
• CLr Raxal clearance
• CO 2 Carbon dioxide
• %CV Coefficient of variation
• Clarkansetron is understood to refer to (R)-(-)-4,5,6,8,9,10- hexahydro-10-[(2-methyl-lH-imidazol-l-yl)methyl]-llH-pyrido-[3,2,l-jk]-carbazol-ll- one (alternative name: (10R)-5,6,9,10-tetrahydro-10-[(2-methyl-lH-imidazol-l- yl)methyl]-4H-pyrido [3,2,l-jk]carbazol-ll(8H)-one), which is disclosed, for example, in U.S. Patent 6,566,369, the contents of which are incorporated herein by reference.
• Cilansetron can be administered in any suitable dose, and using any suitable dosing schedule.
• the dosage of cilansetron administered according to the methods of the present invention may be, for example, from about 0.1 mg to about 40 mg daily, such as from about 1 mg to about 38 mg daily, from about 2 mg to about 36 mg daily, from about 2 mg to about 34 mg daily, from about 2 mg to about 32 mg daily, from about 2 mg to about 30 mg daily, from about 2 mg to about 28 mg daily, from about 2 mg to about 26 mg daily, from about 2 mg to about 24 mg daily, from about 2 mg to about 22 mg daily, from about 2 mg to about 20 mg daily, from about 2 mg to about 18 mg daily, from about 2 mg to about 16 mg daily, from about 2 mg to about 14 mg daily, from about 2 mg to about 12 mg daily, from about 2 mg to about 10 mg daily, from about 2 mg to about 8 mg daily (such as or from about 4 mg to about 8 mg daily, from about 2 mg to about 6 mg daily, or from about 2 mg to about 4 mg
• cilansetron may be administered one or more times a day, such as two or more, three or more, four or more, five or more, or even six or more times daily.
• 2 mg cilansetron is administered three times daily (TID).
• cilansetron can be administered on alternate days or on consecutive days.
• Cilansetron can also be administered in any suitable formulation such as, for example, a tablet, capsule, gelcap, or solution (e.g., injectable or inhalable solution).
• cilansetron is in the form of a 2 mg, 4 mg or 8 mg capsule.
• cilansetron is in the form of a 4 mg/2 mL or 8 mg/4 mL solution.
• cilansetron is in the form of a 1 mg, 2 mg, 4 mg, 8 mg, 16 mg or 32 mg tablet.
• Cilansetron may be administered in the form of a any pharmacologically acceptable acid addition salts, as described for example in U.S. Patent 6,566,369 (the entire contents of which are incorporated herein by reference.
• cilansetron is administered in the form of cilansetron hydrochloride or cilansetron hydrochloride monohydrate.
• cilansetron can be administered in any form and in combination with any known diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, or other material, as disclosed, for example in the '369 patent.
• cilansetron is administered in a composition comprising: 4 parts cilansetron hydrochloride monohydrate, 30 parts corn starch, 70 parts lactose, 5 parts Kollidon 25®, 2 parts magnesium stearate, and 3 parts talcum, as described, for example in U.S. Patent 6,566,369 (the entire contents of which are incorporated herein by reference).
• cilansetron is administered in a 2 mg film-coated tablet for oral use in humans, comprising
• cilansetron is administered in a 2 mg film-coated tablet for oral use in humans, comprising: 2.34 mg cilansetron.HCl.H 2 O, 51.78 mg maize starch, 84.48 mg mannitol; 4.90 mg povidone; 0.50 mg citric acid monohydrate; 3.0 5 mg crospovidone; 1.0 mg colloidal anhydrous silica; 2.0 mg stearic acid; and a coating containing Opadry® 03B28686 (white) or Opadry® Y-l-7000 (white).
• This invention provides a method of treatment of diarrhea-predominant
• BBS in a subject comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL is achieved between about 0.01 hours and about 24 hours following the administering of the composition to the subject.
• the plasma cilansetron concentration achieved by the method is achieved between (i) a first value that is greater than about 0.1 hours, greater than about 0.2 hours, greater than about 0.3 hours, greater than about 0.4 hours, greater than about 0.5 hours, greater than about 0.6 hours, greater than about 0.7 hours, greater than about 0.8 hours, greater than about 0.9 hours, greater than about 1 hour, greater than about 1.1 hours, greater than about 1.2 hours, greater than about 1.3 hours, greater than about 1.4 hours, or greater than about 1.5 hours, and (ii) a second value that is less than about 23 hours, less than about 22 hours, less than about 21 hours, less than about 20 hours, less than about 19 hours, less than about 18 hours, less than about 17 hours, less than about 16 hours, less than about 15 hours, less than about 14 hours, less than about 13 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7 hours, less than about 6 hours, less than about
• the plasma cilansetron concentration achieved by the method is achieved between about 0.01 hours and about 20 hours, between about 0.1 hours and about 18 hours, between about 0.1 hours and about 15 hours, between about 0.1 hours and about 12 hours, between about 0.1 hours and about 8 hours, or between about 0.1 hours and about 4 hours, following administration.
• cilansetron is administered in an amount sufficient to achieve a plasma cilansetron concentration between (i) a first value that is greater than about 0.2 ng/mL, greater than about 0.4 ng/mL, greater than about 0.6 ng/mL, greater than about 0.8 ng/mL, greater than about 1.0 ng/mL, greater than about 1.2 ng/mL, greater than about 1.5 ng/mL, greater than about 2.0 ng/mL, greater than about 2.5 ng/mL, greater than about 3.0 ng/mL, greater than about 3.5 ng/mL, greater than about 4.0 ng/mL, greater than about 4.5 ng/mL, or greater than about 5.0 ng/mL and (ii) a second value that is less than about 25 ng/mL, less than about 24 ng/mL, less than about 23 ng/mL, less than about 22 ng/mL, less than about 21 ng/mL, less
• cilansetron is administered in an amount sufficient to achieve a plasma cilansetron concentration between about 0.5 ng/mL and about 20 ng/mL, between about 1 ng/mL and about 15 ng/mL, between about 3 ng/mL and about 12 ng/mL, or between about 4 ng/mL and about 10 ng/mL, following administration.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method of treatment of diarrhea-predominant TBS in a subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL.
• a statistically significant population is understood to refer to two or more, three or more, four or more, five or more, ten or more, twenty or more, forty or more, sixty or more, eighty or more, or even one hundred or more persons.
• a mean plasma cilansetron concentration between 4 ng/mL and about 9 ng/mL across a statistically significant population of subjects would be understood by skill to refer to a measured mean plasma cilansetron concentration of between 4 ng/mL and about 9 ng/mL as measured across a statistically significant number of subjects.
• the mean plasma cilansetron concentration achieved in a mean time between (i) a first value that is greater than about 0.1 hours, greater than about 0.2 hours, greater than about 0.3 hours, greater than about 0.4 hours, greater than about 0.5 hours, greater than about 0.6 hours, greater than about 0.7 hours, greater than about 0.8 hours, greater than about 0.9 hours, greater than about 1 hour, greater than about 1.1 hours, greater than about 1.2 hours, greater than about 1.3 hours, greater than about 1.4 hours, or greater than about 1.5 hours, and (ii) a second value that is less than about 24 hours, less than about 23 hours, less than about 22 hours, less than about 21 hours, less than about 20 hours, less than about 19 hours, less than about 18 hours, less than about 17 hours, less than about 16 hours, less than about 15 hours, less than about 14 hours, less than about 13 hours, less than about 12 hours, less than about 11 hours, less than about 10 hours, less than about 9 hours, less than about 8 hours, less than about 7
• the mean plasma cilansetron concentration achieved in a mean time between about 0.01 hours and about 24 hours, between about 0.01 hours and about 20 hours, between about 0.1 hours and about 18 hours, between about 0.1 hours and about 15 hours, between about 0.1 hours and about 12 hours, between about 0.1 hours and about 8 hours, or between about 0.1 hours and about 4 hours, following administration.
• cilansetron is administered in an amount sufficient to achieve a mean plasma cilansetron concentration between (i) a first value that is greater than about 0.2 ng/mL, greater than about 0.4 ng/mL, greater than about 0.6 ng/mL, greater than about 0.8 ng/mL, greater than about 1.0 ng/mL, greater than about 1.2 ng/mL, greater than about 1.5 ng/mL, greater than about 2.0 ng/mL, greater than about 2.5 ng/mL, greater than about 3.0 ng/mL, greater than about 3.5 ng/mL, greater than about 4.0 ng/mL, greater than about 4.5 ng/mL, or greater than about 5.0 ng/mL and (ii) a second value that is less than about 25 ng/mL, less than about 24 ng/mL, less than about 23 ng/mL, less than about 22 ng/mL, less than about 21 ng/mL,
• cilansetron is administered in an amount sufficient to achieve a mean plasma cilansetron concentration between about 0.5 ng/mL and about 20 ng/mL, between about 1 ng/mL and about 15 ng/mL, between about 3 ng/mL and about 12 ng/mL, or between about 4 ng/mL and about 10 ng/mL, following administration.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours after the subject has been administered the daily dose for at least 7 consecutive days.
• the plasma cilansetron concentration is substantially maintained between (i) a first value that is greater than about 0.2 ng/mL, greater than about 0.4 ng/mL, greater than about 0.6 ng/mL, greater than about 0.8 ng/mL, greater than about 1.0 ng/mL, greater than about 1.2 ng/mL, greater than about 1.5 ng/mL, greater than about 2.0 ng/mL, greater than about 2.5 ng/mL, greater than about 3.0 ng/mL, greater than about 3.5 ng/mL, greater than about 4.0 ng/mL, greater than about 4.5 ng/mL, or greater than about 5.0 ng/mL and (ii) a second value that is less than about 25 ng/mL, less than about 24 ng/mL, less than about 23 ng/mL, less than about 22 ng/mL, less than about 21 ng/mL, less than about 20 ng/mL, less than about
• cilansetron is administered in an amount sufficient wherein a plasma cilansetron concetnration between about 0.5 ng/mL and about 20 ng/mL, between about 1 ng/mL and about 15 ng/mL, between about 3 ng/mL and about 12 ng/mL, or between about 4 ng/mL and about 10 ng/mL, following administration, is substantially maintained for at least 12 hours after the subject has been administered the daily dose for at least 7 consecutive days.
• the plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 6 hours, for at least 7 hours, for at least 8 hours, for at least 10 hours, for at least 12 hours, for at least 24 hours, for at least 36 hours, or for at least 48 hours, after the subject has been administered the daily dose for at least 2 consecutive days, for at least 3 consecutive days, for at least 4 consecutive days, for at least 5 consecutive days, for at least 7 consecutive days, for at least 10 consecutive days, for at least 14 consecutive days, or for at least 21 consecutive days.
• the invention provides a method for treatment of nonconstipated IBS (such as alternating diarrhea-predominant/constipative IBS or diarrhea-predominant IBS) in subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• nonconstipated IBS such as alternating diarrhea-predominant/constipative IBS or diarrhea-predominant IBS
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL (or any suitable serum concentration described above) is achieved between about 0.1 hours and about 12 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above..
• the invention provides a method for treatment of nonconstipated IBS in subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant EBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time as described above) following the administering of the composition to the subject.
• Non-limiting examples of improvements in quality of life include decreasing interruption in daily activities, enhancing body image, decreasing food avoidance, enhancing interpersonal relationships, enhancing sexual performance capacity, improving social functioning, improving physical functioning, improving general health, improving vitality, enhancing social functioning, and improving mental health.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL (or any suitable serum concentration described above) is achieved between about 0.1 hours and about 12 hours (or any suitable period of time as described above) following the administering of the composition to the subject.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/niL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method of improving quality of life in a subject having diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method for treatment of abnormal bowel habits in a subject afflicted with diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• Non-limiting examples of improvements in bowel habits include improving stool consistency, improving bowel movement frequency, decreasing urgency, and decreasing urgency.
