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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
  • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
  • A23L33/30—Dietetic or nutritional methods, e.g. for losing weight
• • 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
  • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
  • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

• the invention is directed generally to methods of treating AIDS by administering nelfinavir in combination with food such that the bioavailability of nelfinavir is increased compared to its administration without food.
• HIV Human immunodeficiency virus
• HIV Protease an integral protease, Type 1 HIV Protease.
• the HIV protease is important in the maturation of the virus from a noninfectious to an infectious form. Inhibition of the HIV protease prevents post-translational processing such that immature and non-infectious viral particles are released.
• Several inhibitors of HIV protease are known. One such inhibitor is [3S-(3R*. 4aR*, 8aR*, 2'S*.
• Shetty et al. (1996) observed that the oral bioavailability of nelfinavir mesylate was 43% in fed rats, dogs and monkeys, but was 29% in animals fasted overnight.
• Shetty et al. Preclinical pharmacokinetics and distribution to tissue of AG 1343, an inhibitor of human immunodeficiency virus type 1 protease, 40(1 ) Antimicrob. Agents Chemother. 110, 112 (1996).
• the fed state consisted of a meal 30 minutes before drug administration. Id. at 111.
• Aamoutse etal. (2003) reported that meal consumption had a significant effect on the AUC 24h , oorr and C m i n values for nelfinavir and nelfinavir plus M8, the active metabolite of nelfinavir.
• Aarnoutse, et al. Pharmacokinetics, food intake requirements and tolerability of once-daily combinations of nelfinavir and low-dose ritonavir in healthy volunteers, 55 Br. J. Clin. Pharmacol. 115, 120 (2003).
• the full breakfast had 610 kcal, 33% fat (about 22 g), 16% protein (about 24 g), and 51% carbohydrate.
• the Physician's Desk Reference (PDR) entry for Viracept® nelfinavir recommends that it be administered with food.
• the PDR reference discloses that the maximum plasma concentrations and AUC were two to three-fold higher under fed conditions compared to fasting.
• the meals evaluated contained 517 to 759 Kcal, with 153 to 313 Kcal derived from fat. Id.
• the advantage of moderate food intake with nelfinavir administration has been shown, but the effect of fat consumption and high caloric intake with nelfinavir has not been well studied.
• HIV medications have shown strong food effects on bioavailability.
• Some anti- HIV reverse transcriptase inhibitors are recommended to be administered on an empty stomach, including efavirenz, AZT, ddC, and ddl.
• Other reverse transcriptase inhibitors can be taken without or with food.
• Inhibitors of HIV protease vary in their food effects. Indinavir is recommended for administration without food, but with copious amounts of water. In contrast, saquinavir, another HIV protease inhibitor, is recommended for administration with a high fat meal. Amprenavir and Iopinavir may be taken without or with food.
• protease inhibitors such as nelfinavir
• Optimizing dosaging of protease inhibitors such as nelfinavir is desirable both to minimize side effects and ensure efficacy against HIV.
• Protease inhibitor therapy is sometimes associated with side effects such as diarrhea, fat redistribution, insulin resistance, diabetes and hyperlipidemia.
• Lenhard et al. Dietary fat alters HIV protease inhibitor-induced metabolic changes in mice, Am. Soc. Nutr. Sci. 2361 (2000).
• Yet virological failure of nelfinavir-containing HIV regimens has been related to low plasma levels of nelfinavir.
• the invention relates to a method of treating human immunodeficiency virus (HIV) in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of nelfinavir in a pharmaceutical composition at least once daily for at least two weeks, wherein at least once daily nelfinavir is administered with food and the food comprises more than 800 kcal.
• HAV human immunodeficiency virus
• the invention in another aspect relates to a method of treating human immunodeficiency virus (HIV) in a mammal comprising administering orally to a mammal in need thereof a therapeutically effective amount of nelfinavir in a pharmaceutical composition taken with food, wherein the food comprises at least about 500 kcal and at least about 50% fat by energy content.