• the invention provides a method for treatment of abnormal bowel habits in a subject afflicted with diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method for treatment of abnormal bowel habits in a subject afflicted with diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of abnormal bowel habits in a subject afflicted with diarrhea-predominant IBS, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method for treatment of diarrhea-predominant IBS in a female subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject
• the invention provides a method for treatment of diarrhea-predominant IBS in a female subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method for treatment of diarrhea-predominant IBS in a female subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of diarrhea-predominant IBS in a female subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method for treatment of diarrhea-predominant IBS in a male subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject
• the invention provides a method for treatment of diarrhea-predominant IBS in a male subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method for treatment of diarrhea-predominant IBS in a male subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of diarrhea-predominant IBS in a male subject, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method for treatment of extended-duration diarrhea-predominant IBS in a subject in need thereof, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• extended duration diarrhea-predominant IBS is understood to refer to a manifesting by a subject of at least one symptom of IBS-D for a period of time exceeding 12 months, 18 months, 24 months, 30 months, 36 months, 42 months, 48 months, 54 months, 60 months, 66 months, 72 months, 78 months, 84 months, 90 months, 96 months, 102 months, 108 months, 114 months, or 120 months prior to administering of cilansetron or a pharmaceutically acceptable derivative thereof.
• the invention provides a method for treatment of extended-duration diarrhea-predominant IBS in a subject in need thereof, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method for treatment of extended-duration diarrhea-predominant IBS in a subject in need thereof, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of extended-duration diarrhea-predominant IBS in a subject in need thereof, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having a body mass index (BMI) of less than about 40 kg/m 2 , less than about 38 kg/m 2 , less than about 36 kg/m 2 , less than about 34 kg/m 2 , less than about 32 kg/m 2 , less than about 30 kg/m 2 , less than about 28 kg/m 2 , less than about 26 kg/m 2 , less than about 24 kg/m 2 , less than about 22 kg/m 2 , or less than about 20 kg/m 2 , comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18
• BMI body mass index
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having a body mass index (BMI) of less than about 30 kg/m 2 , comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• BMI body mass index
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having a body mass index (BMI) of less than about 30 kg/m , comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having a body mass index (BMI) of less than about 30 kg/m 2 , comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• BMI body mass index
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject receiving selective serotonin reuptake inhibitor (SSRI) therapy, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• SSRI selective serotonin reuptake inhibitor
• Non-limiting examples of SSRF s include paroxetine, fluvoxamine (e.g., fluvoxamine maleate), citalopram, escitalopram oxalate, fluoxetine, and sertraline.
• the SSRI is selected from paroxetine and fluvoxamine.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject receiving selective serotonin reuptake inhibitor (SSRI) therapy, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• SSRI selective serotonin reuptake inhibitor
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject receiving selective serotonin reuptake inhibitor (SSRI) therapy, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method of treatment of diarrhea-predominant IBS in a subject receiving selective serotonin reuptake inhibitor (SSRI) therapy, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• SSRI selective serotonin reuptake inhibitor
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having renal impairment, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 0.1 ng/mL and about 25 ng/mL (or any suitable serum concentration as described above) is achieved between about 0.01 hours and about 18 hours (or any suitable period of time described above) following the administering of the composition to the subject.
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having renal impairment, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration between about 3 ng/mL and about 12 ng/mL is achieved between about 0.1 hours and about 12 hours following the administering of the composition to the subject.
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having renal impairment, comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein the mean plasma cilansetron concentration across a statistically significant population of subjects is between about 0.1 ng/mL and about 25 ng/mL (or any suitable mean serum concentration described above).
• the mean serum concentration is achieved in any suitable mean time or period as discussed above.
• the invention provides a method for treatment of diarrhea-predominant IBS in a subject having renal impairment (or severe renal impairment), comprising providing a composition comprising cilansetron or a pharmaceutically acceptable derivative thereof, and administering a daily dose of the composition to the subject in an amount sufficient for the cilansetron to reach the bloodstream of the subject wherein a plasma cilansetron concentration is substantially maintained between about 0.1 ng/mL and about 25 ng/mL for at least 12 hours (or any suitable duration as discussed above) after the subject has been administered the daily dose for at least 7 consecutive days (or any suitable number of days as discussed above).
• Clinical test data (set forth in the examples set forth below) prove the surprising suitability of cilansetron for the treatment of EBS-D in a subject.
• Intravenous injection formulations and oral solution formulations of cilansetron at strengths of 2 mg/ 40 mL, 4 mg/2 mL and 8 mg/4 niL can also be used.
• Table 2.7.1.1.1 presents a formulation for the 4 mg and 8 mg cilansetron capsules.
• Compositions of the injectable and oral formulations are presented in Table 2.7.1.1.2.
• the capsule formulation proved to be stable for at least 12 months, if stored in polyvinyl chloride/poly vinyl dichloride/Al (PVC/PVDC/A1) blisters or in high density polyethylene (HDPE) bottles. There was only a small increase in the S- enantiomer content, and no organic impurities were found.
• Table 2.7.1.1.4 presents a nonlimiting overview of cilansetron tablet formulations that can be used.
• Figures Ia - d and Figures 2a - d provide dissolution profiles of cilansetron 4 and 8 mg capsules, respectively.
• In vitro dissolution of cilansetron from these capsules was rapid.
• USP United States Pharmacopeia
• complete dissolution in degassed simulated gastric fluid was typically observed within 10 to 20 minutes.
• cilansetron 2 mg film-coated tablets can be classified as rapidly dissolving because more than 85% of cilansetron is dissolved within 15 minutes. In in vivo studies, it was observed that absorption of orally administered cilansetron is rapid and higher than
• HPLC/UV methods were used to perform serum analyses for cilansetron.
• LLOQ lower limit of quantitation
• Cilansetron in Plasma [00169] Validation of a method for the analysis of cilansetron in human plasma was performed by LC/MS/MS. A validation procedure incorporated a 3 -run validation on different days to obtain within- and between-run accuracy and precision data in the concentration range of 0.1 to 52.5 ng/mL. For each validation run, calibration curves were constructed from 9 calibration standards and 6 replicates at each of 4 QC levels were prepared (LLOQ, LOW, MID, and HIGH). The LC/MS/MS method was found to be accurate, precise, and sensitive. Precision and accuracy data were within laboratory- specified limits. Within- and between-run precisions (%CV) at all QC levels ranged from 1.67 to 11.5% and 3.35 to 7.63%, respectively.
• the within-run precisions (%CV) for all QC levels ranged from 1.28 to 11.13% for (4S)-hydroxy cilansetron and 1.44 to 10.69% for (4R)-hydroxycilansetron; the corresponding between-run precisions (%CV) ranged from 4.04 to 8.94%and 2.05 to 6.37%, respectively.
• the corresponding ranges for (4R)-hydroxy cilansetron were 89.5 to 113.7% and 92.3 to 107.5%.
• Cilansetron and 4-Hydroxy Metabolites in Plasma [00171] An analysis for cilansetron and its 4-hydroxy metabolites in human potassium edetic acid (EDTA) plasma was performed by LC/MS/MS. The validation method employed a single sample preparation and two separate LC/MS/MS methods. The validation consisted of a total of 9 analytical runs. Five of these runs were used to assess accuracy and precision, and included calibration curves constructed from 8 calibration standards and 5 replicates at each of the included QC levels (LLOQ, LOW, MID, and HIGH). The method was suitable for the measurement of cilansetron and its main metabolites.
• the LC/MS/MS method was found to be precise and accurate over a concentration range of approximately 0.1 to 50 ng/mL for each analyte, with an LLOQ of 0.1 ng/mL for each analyte.
• the within-run precisions ranged from 1.2 to 7.5%, 0.5 to 6.5%,and 1.6 to 6.6% for cilansetron, (4S) ⁇ hydroxy cilansetron, and (4R)-hydroxy cilansetron, respectively, while the between-run precisions ranged from 3.0 to 7.1%, 2.3 to 5.9%, and 3.9 to 5.7%, respectively.
• the within-run accuracies ranged from -1.4 to 16.0%, -4.6 tol ⁇ .0%, and -4.4 to 7.0% for cilansetron, (4S)-hydroxy cilansetron, and (4R)-hydroxycilansetron, respectively, while the between-run accuracies ranged from 0.4 to 7.0%, -3.6 to 4.0%, and -2.2 to 4.0%, respectively.
• the LC/MS/MS method was found to be precise and accurate over a concentration range of approximately 0.1 to 50 ng/mL for each analyte, with an LLOQ of 0.1 ng/mL for each analyte.
• the within-run precisions ranged from 1.1 to 6.6%, 1.8 tol2.1 %, and 1.4 to 12.2% for cilansetron, (4S)-hydroxy cilansetron, and (4R)-hydroxycilansetron, respectively, while the between-run precisions ranged from 2.6 to 5.7%, 3.7 toll.2%, and 4.0 to 9.8%, respectively.
• the within-run accuracies ranged from 0.3 to 12.2%, -10.9 to 7.0%, and -8.5 to 8.0% for cilansetron, (4S)-hydroxy cilansetron, and (4R)-hydroxycilansetron, respectively, while the between-run accuracies ranged from 4.1 to 7.6%, -6.6 to 2.0%, and -3.0 to 0.0%, respectively.
• Cilansetron and 4-Hydroxy Metabolites in Protein-Free Filtrate Derived from Serum [00173] An analysis for cilansetron and its 4-hydroxy metabolites in protein-free filtrate (derived from human serum) was performed. A validation method employed a single sample preparation and two separate LC/MS/MS methods.
• the validation consisted of a total of 7 analytical runs. Four of the serums were used to assess accuracy and precision, and included calibration curves constructed from 8 calibration standards and 5 replicates at each of the included QC levels (LLOQ, LOW, MID, and HIGH). The method was suitable for the measurement of cilansetron and its main metabolites. The LC/MS/MS method was found to be precise and accurate over a concentration range of approximately 0.04 to 20 ng/mL for each analyte, with an LLOQ of 0.04 ng/mL for each analyte.
• the within-run precisions ranged from 2.1 to 9.5%, 3.4 to 8.7%, and 3.8 to 9.6% for cilansetron, (4S)-hydroxy cilansetron, and (4R)-hydroxycilansetron, respectively, while the between-run precisions ranged from 5.4 to 13.2%, 5.2 to 8.0%, and 4.6 to 10.3%, respectively.
• the within-run accuracies ranged from -9.0 to 17.8%, -4.6 to 7.4%, and -8.5 to 13.8% for cilansetron, (4S)-hydroxy cilansetron, and (4R)-hydroxycilansetron, respectively, while the between-run accuracies ranged from 1.3 to 7.5%, -2.5 to 0.7%, and -1.7 to 6.0%, respectively.
• the plasma validation runs contained duplicates at each of three QC levels (LOW, MID, and HIGH), while the urine validation runs contained triplicate QCs at the LOW level and duplicate QCs at the MID and HIGH levels.
• the HPLC methods for plasma and urine were accurate, precise, and sensitive.
• Within-run precisions (%CV) of the LOW, MID, and HIGH QC levels ranged from 2.20 to 4.51 % in plasma and 2.76 to 6.96% in urine; between-run precisions ranged from 3.47 to 5.88% in plasma and 4.15 to 14.0% in urine.
• Between-run accuracy ranged from -9.6 to 0.74% in plasma and -9.3 to 3.6% in urine.
• LLOQs were established at 79.8, 20.0, and 19.9 pg/mL for NGL, NGM,and 17-d-NGM respectively.
• the within- and between-run precision (%CV) for all QC levels ranged from 4.6 to 7.5% and 3.9 to 13.6% for NGL; 2.4 to 8.6% and 2.8 to 16.8% for NGM; and 0.7 to 10.8% and 2.9 to 8.4% for 17-d-NGM.
• the within- and between-run accuracy (% nominal) for all QC levels ranged from 87.3 to 101.6% and 95.5 to 101.8% for NGL; 95.9 to 106.1% and 94.0 to 117.7% for NGM; and 105.2 to 112.5% and 105.8 to 113.4% for 17-d-NGM.
• the mean concentration-time profiles for cilansetron and its 4-hydroxy metabolites were generally superimposable for the two treatments, and the geometric least squares mean ratios and 90% confidence intervals for both cilansetron Cmax and AUC(O-inf) were within the regulatory 80-125% bioequivalence limits. Descriptive statistics indicated that the pharmacokinetic parameters for the 4-hydroxy metabolites were also very similar between treatments.
• Table 2.7.1.2.3 presents descriptive statistics for the pharmacokinetic parameters of cilansetron capsule and oral solution, and the results of statistical comparisons between treatments (capsule versus solution). Although the confidence intervals for AUC and Cmax were outside the 80-125% limits for statistical bioequi valence, the geometric least squares mean ratios demonstrated that the bioavailability of the 8 mg capsule was similar to the oral solution. The mean extent of exposure [AUC(O-inf) and AUC(O-last)] of the 8 mg capsule was comparable to the oral solution, and the mean Cmax was only slightly lower (12%) than that of the solution. Median Tmax was also similar between the capsule and oral solution.
• Cilansetron is rapidly absorbed following oral administration, with a median Tmax of 1.0 to 1.75 hours following single and multiple dosing. Peak concentrations of its main metabolites, (4R)-hydroxy and (4S)-hydroxy cilansetron, are achieved at approximately 2 hours and 3-4 hours following dosing, respectively.
• Cilansetron is completely absorbed from the gastrointestinal tract, based on a study utilizing orally administered 14 C-cilansetron. It is a high extraction drug, with a low absolute bioavailability of 25%, indicating that it undergoes significant first pass metabolism on oral administration. It has a systemic plasma clearance of approximately 550-800 mL/min.
• Cilansetron and its 4-hydroxy metabolites exhibit linear pharmacokinetics between single and multiple dosing. Consistent with their respective half-lives of approximately 1-2 hours, 4 hours, and 7.5 hours, cilansetron does not accumulate but (4R)-hydroxy cilansetron shows 35-47% accumulation and (4S)-hydroxy cilansetron shows greater than 2-fold accumulation following TID dosing.
• Vss The steady-state volume of distribution (Vss) of cilansetron is about 56 L, which is slightly higher than total body water, suggesting limited distribution into tissues.
• Cilansetron is approximately 96% plasma protein bound in humans over the therapeutic concentration range. (4R)-hydroxy cilansetron is 72-75% protein bound and (4S)-hydroxy cilansetron is 42-48% bound in plasma. The protein binding of cilansetron and its 4-hydroxy metabolites is not affected by mild to severe renal impairment. Protein binding of cilansetron is not affected by hepatic impairment.
• Cilansetron is rapidly cleared from plasma with a mean elimination half-life of approximately 1-2 hours.
• Half-lives of (4R)-hydroxy and (4S)-hydroxy cilansetron are approximately 4 hours and 7.5 hours, respectively.
• Cilansetron is highly metabolized, and in vitro studies have shown that the enzymes CYP3A4, CYP2D6, CYPlAl, CYP1A2, and CYP2C19 may be involved in its metabolism.
• fluvoxamine inhibitor of CYP1A2, but also of CYP2C9, CYP2C19, and CYP3A
• fluvoxamine caused a 3.7- to 6.6-fold increase in cilansetron exposure.
• a 40-51% increase in exposure was observed with the CYP3A4 inhibitor, ketoconazole, and no significant effect was observed with the CYP2D6 inhibitor, paroxetine.
• Cilansetron pharmacokinetics are dose proportional over a single IV dose range of 4-16 mg, and a single and multiple oral dose range of 2-32 mg.
• the cilansetron 2 mg tablet is bioequivalent to an oral solution with respect to both cilansetron Cmax and AUC.
• Cilansetron has no effect on the mean or maximum QTc interval (Bazett's correction) following single or TID dosing in healthy subjects.
• Figure 10, Figure 11, and Figure 12 present geometric mean plasma concentration-time profiles for cilansetron and its 4-hydroxy metabolites following single dosing and at steady state.
• Table 2.7.2.3.1 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites, and the results of statistical comparisons of parameters on Day 7 and Day 1 (steady state versus single dose).
• Two randomized, double-blind, placebo controlled, rising dose, crossover studies evaluated the single-dose pharmacokinetics of oral cilansetron over a 4 mg to 64 mg dose range.
• 24 male subjects (aged 21-36 years) received, at intervals of 21 week, single oral doses of 4, 8, and 16 mg cilansetron in ascending order and a randomized placebo.
• 24 male subjects received, at intervals of >1 week, single oral doses of 16, 32, and 64 mg cilansetron in ascending order and a randomized placebo.
• AU doses were administered under fasted conditions. Serial blood sampling and urine collection was performed up to 24 hours following each dose and cilansetron pharmacokinetic parameters were evaluated.
• Cilansetron was rapidly absorbed following oral administration, with a median Tmax of 1 to 1.4 hours following single and multiple dosing and was rapidly cleared from plasma with a mean half-life of 1.6 to 1.9 hours. No differences were observed in half-life between single and multiple dosing.
• cilansetron has a high systemic plasma clearance of about 550-700 mL/min (Table 2.7.2.3.6).
• its mean elimination half -life ranged from 1.4 to 1.7 hours, and was independent of dose, demonstrating the absence of nonlinear pharmacokinetics over this dose range.
• the elimination half-life of cilansetron after IV dosing was comparable to the terminal half -life after oral dosing, demonstrating that flip-flop pharmacokinetics do not occur with oral dosing.
• renal elimination was negligible ( ⁇ 1% of dose) for all the IV doses studied.
• cilansetron On IV administration, cilansetron exhibits a mean steady-state volume of distribution (Vss) of cilansetron of about 56 L, which is slightly higher than total body water, and indicates limited distribution into tissues (Table 2.7.2.3.9).
• Cilansetron easily passes biological membranes, probably including the blood-brain barrier. However, cilansetron is a substrate for P-glycoprotein (Table 2.7.2.3.8) and, therefore, brain concentrations are probably kept at a low level at therapeutic concentrations (plasma Cmax of approximately 6-7 ng/mL at a dose of 2 mg TID). Much higher concentrations, above 1000 ng/mL, were required to saturate P- glycoprotein in vitro. The 4-hydroxy metabolites of cilansetron were found to be six times stronger substrates for P-glycoprotein than cilansetron and passed biological membranes more slowly than cilansetron.
• the systemic plasma clearance of cilansetron was approximately 600 mL/min, and the absolute bioavailability of an oral solution of cilansetron was 25%. Its low bioavailability, complete absorption from the GI tract, and its 4.5- to 5-fold higher apparent oral clearance in comparison to systemic clearance indicate that cilansetron is a high extraction drug and undergoes significant first pass metabolism on oral administration. Intersubject %CVs were higher for oral (47-73%) than for IV administration (19-20%), reflecting increased variability due to oral absorption. Intrasubject %CVs ranged from 37-47% following oral and IV administration.
• Cilansetron concentrations in this study were also modeled using a standard 2-compartment model for the IV data and a 1 -compartment model for the oral data (using TOPFIT 2.0). The results from modeling are compared to the results obtained from non-compartmental analysis in Table 2.7.2.3.10 below, for the oral and IV solution. The results obtained by the two methods are very similar.
• the relative bioavailability of the cilansetron 2 mg tablet was evaluated in comparison to a 2 mg oral solution in a randomized, open-label, single-dose, three-period, crossover study in 12 male and 6 female subjects, aged 21 to 41 years. Additionally, the relative bioavailability of a cilansetron 8 mg capsule was evaluated in comparison to an 8 mg oral solution in a randomized, open-label, single-dose, three-period, crossover study in 18 male subjects, aged 21 to 38 years. In brief, the tablet was found to be bioequivalent to the oral solution with respect to both cilansetron Cmax and AUC. Pharmacokinetic parameters for the 4-hydroxy metabolites were also similar between treatments.
• Descriptive statistics of cilansetron and metabolite plasma concentrations, the corresponding percents unbound of each analyte, and statistical comparisons of percents unbound between study groups (renally impaired: healthy) are presented in Table 2.7.2.3.12 below.
• cilansetron was 96.0-96.6% protein bound on average, and its metabolites, (4R)-hydroxy and (4S-hydroxy cilansetron, were 72.4-75.3% and 42.0-48.1% protein bound on average, respectively. Extent of binding of all three analytes did not vary with plasma concentrations over the range of concentrations encountered. Additionally, no significant increases or trends toward an increase were observed in percent unbound of cilansetron or its 4-hydroxy metabolites with increasing renal impairment.
• Plasma protein binding was also measured in blood samples collected at
• Protein binding was also evaluated in an in vitro study in human, mouse, rat, and dog plasma using equilibrium dialysis (12-14K molecular weight cut-off membrane). This study measured the binding of ( 14 C)-cilansetron in plasma at nominal concentrations (30, 90, and 300 ng/mL) which are much higher than those encountered in vivo in humans. This study also measured the binding of ( 14 C)-cilansetron to purified human serum albumin at cilansetron concentrations ranging from 30-3000 ng/mL and to purified human alpha-1 acid glycoprotein (AAG) at concentrations ranging from 30- 10000 ng/mL.
• AAG alpha-1 acid glycoprotein
• Cilansetron was 93-96% protein bound in the absence of warfarin and 94-96% bound in the presence of warfarin over these concentrations. The effect of cilansetron on the binding of warfarin was not evaluated.
• FIG. 16 to Figure 19 present box plots of cilansetron AUC(O-inf) and Cmax from these three studies (males only), and corresponding dose-normalized values (normalized to a 1 mg dose). Data from two different formulations (tablet and capsule) under different conditions of food intake (fed and fasted) have been combined in these plots, since previous studies have shown that formulation and food intake do not have a clinically significant effect on the bioavailability of cilansetron.
• Table 2.7.2.3.14 presents descriptive statistics of cilansetron dose-normalized AUC and Cmax in these studies, and the results of statistical comparisons between doses. These data demonstrate that the pharmacokinetics of cilansetron are approximately dose proportional over a dose range of 2-32 mg, with a slightly greater than proportional increase (approximately 30%) at the higher dose (64 mg)-
• Figure 20, Figure 21 , Figure 22, and Figure 23 present box plots of cilansetron AUC(O- ⁇ ) and Cmax from these four studies (males only), and corresponding dose-normalized values (normalized to a 1 mg dose).
• AUC(O- ⁇ ) and Cmax from these four studies (males only)
• corresponding dose-normalized values normalized to a 1 mg dose.
• data from two different formulations (tablet and capsule) under different conditions of food intake (fed and fasted) have been combined in these plots because of the absence of significant formulation or food effects on the bioavailability of cilansetron.
• the data in these plots show that the pharmacokinetics of cilansetron are dose proportional over a multiple-dose range of 2 mg to 32 mg.
• Cilansetron, (4R)-hydroxy cilansetron, and (4S)-hydroxy cilansetron accounted for 29.3%, 25.7%, and 13.8% of the total radioactivity, respectively, in plasma at 6 hours after oral administration, and for 46.2%, 20.0% and 14.1%3 of the total radioactivity in plasma at 3 hours after IV administration.
• the cumulative percent of cilansetron and 4-hydroxy metabolites excreted in urine over a 48- hour interval following dosing was 0.5% and 32.8% of the dose, respectively, following oral dosing, and 1.1% and 31.9% of the dose following IV dosing.
• (4R)-hydroxy and (4S)-hydroxy cilansetron both of which have much lower activity than cilansetron.
• (4R)-hydroxy and (4S)-hydroxy cilansetron bind to the human 5-HT 3 receptor in the nanomolar range and exhibit pKi values of 8.5 and 8.0, respectively, compared to cilansetron which exhibits subnanomolar affinities to the human 5-HT 3 receptor with a pKi value of 9.4.
• the ratio of formation of (4R)-hydroxy to (4S)-hydroxy cilansetron in vitro was found to be approximately 1.0 for humans.
• CYP mRNA induction potentials of cilansetron and its two main metabolites, (4S)-hydroxy and (4R)-hydroxy cilansetron were determined in human hepatocytes and compared to three model inducers, 3-methylcholantrene, phenobarbital, and rifampin.
• Cilansetron and its metabolites increased CYP2C19 to a level that was about half of that caused by phenobarbital.
• Phenobarbital is a moderate inducer of CYP2C19 in vitro but is reportedly inactive in inducing this enzyme in humans in vitro. Comparison with the other model inducer used, rifampin, gave variable results, suggesting that the significance of any findings was doubtful. Cilansetron and its two metabolites did not induce CYP3A4 mRNA but doubled CYP3A5 mRNA, which was similar to the effect seen with the model inducers 3-methylcholantrene and phenobarbital.
• CYP3A5 is a minor isoform in human liver, shares substrate specificity with CYP3 A4, and has a low activity compared to that of CYP3 A4, limited variations in CYP3 A5 activity are unlikely to cause major changes in the overall CYP3A activity.
• the lack of a significant inductive effect on CYP3 A by cilansetron is also supported by the results of a clinical study which show that concomitantly administered cilansetron does not affect the pharmacokinetics or pharmacodynamics of the CYP3 A substrate, Ortho Tri-Cyclen. Cilansetron and its 4- hydroxy metabolites did not show an inductive effect on other CYP isozymes (CYP2A6, CYP2B6, CYP2C9, CYP2D6, and CYP2E1).
• cilansetron showed only weak inhibition (IC50 of 60 ⁇ M, which is >3000 x Cmax at the proposed dose of 2 mg TID) of 7-ethoxyresorufin O-deethylation (a marker of CYP1A2 activity) and no inhibition of any other cytochrome P450 enzyme activity, suggesting that potential drug interactions due to inhibition of CYP enzymes by cilansetron are unlikely.
• (4R)-hydroxy and (4S)-hydroxy cilansetron were shown to have no significant inhibitory effect on any cytochrome P450 enzyme (IC50 > 100 ⁇ M).
• CYP3A4, CYPlA, and CYP2D6 a clinical study was conducted to evaluate the effect of ketoconazole (CYP3A4 inhibitor), fluvoxamine (inhibitor of CYP1A2, but also of CYP2C9, CYP2C19, and CYP3A), and paroxetine (CYP2D6 inhibitor) on the pharmacokinetics of cilansetron 2 mg TID.
• the results showed that concomitant administration of fluvoxamine had a profound effect on the pharmacokinetics of cilansetron, causing a mean 6.6-fold and 3.7-fold increase in AUC and Cmax, respectively.
• Mean cilansetron AUC increased by 20% and mean Cmax by 36%.
• Mean (4R)-hydroxy cilansetron AUC and Cmax increased by 16% and 27%, respectively, but there was no change in the pharmacokinetics of (4S)-hydroxy cilansetron.
• One subject receiving paroxetine was identified by genotyping as a poor metabolizer for CYP2D6 and another was identified as a poor metabolizer for CYP2C 19. No difference in cilansetron pharmacokinetics was observed in the poor metabolizer for CYP2D6 but an approximate 2-fold increase was observed in AUC(O- ⁇ ) and Cmax in the poor metabolizer for CYP2C19, following coadministration of paroxetine.
• CYP2D6, CYPlAl, CYPl A2, and CYP2C19 may be involved in the metabolism of cilansetron
• this clinical study showed that cilansetron pharmacokinetics are affected during coadministration with fluvoxamine (inhibitor of CYP1A2 and other CYP enzymes such as CYP2C19) and with ketoconazole (CYP3A4 inhibitor).
• This apparent discrepancy may be due to the inhibitory effect of fluvoxamine on multiple enzymes, differences in expressiodactivity of these enzymes in vitro compared to in vivo, or the use of cilansetron concentrations (20-100 ⁇ M) in the in vitro studies which were much higher than therapeutic concentrations (Cmax of 6-7 ng/mL for 2 mg TID dose).
• Healthy subjects were matched to renally- impaired subjects with respect to age, weight, gender, and smoking status.
• AU subjects received oral cilansetron 2 mg TID on Days 1 to 5, and a single dose on the morning of Day 6.
• Blood samples for measurement of plasma pharmacokinetics of cilansetron and its 4-hydroxy metabolites were collected up to 24 hours following dosing on Day 6, and log- transformed pharmacokinetic parameters for these analytes were statistically compared between study groups. Serum concentrations of unbound cilansetron and its 4-hydroxy metabolites were also measured prior to dosing and at 1 and 1.5 hours postdose on Day 6.
• Table 2.7.2.3.20 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites by study group on Day 6, and Figures 29a - b.
• Figures 30a - b, and Figures 31a - b present individual, mean, and median
• Table 2.7.2.3.2 1 presents the results of statistical comparisons of pharmacokinetic parameters between study groups (renally impaired to healthy) for cilansetron and its 4-hydroxy metabolites.
• Figure 32, Figure 33, and Figure 34 show the results of linear regressions of AUC(O- ⁇ ) of cilansetron and its 4-hydroxy metabolites versus creatinine clearance. The results of this study showed that the steady- state pharmacokinetics of cilansetron were not significantly affected by renal impairment.
• FIG. 35 and Figure 36 present mean plasma concentration-time profiles for cilansetron and its 4-hydroxy metabolites on Day 6, in healthy and hepatically impaired subjects.
• Table 2.7.2.3.23 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites, and the results of statistical comparisons between study groups (hepatically impaired versus healthy).
• Plasma protein binding did not show any notable difference between impaired and healthy subjects. Consistent with the decrease in cilansetron clearance with hepatic impairment, the extent of formation of the 4-hydroxy metabolites of cilansetron was also decreased. On average, (4R)-hydroxy cilansetron AUC(O- ⁇ ) and Cmax decreased by 14% and 30% respectively, and (4S)- hydroxy cilansetron AUC(O- ⁇ ) and Cmax decreased by 32% and 36% respectively, in impaired compared to healthy subjects.
• hepatic function total bilirubin, albumin, prothrombin time, Child- Pugh scores, encephalopathy, and ascites
• body weight adjusted and unadjusted AUC, CLE, and Vz/F for cilansetron was evaluated using correlation analyses. Statistically significant correlations (p ⁇ 0.05) were found between the hepatic parameters, bilirubin, albumin, and prothrombin time, and AUC and/or CLfF. Particularly strong negative correlations were observed between albumin and cilansetron AUC or CL/F (r>0.7).
• Blood samples for measurement of plasma cilansetron pharmacokinetics were collected up to 24 hours postdose following each treatment, and log-transformed cilansetron AUC(O-last), AUC(O-inf), and Cmax values were statistically compared between treatments.
• Figure 37 presents the mean plasma cilansetron concentration- time profile following each treatment and Table 2.7.2.3.24 presents descriptive statistics for cilansetron pharmacokinetic parameters and the results of statistical comparisons between treatments.
• the results of this study show that concomitant administration of Maalox has no significant effect on the extent of exposure [AUC(O-last) and AUC(O-inf)] of cilansetron.
• a small decrease (13% mean decrease) was observed in cilansetron Cmax following concomitant administration, but this decrease is not considered to be clinically significant.
• Figure 38, Figure 39, and Figure 40 present mean plasma concentration- time profiles for EE, NGL, and 17-d-NGM on Day 21 following each treatment. Insufficient quantifiable NGM concentrations were available to evaluate the pharmacokinetics of this analyte. Steady state was shown to be achieved for both EE and 17-d-NGM by Day 21.
• Table 2.7.2.3.25 presents descriptive statistics for EE, NGL, and 17-d-NGM pharmacokinetic parameters and the results of statistical comparisons between treatments for EE and 17-d-NGM. The results of this study showed that concomitant administration of cilansetron does not affect the steady-state pharmacokinetics of EE or 17-d-NGM.
• Figures 41a - c presents mean predose serum concentrations of PG, LH, and FSH on Days 18, 19, 20, 26, 27, and 28 following treatment with ORC + cilansetron or ORC + placebo. Mean concentrations of FSH and LH were generally superimposable between treatments. Mean concentrations of PG were slightly higher for ORC + cilansetron, but this was attributable to elevated levels in one subject, as demonstrated by the inset plot in Figures 41a - c which shows superimposable mean concentrations of PG when the subject was excluded. No statistically significant differences were found between treatments for any of the three analytes.
• CYPIA CYPIA
• CYP2D6 inhibitor the potential for inhibitors of these enzymes to affect the metabolism of cilansetron was evaluated using ketoconazole (CYP3A4 inhibitor), fluvoxamine (inhibitor of CYP1A2, but also of CYP2C19, CYP2C9, and CYP3A), and paroxetine (CYP2D6 inhibitor).
• ketoconazole CYP3A4 inhibitor
• fluvoxamine inhibitor of CYP1A2
• CYP2C9 CYP2C9
• CYP3A paroxetine
• subjects in one group received fluvoxamine (Fevarin ® ) 50 mg QD on Days 8-14, the second group received paroxetine (Seroxat ® ) 20 mg QD on Days 8- 14, and the third group received ketoconazole (Nizoral ® ) 200 mg BID on Days 12- 14.
• AU morning doses of cilansetron and enzyme inhibitors were administered immediately after a standard breakfast.
• Serial blood samples for the measurement of steady-state pharmacokinetics of cilansetron and its 4-hydroxy metabolites were collected on Day 7 (cilansetron alone) and Day 14 (cilansetron + enzyme inhibitor) for each of the three groups.
• Figure 42, Figure 43, and Figure 44 present geometric mean steady-state plasma concentration-time profiles for cilansetron and its 4-hydroxy metabolites in the absence and presence of concomitant fluvoxamine.
• Table 2.7.2.3.26 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites, and the results of statistical comparisons between treatments (cilansetron + fluvoxamine versus cilansetron alone), and Figures 45a - c shows the distribution of AUC(O- ⁇ ) values for the two treatments.
• the results showed that coadministration of fluvoxamine produced a large increase in exposure to cilansetron.
• Mean cilansetron AUC(O- ⁇ ) and Cmax increased by 6.6-fold and 3.7-fold, respectively, in the presence of concomitant fluvoxamine.
• Figure 46, Figure 47, and Figure 48 present geometric mean steady- state plasma concentration-time profiles for cilansetron and its Chydroxy metabolites in the absence and presence of concomitant ketoconazole.
• Table 2.7.2.3.27 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites, and the results of statistical comparisons between treatments (cilansetron + ketoconazole versus cilansetron alone), and Figures 49a - c presents the distribution of AUC(O- ⁇ ) values for the two treatments. The results showed that coadministration of ketoconazole caused an increase in exposure to cilansetron and its 4-hydroxy metabolites.
• Mean cilansetron AUC(O- ⁇ ) and Cmax increased by 40% and 51%, respectively.
• mean (4R)-hydroxy cilansetron AUC(O- ⁇ ) and Cmax increased by 76% and 109%, respectively, and (4S)-hydroxy cilansetron AUC(O- ⁇ ) and Cmax increased by 63% and 74%, respectively.
• Figure 50, Figure 51, and Figure 52 present geometric mean steady-state plasma concentration-time profiles for cilansetron and its 4-hydroxy metabolites in the absence and presence of concomitant paroxetine.
• Table 2.7.2.3.28 presents descriptive statistics for the pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites, and the results of statistical comparisons between treatments (cilansetron + paroxetine versus cilansetron alone), and Figures 53a - c shows the distribution of AUC(O- ⁇ ) values for the two treatments. The results showed that coadministration of paroxetine produced a small increase in exposure to ilansetron.
• (4R)-hydroxy and (4S)-hydroxy cilansetron were shown to have no significant inhibitory effect on any cytochrome P450 enzyme (IC50s >100 ⁇ M).
• An in vitro study using human hepatic microsomes evaluated the effect of some enzyme inhibitors on the metabolism of cilansetron (100 ⁇ M). The inhibitors tested were troleandomycin (10 ⁇ M, CYP3A4 inhibitor) and ketoconazole at lower (1 ⁇ M, CYP3A4 inhibitor) and higher (25 ⁇ M, general inhibitor) concentrations.
• troleandomycin (10 ⁇ M) and ketoconazole (1 ⁇ M) inhibited about 70% of cilansetron metabolism while ketoconazole (25 ⁇ M) inhibited 93% of its metabolism.
• Troleandomycin (10 ⁇ M) and ketoconazole (1 ⁇ M) inhibited 34% and 47%, respectively, of the formation of the 4-hydroxy metabolites while ketoconazole (25 ⁇ M) inhibited 69% of formation.
• the inductive effect of cilansetron and its 4-hydroxy metabolites on various cytochrome P450 enzymes was evaluated in cultured human hepatocytes using an RT-PCR assay.
• cilansetron is a very weak inducer of CYPlA (2% that of 3-methylcholantrene), but this effect is considered negligible. Its 4-hydroxy metabolites have no effect on this enzyme. Cilansetron and its 4-hydroxy metabolites increased CYP2C19 and this effect was about half of that caused by phenobarbital. Phenobarbital is a moderate inducer of CYP2C19 in vitro but is reportedly inactive in inducing this enzyme in humans in vivo. Comparison with the other model inducer used, rifampin, gave variable results indicating that the significance of any findings was doubtful.
• Cilansetron and its two metabolites did not induce CYP3A4 mRNA but doubled CYP3 A5 mRNA, which was similar to the effect seen with the model inducers 3- methylcholantrene and phenobarbital. Since CYP3A5 is a minor isoform in human liver, it shares substrate specificity with CYP3 A4, and its activity is low compared to that of CYP3A4, limited variations in CYP3 A5 activity may not cause major changes in the overall CYP3A activity.
• the population analysis included data from 160 patients (63 males and 97 females) with a median age of 45.5 years (range: 20-81 years), median weight of 78 kg (range: 47-121 kg), and median height of 170 cm (range: 147-196 cm). More than 90% of the patients were White and 18.8% of the patients were considered smokers.
• the demographics of the patient population in this analysis were comparable to the overall study population.
• a total of 392 quantifiable concentrations for cilansetron, 393 quantifiable concentrations for (4S)-hydroxy cilansetron, and 397 quantifiable concentrations for (4R)-hydroxy cilansetron from 160 patients were included in the NONMEM datasets for population analyses.
• Figure 54, Figure 55, and Figure 56 present mean steady-state plasma concentration-time profiles for cilansetron and its 4-hydroxy metabolites
• Table 2.7.2.3.29 and Table 2.7.2.3.30 present descriptive statistics for the estimated pharmacokinetic parameters of cilansetron and its 4-hydroxy metabolites from the final covariate population pharmacokinetic model.
• the cilansetron concentration data were best described by a one-compartment model with first-order input, an absorption lag time, and first-order elimination.
• a log-normal distribution was used to describe the variability of clearance, volume of distribution and absorption rate constant between patients.
• the residual error was best described by an exponential model.
• model parameters apparent clearance, apparent volume of distribution, half-life, and predicted AUC and Cmax at steady state were also similar to estimates in healthy subjects.
• the primary efficacy parameter was the distension volume inducing esophageal pain. Secondary parameters were the distension volumes and pressures leading to first esophageal sensation.
• the pain threshold and other secondary parameters for each of the cilansetron doses was compared to placebo using a one-sided Dunnett t-test. [00276] The results of the analysis are summarized in Table 2.7.2.3.32. A small mean increase in the pain perception threshold volume and pressure was observed with the cilansetron treatments compared to placebo, but the differences were not statistically significant. Similarly, no significant differences were found in the volume or pressure for the threshold of sensation perception.
• An electronic barostat was used to produce isobarometric distensions (starting from 2 mmHg, progressive distensions in 2 mmHg increments were performed every 2 minutes until gastric pain occurred or an upper limit of 20 rnmHg was reached) and isovolumetric distensions (starting fi-om an initial volume of 200 mL, progressive distensions in 100 mL increments were performed every 2 minutes until gastric pain occurred or an upper limit of 1100 mL was reached).
• the primary efficacy parameter was the difference in pain threshold from baseline to poststudy, measured by the amount of distension pressure inducing gastric pain. Secondary parameters were the mean distension pressure/volume inducing the first feelings of gastric sensation and gastric discomfort, and changes in bowel habits over the treatment period.
• a 2-sample t-test was used to compare baseline-adjusted pain threshold and other secondary efficacy parameters between cilansetron and placebo treatments.
• the volumes at the different thresholds were comparable between cilansetron and placebo indicating that the different thresholds are not caused by differences in accommodation status.
• the primary efficacy parameter was the mean distension pressure inducing a sensation of abdominal pain.
• Secondary effect parameters were the mean distension pressure inducing a sensation of abdominal discomfort, and the response rate, defined as the number of patients experiencing no abdominal pain at the maximum pressure of 40 mmHg.
• the primary and secondary parameters were compared between cilansetron and placebo treatments using an ANOVA.
• the primary efficacy parameter was the distension pressure required to induce a sensation of abdominal pain.
• Secondary parameters were the distension pressure at the first feeling of abdominal/rectal sensation and the first feeling of need to defecate, and the response rate (defined as the number of subjects who experienced no abdominal pain at the maximum pressure of 44 mmHg).
• the pain threshold for each of the three cilansetron doses was compared to placebo using a one-sided Dunnett t-test.
• colonic transit time was measured by administration of radio-opaque markers for the last six days of each treatment period, followed by a single abdominal X-ray image at 24 hours after ingestion of the last set of markers. The numbers of markers within the colon were used to calculate segmental (right colon, left colon, and rectosigmoid) and total colonic transit time.
• Study K.241.5013 was a randomized, double-blind, placebo-controlled, 3- way crossover study in 12 healthy male subjects (ITT population), aged 20-27 years. Subjects received cilansetron 4 mg, cilansetron 8 mg, or placebo orally TID for 14 days during each of the treatment periods, with a 14-day washout between periods.
• the primary efficacy parameter was the total mean colonic transit time during each treatment and the secondary parameters were the segmental colonic transit times and the gastric emptying measurements.
• a one-sided Dunnett t-test procedure was used to compare efficacy parameters between the cilansetron and placebo treatments.
• the primary efficacy parameter was the total mean colonic transit time during each treatment and the secondary parameters were the segmental colonic transit times and the gastric emptying measurements.
• One-sided t-tests were used to compare efficacy parameters between the cilansetron and placebo treatments. [00289] The results of these studies are summarized in Table 2.7.2.3.39 and Table
• Cilansetron has no effect p>0.05) on the mean or maximum QTc interval following single or multiple dosing.
• slightly higher mean and maximum QTc intervals were observed in females than in males in this study, resulting in a significant gender effect (p ⁇ 0.10) for statistical comparisons of some QTc parameters.
• p ⁇ 0.10 a significant gender effect
• Study S241.3.011 were performed to assess the efficacy of cilansetron in treating IBS-D in men and women. Some of the findings of the studies are summarized here, but a more complete discussion of each study is presented later in the application.
• Study S241.2.112 was a Phase II, double-blind, placebo-controlled, randomized, multicenter parallel-group, dose-ranging study to investigate the efficacy and safety of cilansetron in non-constipated subjects with irritable bowel syndrome. The study was conducted in 51 study centers in the U.S.
• Efficacy was evaluated by weekly global questions concerning adequate relief of IBS symptoms (abdominal pain/discomfort, abnormal bowel habits).
• a responder is a subject who responded "Yes" at least 50% of the time after randomization, with a minimum treatment duration of four weeks.
• the 2 mg cilansetron dose group showed a slightly stronger efficacy evidence with regard to some of the secondary parameters compared to the 1 mg cilansetron group.
• the 2 mg group showed a larger increase in stool firmness over time towards harder stools than the 1 mg and the number of stools decreasted more with 2 mg cilansetron treatment than with 1 mg cilansetron; (vi) all treatments showed trends towards improvement in the quality of life factors 'physical functioning', 'role physical', 'bodily pain', 'general health', 'vitality', 'social functioning' , 'role-emotional' and 'mental health' , although the general quality of life (QOL) scale used may have lacked sensitivity to assess QOL in IBS subjects.
• QOL general quality of life
• Study S241.2.113 was a Phase II, double-blind, placebo-controlled, randomized, multi-center, parallel-group, dose-ranging study to investigate the efficacy and safety of cilansetron in nonconstipated subjects with irritable bowel syndrome. The study was conducted in 55 study centers in Canada, France, Austria, Germany, United Kingdom, Italy, Belgium, and The Netherlands.
• a total of at least 88 subjects per treatment group evaluable for efficacy were planned, in total 440 to complete the study; 776 subjects were screened; 485 subjects were randomized (479 in the safety sample).
• Diagnosis and main criteria for inclusion were IBS subjects satisfying the Rome criteria (1992) and minimum abdominal pain/discomfort, stool frequency and consistency determined during the run-in period.
• Subjects were treated with cilansetron 1 mg, 2 mg, 4 mg and 16 mg tablets given orally TDD or matching placebo tablets given orally TID for 12 weeks.
• the primary efficacy parameter was the weekly global question concerning adequate relief of IBS symptoms (abdominal pain/discomfort, abnormal bowel habits).
• a responder is a subject who responded "Yes" at least 50% of the time after randomization, with a minimum treatment duration of four weeks.
• Safety was evaluated by AEs, concomitant medications, laboratory evaluations, vital signs, physical examination and ECG.
• Cilansetron increased stool firmness, especially with the 4 mg and 16 mg dosages, and decreased stool frequency with no apparent effect difference between the dosages; (iii) cilansetron treatment showed most improvement compared to placebo treatment in all QOL factors of the SF-36 scale. A difference of more than 10 points relative to placebo treatment were observed for the 1 mg, 2 mg and 4 mg cilansetron groups for the factors Role-physical and Role-emotional.
• Study S241.3.006 was a Phase III, double-blind, placebo-controlled, randomized, multicenter study to investigate the safety and efficacy of 2 mg TID of cilansetron over 12 weeks in diarrhea-predominant irritable bowel syndrome subjects.
• the study was conducted in 129 study centers in the United States. At total of 2080 subjects consented to participate, and 7 1 1 subjects were randomized. A total of 692 subjects were analyzed for efficacy and 701 subjects were analyzed for safety. Diagnosis and main criteria for inclusion were BBS subjects satisfying the Rome I criteria (1 992); the diarrhea predominant sub-population of the Rome II criteria; and a minimum abdominal pain/discomfort, stool frequency and consistency determined during the run-in period.
• the primary efficacy parameter was the number of months that a subject was a responder for IBS symptoms (abdominal pain, abdominal discomfort, abnormal bowel habits) over the 12-week treatment period.
• a responder for a month was defined as a subject who answered the weekly question with "yes" at least twice for that month.
• Cilansetron treatment was also associated with statistically significant increased stool firmness and decreased stool frequency with increased straining; (vii) the cilansetron 2 mg TID group demonstrated a statistically significant greater improvement compared with the placebo group in the IBS-QOL total score and each subscore interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships, and dysphoria).
• Cilansetron 2 mg TDD was safe and well tolerated during this trial.
• Other common events possibly associated with cilansetron treatment were upper respiratory tract infections, headache, and blood creatinine phosphokinase increased.
• Study S241.3.009 was a Phase HI, a double-blind, placebo-controlled, randomized, multinational study to investigate the safety and efficacy of 2 mg TID of cilansetron over 26 weeks in diarrhea-predominant IBS subjects.
• the study was conducted in 146 multinational study centers. A total of 1307 subjects consented to participate, and 806 subjects were randomized. A total of 792 subjects were analyzed for efficacy and 799 subjects were analyzed for safety. Diagnosis and main criteria for inclusion were IBS subjects satisfying the Rome I criteria (1992); the diarrhea- predominant sub-population of the Rome II criteria; and a minimum abdominal pain/discomfort, stool frequency and consistency determined during the run-in period. Subjects were treated with cilansetron 2 mg tablets given orally TID or matching placebo tablets given orally TID for 26 weeks.
• the primary efficacy parameter was the overall response rate for IBS symptoms, based on the weekly question concerning adequate relief of IBS symptoms (abdominal pain/discomfort, abnormal bowel habits) over the 26 weeks period.
• a responder was a subject who responded "yes" at least 50% of the time during his/her treatment period, with minimum treatment duration of four weeks.
• the two main secondary efficacy parameters were overall responder rate based on the weekly question on adequate relief of abdominal pain/discomfort and abnormal bowel habits during the 26-week treatment period.
• An additional key secondary Efficacy parameter was the number of months (one month equals four weeks) up to six months (24-weeks) that a subject was a responder for IBS symptoms, where a responder was defined as a subject who answered the weekly question with "yes" at least twice for that month.
• the responder rate for the weekly diary questions on adequate relief at each month and all months, the adequate relief rate, the number of subjects with adequate relief by week, daily diary questions, IBS-QOL scores, and the interruption of activities were also assessed.
• Safety was evaluated by physical examination, ECG, vital signs, laboratory evaluations, concomitant medications, and AEs.
• Cilansetron treatment was also associated with statistically significant increased stool firmness, decreased stool frequency, and increased straining. Cilansetron had no effect on the feeling of incomplete evacuation; (vii) the cilansetron 2 mg TED group demonstrated a statistically significant greater improvement compared with the placebo group in the EBS- QOL total score and each subscore interference with activity, body image, health worry, food avoidance, social reaction, relationships, and dysphoria) with the exception of the sexual subscore, which, however, also showed a trend in favor of cilansetron.
• Cilansetron 2 mg TID was safe and well tolerated during this 26-week trial. A total of 56% versus 50% of subjects in cilansetron 2 mg TDD and placebo groups experienced at least one TEAE in the study. The most frequently reported TEAEs with a higher incidence in the cilansetron 2 mg TE) group compared with the placebo group were GI disorders including constipation (12% versus 3%), abdominal pain (9% versus 6%), and abdominal distension (3% versus 1%). Other events possibly associated with cilansetron treatment were headache and various infections including rhinoviral infections, upper respiratory tract infections, and nasopharyngitis.
• Study S241.3.011 was a Phase III, double-blind, placebo-controlled, randomized, multinational study to investigate the safety and efficacy of 2 mg TID of cilansetron for a period of 12 weeks followed by a rerandomized, placebo-controlled four-week treatment period, in diarrhea-predominant IBS subjects.
• the study was conducted in six countries including the US. A total of 2115 subjects consented to participate, and 770 subjects were randomized. A total of 746 subjects were analyzed for efficacy and 755 subjects were analyzed for safety.
• Diagnosis and main criteria for inclusion were IBS subjects satisfying the Rome I criteria (1992); the diarrhea predominant sub-population of the Rome II criteria; and a minimum abdominal pain/discomfort, stool frequency and consistency determined during the run-in period.
• Subjects were treated with cilansetron 2 mg tablets given orally TID or matching placebo tablets given orally TID for 12 weeks followed by a rerandomized, placebo-controlled four-week treatment period.
• the primary efficacy parameter was the number of months that a subject was a responder for IBS symptoms (abdominal pain, abdominal discomfort, abnormal bowel habits) over the 12-week treatment period.
• a responder for a month was defined as a subject who answered the weekly question with "yes" at least twice for that month.
• the two main secondary efficacy parameters were the monthly responder rates based on the "adequate relief questions regarding abdominal pain/discomfort and abnormal bowel habits during the 12-week treatment period.
• the overall response rate and responder rate for the weekly diary questions on adequate relief at each month and all months, the adequate relief rate, the number of subjects with adequate relief by week, daily diary questions, IBS-QOL scores, and the interruption of activities were also assessed.
• Cilansetron had no effect on the feeling of incomplete evacuatio; (vii) the cilansetron 2 mg TDD group demonstrated a statistically significant greater improvement compared with the placebo group in the IBS- QOL total score and each subscore (interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships, and dysphoria). Analysis of responses to the interruption of activities assessment demonstrated a clinically meaningful greater improvement in the cilansetron 2 mg TID group compared with the placebo group in the subjects' ability to effectively perform their everyday activities; (ix) all subgroups of age category, race, BMI category, severity of IBS, duration of IBS, and tobacco use showed similar responses to cilansetron treatment compared to the overall ITT population.
• Cilansetron 2 mg TID was safe and well tolerated during this 16- week trial.
• the incidence of rerandomizati on-emergent AEs was higher in the P/C treatment group (44%) compared with the C/C (35%), C/P (34%), or P/P (36%) treatment groups.
• the incidence of at least one TEAE during the entire four-month treatment period was 78% versus 75% in the C/C and P/P treatment groups , respectively.
• the treatment group difference for constipation increased with increasing age and trends for similar type of interaction (i.e., larger treatment group differences with older age) were seen for back pain, upper respiratory tract infections, and diarrhea. The opposite trend was seen for flatulence.
• Other TEAEs in the GI system organ class with a small, not clinically relevant treatment group difference included abdominal pain NOS (6% versus 5%), flatulence (4% versus 3%), and abdominal pain upper (2% versus 1 0 Io) during the three-month treatment period.
• Study S241.3 .006 was conducted at 129 study centers in the United States.
• Study S241.3 .009 was conducted at 146 study centers in 19 countries outside the United States with the following 18 countries that randomized subjects: Australia, Belgium, Bulgaria, Canada, Denmark, France, Germany, India, Ireland, Israel, Netherlands, New Zealand, Tru, Bulgaria, Russia, South Africa, Spain, and Ukraine.
• Study S241.3.011 was conducted at 202 study sites in six countries (Argentina, Brazil, Chile, Columbia, Peru, and the United States) with most subjects randomized in the United States (83%, 640 of 770 randomized subjects).
• the duration of treatment was 12 weeks in Study S241.3.006, 26 weeks in Study S241.3 .009, and a total of 16 weeks in Study S241.3.011 (12 weeks treatment followed by a four-week rerandomized treatment period).
• the primary efficacy parameter in Studies S241.3.006 and S241.3.011 was changed prior to study database lock and unblinding by a protocol amendment (based on discussions with the FDA).
• the new primary efficacy parameter in Studies S241.3.006 and S241.3.011 corresponds to a key secondary efficacy parameter in Study S241.3.009 (for details, see Section 2.7.3.3.2).
• Study S24 1.3 -006 was conducted at 129 study centers in the United States.
• Study S241.3.011 was conducted at 202 study sites in six countries (Argentina, Brazil, Chile, Columbia, Peru, and the United States) with most subjects randomized in the United States (83%, 640 of 770 randomized subjects).
• Study S241.3 .OO9 was conducted at 146 study centers in 19 countries outside the United States with the following 18 countries that randomized subjects: Australia, Belgium, Bulgaria, Canada, Denmark, France, Germany, India, Ireland, Israel, Netherlands, New Zealand, Tru, Bulgaria, Russia, South Africa, Spain, and Ukraine.
• 591 subjects who completed the three-month treatment period 576 subjects were rerandomized and thus divided into the following treatment groups: 150 subjects in the C/C treatment group, 140 subjects in the C/P treatment group, 136 subjects in the P/C treatment group, and 150 subjects in the P/P treatment group.
• the overall withdrawal rate was relatively stable when examined by one- month intervals during the first three months of the study (6%, 6%, and 5%) and decreased from 16% during the first three-month interval to 6% during the second three- month interval. No meaningful treatment group differences were observed in the reasons for withdrawal during any of the time intervals.
• the age of the subjects ranged from 18 years to 86 years in the ITT population and the mean age was similar between the groups (48.1 years in the cilansetron 2 mg TID group and 49.3 years in the placebo group). Most subjects in the cilansetron 2 mg TID and placebo groups were in the 41 to 64 years age category (56% versus 6 1 %) followed by the 18 to 40 years category (31 % versus 26%), while 13% of subjects in both treatment groups were 65 years or older. There was a total of 30% male subjects (29% in cilansetron 2 mg TID group versus 30% in the placebo group).
• the racial composition was similar between the groups with 94% versus 95% of subjects in the Caucasian category and 3% or less of the subjects in the other categories. Twenty-one percent of the subjects were using tobacco products at Baseline and only 1% of subjects had a history of prior laxative use. Analysis of demographic data for the per-protocol population showed results consistent with the ITT analyses.
• the age of the subjects ranged from 18 years to 82 years in the ITT population and the mean age was similar between the groups (48.6 years in the cilansetron 2 mg TDD group and 48.3 years in the placebo group). Most subjects in the cilansetron 2 mg TID and placebo groups were in the 41 to 64 years age category (64% versus 58%) followed by the 18 to 40 years category (26% versus 30%), while 10% versus 13% of subjects were 65 years or older. Approximately one third of subjects were male in both the cilansetron 2 mg TED group (31 %) and the placebo group (33%).
• the racial composition was similar between the groups with 85% versus 86% of subjects in the Caucasian category and 11% of the subjects in both groups in the category of other. Approximately one-fifth of the subjects were using tobacco products at Baseline and only 3% of subjects had a history of prior laxative use. Analysis of demographic data for the per-protocol population showed results consistent with the ITT analyses. [00360] Analysis of demographic data by gender revealed younger overall age for male subjects (46.2 years) compared with female subjects (49.5 years). In addition, male subjects in the cilansetron 2 mg TID group were slightly older than male subjects in the placebo group (47.7 years versus 44.9 years). For all other demographic variables, the treatment groups were well balanced within both subgroups.
• the age of the subjects ranged from 18 years to 84 years in the ITT population and the mean age was similar between the groups (44.6 years in the cilansetron 2 mg TED group and 44.5 years in the placebo group). Most subjects in the cilansetron 2 mg TED and placebo groups were in the 41 to 64 years age category (55% versus 52%) followed by the 18 to 40 years category (39% versus 40%), while only 6% versus 8% of subjects were 65 years or older. The proportion of male subjects was slightly higher in the cilansetron 2 mg TED group (47%) compared with the placebo group (43%).
• the racial composition was similar between the groups with 91% versus 89% of subjects in the Caucasian category and 9% versus 10% of the subjects in the Asian category. Approximately one-fourth of the subjects were using tobacco products at Baseline and only 2% of subjects had a history of prior laxative use. Analysis of demographic data for the Per-protocol population showed results consistent with the ITT analyses.
• treatment group imbalances were observed within some of these countries for some of the demographic variables, for example, Romania, current use of tobacco products 29% (cilansetron 2 mg TID) versus 7% (placebo); Russia, male subjects 49% (cilansetron 2 mg TID) versus 29% (placebo); South Africa, male subjects 50% (cilansetron 2 mg TID) versus 29% (placebo).
• Romania current use of tobacco products 29% (cilansetron 2 mg TID) versus 7% (placebo); Russia, male subjects 49% (cilansetron 2 mg TID) versus 29% (placebo); South Africa, male subjects 50% (cilansetron 2 mg TID) versus 29% (placebo).
• IBS history and disease definition were assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the Rome I criteria.
• the mean duration of IBS was 15 1.7 months and 152.7 months in the cilansetron 2 mg TID and placebo groups, respectively.
• Per-protocol analyses showed results consistent with the ITT analyses. No relevant gender-related overall differences were observed, however, among male subjects a longer duration of IBS was observed in the cilansetron 2 mg TID group (160.6 months) compared with the placebo group (146.4 months).
• Diarrhea-predominant IBS subject eligibility were assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the criteria.
• IBS history and disease definition were assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the Rome I criteria.
• the mean duration of IBS was 119.7 months versus 121.8 months in the cilansetron 2 mg TID and placebo groups, respectively.
• Per-protocol analyses showed results consistent with the ITT analyses. Analysis of demographic data by gender showed shorter duration of IBS overall, among male subjects (106.2 months) compared with female subjects (127.6 months).
• Diarrhea-predominant IBS subject eligibility (Rome II criteria) were assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the criteria. Most subjects in both treatment groups had the following diarrhea-related symptoms almost always or very often (more than half of the time) during the six months pnor to enrollment: more than three bowel movements a day (67% versus 64%), loose, mushy, or watery bowel movements (84% versus 85%), and urgency (73% versus 76%).
• Baseline mean systolic (ranging from 120.4 mmHg to 124.9 rnmHg) or diastolic (ranging from 74.6 mmHg to 76.7 mmHg) blood pressure, pulse rate (ranging from 72.6 bpm to 73.5 bpm), or body temperature (ranging from 36.5 0 C to 36.6°C).
• the proportion of subjects with severe IBS was smaller among subjects who were on cilansetron 2 mg TDD during the three-month treatment period (C/C, 7%; C/P, 6%) compared with subjects who were on placebo during the three-month treatment period (P/C, 18%; P/P, 18%).
• the proportion of subjects with mild IBS was larger among subjects who were on cilansetron 2 mg TE) during the three-month treatment period (C/C, 52%; C/P, 50%) compared with subjects who were on placebo during the three-month treatment period (P/C, 40%; P/P, 30%).
• the mean BMI was higher in Canada (27.00 kg/m 2 ) and lower in India (22.89 kg/m 2 ) than in the overall population.
• treatment group imbalances were observed within some of these countries, for example, in Bulgaria, the mean BMI was higher in the cilansetron 2 mg TED group (26.18 kg/m 2 ) compared with the placebo group (23.57 kg/m ).
• the clinical consequences to efficacy and how efficacy is modified due to the differences among the countries and the treatment group imbalances within the countries are difficult to assess.
• IBS history and disease definition was assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the Rome I criteria.
• the mean duration of IBS was 88 months and 86 months in the cilansetron 2 mg TID and placebo groups, respectively.
• Per-protocol analyses showed results consistent with the ITT analyses. No clinically relevant gender- related differences were observed. Analyses by country revealed some difference among the countries. For example, among the seven countries that enrolled at least 5% of the total population, longer overall duration of IBS was observed in Canada (131.9 months) and Germany (105.2 months) versus shorter duration of IBS in Bulgaria (67.3 months), Romania (57.1 months), Russia (69.5 months), and Ukraine (50.1 months).
• Diarrhea-predominant IBS subject eligibility was assessed for the treatment group. No clinically relevant differences were observed between the treatment groups for any of the criteria. Most subjects in both treatment groups had the following diarrhea-related symptoms almost always or very often (more than half of the time) during the six months prior to enrollment: more than three bowel movements a day (55% versus 57%), loose, mushy, or watery bowel movements (68% versus 69%), and urgency (45% versus 42%).
• concomitant medications included other analgesics and antipyretics (35% versus 32%), antiinflammatory/antirheumatic products (32% versus 27%), antidepressants (26% versus 25%), multivitamins (combinations) (24% versus 26%), drugs for treatment of peptic ulcer (24% versus 22%), topical products for joint and muscular pain (22% versus 20%), estrogens (19% versus 20%), hormones and related agents (19% in both groups), antihistamines for systemic use (19% versus 17%), other gynecologicals (19% versus 17%), calcium (14% versus 19%), stomatological preparations (15% in both groups), antithrombotic agents (13% versus 14%), cholesterol and triglyceride reducers (13% in both groups), hormonal contraceptives for systemic use (15% versus 11%), other plain vitamin preparations (11% versus 14%), laxatives
• the WHO generic terms with >10% of subjects in either group included paracetamol (18% versus 14% in the cilansetron 2 mg TID and placebo groups, respectively), acetylsalicylic acid (11% versus 13%), ibuprofen (13% in both groups), multivitamins (19% versus 20%), conjugated estrogen (11 % in both groups), calcium (10% versus 9%), and tocopherol (10% versus 13%). There were no relevant treatment group differences or trends observed for any WHO generic term. No impact on efficacy was noted with these medications.
• concomitant medications included other analgesics and antipyretics (29% versus 30%), antiinflammatory/antirheumatic products, non-steroids (27% versus 22%), drugs for treatment of peptic ulcer (21% versus 25%), antidepressants (23% in both groups), antihistamines for systemic use (19% versus 18%), topical products for joint and muscular pain (18% versus 15%), multivitamins, combinations (15% versus 17%), estrogens (12% versus 17%), hormones and related agents (12% versus 17%), other gynecologic als (15% versus 13%), cholesterol and triglyceride reducers (14% versus 12%), beta blocking agents (12% versus 11%), stomatological preparations (11 % versus 12%), calcium (11% in both groups), corticosteroids, plain (11 % in both groups), laxatives (13% versus 7%), anx
• concomitant medications took at least one concomitant medication. Categories of the most frequently used (>5% in either group) concomitant medications included other analgesics and antipyretics (21% versus 20%), beta blocking agents (10% versus 9%), drugs for treatment of peptic ulcer (10% versus 9%), hormonal contraceptives for systemic use (9% versus 8%), nonsteroidal antiinflammatory/ antirheumatic products (8% versus 8%), ACE-inhibitors (7% versus 9%), antidepressants (7% versus 6%), hormones and related agents (6% versus 7%), decongestants and other nasal preparations for topical use (6% versus 7%), estrogens (5% versus 8%), topical products for joint and muscular pain (6% versus 5%), stomatological preparations (5% versus 6%), antithrombotic agents (5% versus 6%), all other therapeutic products (5% versus 5%), laxatives (5% versus 4%), anxiolytics (5% versus 4%), cholesterol and
• the mean overall compliance was 92.64% versus 93.79% in the cilansetron 2 mg TID and placebo groups, respectively, with 90% versus 93% of subjects in the 80% to 120% compliance rate category.
• the mean overall compliance was 91.64% versus 92.26% in the cilansetron 2 mg TID and placebo groups, respectively, with 87% versus 89% of subjects in the 80% to 120% compliance rate category. Three subjects in the cilansetron 2 mg TID group had >120% compliance.
• the mean overall compliance was 98.71 % versus 97.66% in the cilansetron 2 mg TID and placebo groups, respectively, with 95% versus 93% of subjects in the 80% to 120% compliance rate category.
• abdominal pain/discomfort five-point scale
• stool consistency forty-point Bristol Stool Scale
• stool frequency number of bowel movements each day
• urgency five-point scale
• straining yes or no
• feeling of incomplete defecation yes or no
• bloating or feeling of abdominal distension five-point scale
• the two main secondary efficacy parameters were the overall responder rate for abdominal pain/discomfort and abnormal bowel habits during the 26-week treatment period.
• the overall responder rate during the 12-week treatment period was a secondary efficacy parameter.
• Responder rate for the weekly diary questions on adequate relief at each month where a responder for a month (monthly responder) was defined as a subject who answered the weekly question with "yes" at least twice for that month.
• the responder rate was the percentage of responders within a treatment group.
• the all- month responder rate for the weekly diary questions on adequate relief was also evaluated, where an all-month responder was defined as a subject who answered the weekly question with "yes" at least twice for each month.
• the all-month responder rate was the percentage of all-month responders within a treatment group;
• Adequate relief rate for the weekly diary questions was calculated for each subject as the number of weekly assessments with adequate relief ("yes") divided by the total number of weekly assessments;
• a subject was defined as a responder for a month (monthly responder) if he/she answered the weekly question with "yes" at least twice for that month regardless of the number of missing responses for the weekly diary question, where a month was defined as a four-week period. Subjects who had at least one weekly question response but did not have at least two answers of "yes" for that month were considered a non-responder for that month. If a subject had missing responses for the entire month, the subject had the last non-missing monthly responder determination (responder or non-responder) carried forward for the missing response. If a subject had missing responses for the entire month of Month 1, the subject was considered a non-responder. 3. Conservative approach for all efficacy analyses
• Subjects in the cilansetron 2 mg TID group were responders for more months in general compared to subjects in the placebo group for the diav question on adequate relief of IBS symptoms as reflected by the statistically significant (p ⁇ 0.001) treatment group difference in the distribution of subjects among the number of months categories (monthly LOCF imputation approach, ITT population).
• the treatment by gender and pooled center interactions were not significant for the diary question on adequate relief of IBS symptoms.
• Analysis using the conservative imputation approach showed similar results to the analysis using the monthly LOCF imputation.
• Per-protocol analyses showed results consistent with the ITT analyses.
• Subjects in the cilansetron 2 mg TID group were responders for more months in general compared to subjects in the placebo group for the diary question on adequate relief of abdominal pain/discomfort symptoms as reflected by the statistically significant (p ⁇ 0.001) treatment group difference in the distribution of subjects among the number of months categories (monthly LOCF imputation approach, ITT population).
• the treatment by gender and pooled center interactions were not significant for the diary question on adequate relief of abdominal pain/discomfort symptoms.
• Analysis using the conservative imputation approach showed similar results to the analysis using the monthly LOCF imputation.
• Per-protocol analyses showed results consistent with the ITT analyses.
• Subjects in the cilansetron 2 mg TID group were responders for more months in general compared to subjects in the placebo group for the diary question on adequate relief of abnormal bowel habits as reflected by the statistically significant (p ⁇ 0.001) treatment group difference in the distribution of subjects among the number of months categories (monthly LOCF imputation approach, ITT population).
• the treatment by gender and pooled center interactions were not significant for the diary question on adequate relief of abnormal bowel habits.
• Analysis using the conservative imputation approach showed similar results to the analysis using the monthly LOCF imputation.
• Per- protocol analyses showed results consistent with the ITT analyses.
• Additional analyses of the number of months a subject was a responder during the three-month treatment period by gender, age category, race, BMI, severity of IBS, duration of IBS, tobacco use, and pooled center are presented below.
• Subjects in the cilansetron 2 mg TID group were responders for more months in general compared to subjects in the placebo group for the diary question on adequate relief of abnormal bowel habits as reflected by the statistically significant (p ⁇ 0.001) treatment group difference in the distribution of subjects across the number of months categories (monthly LOCF imputation approach, ITT population).
• ITT population monthly LOCF imputation approach
• Analysis using the conservative imputation approach showed similar results to the analysis using the monthly LOCF imputation.
• Per-protocol analyses showed results consistent with the ITT analyses.
• the overall responder rate for each of the three weekly diary questions on adequate relief during the entire four-month treatment period was higher in the C/C treatment group compared with the P/P treatment group (observed case analysis: IBS symptoms, 66% versus 28%; abdominal pain/discomfort, 70% versus 36%; and abnormal bowel habits, 69% versus 28%, respectively).
• Analysis using the weekly LOCF approach showed similar results to the observed case analysis.
• the treatment group differences in the overall responder rate were 12% to 15% larger across the diary questions for the entire four-month treatment period compared with the three-months treatment period. This was due to the higher overall responder rate for the entire four- month treatment period compared with the three-months treatment period for subjects taking cilansetron 2 mg TID, while no substantial differences were seen for subjects taking placebo.
• the percentage of subjects who were responders for each month during the three-month treatment period was 35% to 40% (cilansetron 2 mg TID) versus 17% to 23% (placebo) across the three diary questions in Study S241.3.006 (p ⁇ 0.001), 39% to 42% (cilansetron 2 mg TID) versus 17% to 25% (placebo) in Study S241.3.0011 (p ⁇ 0.001), and 38% to 42% (cilansetron 2 mg TID) versus 21 % to 23% (placebo) in Study S241.3.009 (p ⁇ 0.001).
• the responder rate for the weekly diary questions on adequate relief was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TID group compared with the placebo group for each of the three weekly diary questions on adequate relief at each month during the three months of treatment.
• the responder rate was 51% to 56% (cilansetron 2 mg TE)) versus 28% to 36% (placebo) across the three diary questions for Month 1 and remained relatively stable for the rest of the study with a responder rate of 49% to 53% (cilansetron 2 mg TID) versus 30% to 36% (placebo) at Month 3 of treatment.
• the percentage of subjects who were responders for each month during the three-month treatment period was 35% to 40% (cilansetron 2 mg TID) versus 17% to 23% (placebo) across the three diary questions.
• Analyses using the conservative imputation approach showed similar results to the analysis using the monthly LOCF imputation.
• Per-protocol analyses showed results consistent with the ITT analyses.
• the responder rate for the weekly diary questions on adequate relief was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TID group compared with the placebo group for each of the three weekly diary questions on adequate relief at each month during the three months of treatment.
• the responder rate was 57% to 58% (cilansetron 2 mg TID) versus 28% to 40% (placebo) across the three diary questions for Month 1 and remained relatively stable for the rest of the three-month treatment period with a responder rate of 55% to 58% (cilansetron 2 mg TID) versus 34% to 41% (placebo) at Month 3 of treatment.
• Shifts in the Number of Responders from Month 3 to Month 4 [00438] Shifts from responder at Month 3 to non-responder at Month 4 were consistently more common in the C/P treatment group compared with the other three treatment groups for each of the three diary questions regardless of the imputation approach (conservative or weekly LOCF) used for the analyses. Correspondingly, shifts from non-responder at Month 3 to responder at Month 4 were consistently less common in the C/P treatment group compared with the other three groups.
• the responder rate was 49% to 54% (cilansetron 2 mg TID) versus 33% to 34% (placebo) across the three diary questions for Month 1 and increased to 61 % to 64% (cilansetron 2 mg TID) versus 46% to 48% (placebo) by Month 3 of treatment.
• the responder rate was 59% to 62% (cilansetron 2 mg TID) versus 47% to 50% (placebo) across the three diary questions demonstrating that the favorable effect of cilansetron was sustained for up to six months.
• the percentage of subjects who were responders for each month during Months 1 to 3 was 38% to 42% (cilansetron 2 mg TID) versus 21% to 23% (placebo) and for each month during Months 4 to 6 the responder rate was 49% to 52% (cilansetron 2 mg TID) versus 36% to 39% (placebo) across the three diary questions.
• the mean adequate relief rate (the individual proportion of "yes") for the weekly diary questions during the three-month treatment period was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TED group compared with the placebo group for each of the three weekly diary questions on adequate relief.
• the median adequate relief rates were 0.50 versus 0.08 for IBS symptoms, 0.58 versus 0.17 for abdominal pain/discomfort, and 0.50 versus 0.08 for abnormal bowel habits in the cilansetron 2 mg TED and placebo groups, respectively.
• Analyses using the weekly LOCF imputation approach showed similar results to the observed case analysis. Per-protocol analyses showed results consistent with the ITT analyses.
• the mean adequate relief rate (the individual proportion of "yes") for the weekly diary questions during the three-month treatment period was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TED group compared with the placebo group for each of the three weekly diary questions on adequate relief.
• the median adequate relief rates were 0.58 versus 0.1 7 for EBS symptoms, 0.58 versus 0.28 for abdominal pain/discomfort, and 0.58 versus 0.17 for abnormal bowel habits in the cilansetron 2 mg TED and placebo groups, respectively.
• Analyses using the weekly LOCF imputation approach showed similar results to the observed case analysis. Per-protocol analyses showed results consistent with the ITT analyses.
• the mean adequate relief rate (the proportion of "yes") for the weekly diary questions during Months 1 to 3 was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TED group compared with the placebo group for each of the three weekly diary questions on adequate relief.
• the median adequate relief rates were 0.58 versus 0.33 for IBS symptoms, 0.58 versus 0.33 for abdominal pain/discomfort, and 0.67 versus 0.33 for abnormal bowel habits in the cilansetron 2 mg TED and placebo groups, respectively.
• Analyses using the weekly LOCF imputation approach showed similar results to the observed case analysis. Per-protocol analyses showed results consistent with the ITT analyses.
• the mean adequate relief rate (the proportion of "yes") for the weekly diary questions during the six months of treatment was significantly higher (p ⁇ 0.001) in the cilansetron 2 mg TID group compared with the placebo group for each of the three weekly diary questions on adequate relief.
• the median adequate relief rates were 0.64 versus 0.40 for IBS symptoms, 0.63 versus 0.42 for abdominal pain/discomfort, and 0.70 versus 0.40 for abnormal bowel habits in the cilansetron 2 mg TID and placebo groups, respectively.
• Analyses using the weekly LOCF imputation approach showed similar results to the observed case analysis. Per-protocol analyses showed results consistent with the ITT analyses.
• Figure 62 for abdominal pain/discomfort, and Figure 63 for abnormal bowel habits.
• Cilansetron 2 mg TID treatment was also associated with statistically significant increased stool firmness, decreased stool frequency, and increased straining at the end of treatment in all three studies.
• the mean scores for daily stool consistency suggesting increased stool firmness in the three studies did not reach the other end of the spectrum of hard and lumpy stools (scores of 1 and 2 in the Bristol stool form scale).
• the mean stool frequency decreased in the cilansetron 2 mg group to 2.45 (Study S241.3.006), 2.41 (Study S241.3.011), and 1.96 (Study S241.3.009) stools per day at the end of treatment.
• Study S241.3.011 there was an immediate (within a week) loss of the treatment effect following blinded withdrawal of cilansetron 2 mg TID with no evidence of rebound within four weeks.
• the rate of pain-free days was also calculated from treatment start to treatment stop and presented for the ITT population in Table 2.7.3.6.3.1. During the three-month treatment period, the rate of pain-free days was almost twice as high in the cilansetron 2 mg TED group compared with the placebo group (median rate of 0.19 versus 0.10 for the three-month treatment period).
• the rate of pain-free days was approximately twice as high in the cilansetron 2 mg TDD group compared with the placebo group (median rate of 0.22 versus 0.11 for the three-month treatment period).
• the rate of pain-free days was also calculated from treatment start to treatment stop and presented for the ITT population in Table 2.7.3.6.3.2 (overall) and Table 2.7.3.6.3.3 (Month 1 to 3 and Month 4 to 6). During the six-month treatment period, the rate of pain-free days was more than twice as high in the cilansetron 2 mg TID group compared with the placebo group (median rate of 0.19 versus 0.08 for the six- month treatment period).
• the rate of pain-free days was more than twice as high in the cilansetron 2 mg TID group compared with the placebo group during Month 1 to Month 3 (median rate of 0.13 versus 0.05 for the three-month treatment period) and during Month 4 to Month 6 (median rate of 0.31 versus 0.12 for the three-month treatment period).
• TID group having a lower mean score at every week compared with the placebo group.
• the rate of urgency-free days was calculated from treatment start to treatment stop and presented for the ITT population in Table 2.7.3.6.4.1. During the three-month treatment period, the rate of urgency-free days was higher in the cilansetron
• the rate of urgency-free days was higher in the cilansetron 2 mg TID group compared with the placebo group during Month 1 to Month 3 (median rate of 0.05 versus 0.02 for the three-month treatment period) and during Month 4 to Month 6 (median rate of 0.10 versus 0.03 for the three-month treatment period).
• Subjects with diarrhea-predominant IBS have a constellation of symptoms that significantly affect their well-being and their ability to function normally. Limits in daily activities and food avoidance are just some examples in how they may have to adapt because of their illness. Because of this, subjects with diarrhea-predominant IBS may feel a sense of helplessness and a loss of control of their lives. Therefore, it is important to evaluate the changes in quality of life for these subjects in order to understand the impact of their IBS symptoms under treatment.
• Subscales of the IBS-QOL questionnaire such as food avoidance (mean scores of 36.3 to 46.6), interference with activity (38.6 to 45.2), and dysphoria (45.8 to 49.3) showed the most impairment in the subjects' quality of life at Baseline in all three studies.
• the IBS-QOL is presented for the ITT population in Figure 82 (change from Baseline).
• the Baseline values for the overall score and each individual score were comparable between the cilansetron 2 mg TID and placebo groups.
• the mean overall IBS-QOL score was 50.6 in the cilansetron 2 mg TID group versus 52.8 in the placebo group at Baseline.
• the subscales that showed the most impairment in the subjects' quality of life at Baseline included interference with activity (38.6 versus 41.6), food avoidance (36.3 versus 37.2) and dysphoria (45.8 versus 49.3).
• the treatment difference in the mean change from Baseline at Endpoint was 7.37.
• Subscales with the greatest treatment difference included interference with activity (9.73), body image (7.43), food avoidance (8.92), and dysphoria (7.34). Smaller treatment differences were observed for health worry (3.21), social reaction (6.19), sexual (5.64), and relationships (5.19).
• the IBS-QOL is presented for the ITT population in Figure 83 (change from Baseline).
• the Baseline values for the overall score and each individual subscore were comparable between the cilansetron 2 mg TED and placebo groups.
• the mean overall IBS-QOL score was 52.4 in the cilansetron 2 mg TID group versus 53.4 in the placebo group at Baseline.
• the subscales that showed the most impairment in the subjects' quality of life at Baseline included interference with activity (41.3 versus 42.0), food avoidance (37.4 versus 37.7), and dysphoria (48.3 versus 49.1).
• the cilansetron 2 mg TID group demonstrated a statistically significant greater improvement from Baseline to Endpoint compared with the placebo group in the overall IBS-QOL score (p ⁇ 0.001) and each subscore (interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships, and dysphoria, p ⁇ 0.001 for each subscore).
• the treatment difference in the mean change from Baseline at endpoint was 7.53.
• Subscales with the greatest treatment difference included interference with activity (10.57), food avoidance (9.64), and dysphoria (8.16). Smaller treatment differences were observed for body image (6.60), health worry (4.05), social reaction (5.53), sexual (5.93), and relationships (4.72).
• the IBS-QOL is presented for the ITT population in Figure 84 (change from Baseline).
• the IBS-QOL questionnaire was completed only in countries for which there was a validated translation available. Subjects in the following countries did not complete the IBS-QOL questionnaire: Bulgaria, Israel, Tru, Romania, Russia, and Ukraine.
• the Baseline values for the overall score and each individual subscore were comparable between the cilansetron 2 mg TID and placebo groups.
• the mean overall IBS-QOL score was 55.0 in the cilansetron 2 mg TID group versus 55.5 in the placebo group at Baseline.
• the subscales that showed the most impairment in the subjects' quality of life at Baseline included interference with activity (45.2 in both groups), food avoidance (42.9 versus 46.6), and dysphoria (48.8 versus 48.9).
• the remaining subscales had modestly higher scores at Baseline, including body image (67.3 versus 66.4), health worry (63.1 in both groups), social reaction (58.6 versus 62.1), sexual (76.3 versus 74.8), and relationships (64.9 versus 65.1).
• the treatment difference in the mean change from Baseline at Endpoint was 7.90.
• Subscales with the greatest treatment difference included interference with activity (10.85), food avoidance (10.09), and dysphoria (8.78). Smaller treatment differences were observed for body image (5.04), health worry (5.41), social reaction (8.70), sexual (2.93), and relationships (5.66).
• Age category (18-40 years; 41-64 years; or ?65 years) Race (Caucasians or non- Caucasians) • BMI category ( ⁇ 30 kg/m2 or D 3-0 kg/m2) Severity of IBS (severe or non-severe)

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