• HAV human immunodeficiency virus
• the invention in yet a further aspect relates to a method of treating human immunodeficiency virus (HIV) in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of nelfinavir in a pharmaceutical composition at least once daily for at least two weeks, wherein at least once daily nelfinavir is taken with food and the food comprises more than about 500 kcal and more than about 50% fat by energy content.
• the invention also relates to a kit comprising a therapeutically effective oral dose of nelfinavir and a printed label comprising instructions for administering the dose with food comprising at least 800 kcal in a high-fat meal.
• the invention further relates to a therapeutic composition for the treatment of human immunodeficiency virus (HIV) in a mammal comprising fat and a therapeutically effective amount of nelfinavir in a weight ratio of at least about 25 fat: 1 nelfinavir.
• HIV human immunodeficiency virus
• FIGURES Figure 1 Mean nelfinavir plasma concentration-time profiles following administration of 1250-mg oral doses to fasting subjects (closed circles), with a low calorie/low fat meal
• Figure 3 Mean nelfinavir plasma concentration as a function of meal caloric content.
• the AUC(O- ⁇ ) (lozenge, solid line) values are in units of ⁇ g • hr / mL and have a correlation of r 2 > 0.97.
• the C ma ⁇ (squares, dashed line) values are in units of ⁇ g /mL and have a correlation of r 2 > 0.89. Measurement followed administration of a 1250 mg oral dose of nelfinavir.
• Figure 4 Mean nelfinavir plasma concentrations as a function of meal protein content.
• the AUC(O- ⁇ ) (lozenge, solid line) values are in units of ⁇ g • hr / mL and have a correlation of r 2 > 0.99.
• the C max (squares, dashed line) values are in units of ⁇ g /mL and have a correlation of r 2 > 0.96. Measurement followed administration of a 1250 mg oral dose of nelfinavir.
• Figure 5 Mean simulated nelfinavir steady-state plasma concentration-time profiles following BID administration of 1250-mg oral doses to fasting subjects (closed circles), with a low calorie/low fat meal (open circles), with a moderate calorie/low fat meal (closed squares), and with a high calorie/high fat meal (open squares). The bars represent standard errors.
• Figure 6 Mean M8 plasma concentration-time profiles following administration of 1250-mg nelfinavir oral doses to fasting subjects (closed circles), with a low calorie/low fat meal (open circles), with a moderate calorie/low fat meal (closed squares), and with a high calorie/high fat meal (open squares).
• Upper and lower panels represent linear and semi- logarithmic plots, respectively.
• Figure 7 Individual M8 C max (upper panel) and AUC(O- ⁇ ) (lower panel) values following administration of 1250-mg nelfinavir oral doses to fasting subjects (0 Kcal), with a low calorie/low fat meal (125 Kcal), with a moderate calorie/low fat meal (500 Kcal), and with a high calorie/high fat meal (1000 Kcal). Individual subject and mean values are illustrated by numbers and triangles, respectively.
• Figure 8 Mean nelfinavir plasma concentration-time profiles following administration of 5 x 250-mg nelfinavir tablets to fasting subjects (filled circles), during a moderate calorie/low fat meal (open circles), and during a moderate calorie/high fat meal (filled squares), according to example 2.
• Upper and lower panels are linear and semi-logarithmic plots, respectively.
• Figure 9 Individual nelfinavir C max (upper panel) and AUC(0- « ) values (lower panel) following administration of 5 x 250-mg nelfinavir tablets to fasting subjects, during a moderate calorie/low fat meal, and during a moderate calorie/high fat meal, according to example 2. Individual and mean values are represented by open circles and triangles, respectively.
• Figure 10 Mean M8 plasma concentration-time profiles following administration of 5 x 250-mg nelfinavir tablets to fasting subjects (filled circles), during a moderate calorie/low fat meal (open circles), and during a moderate calorie/high fat meal (filled squares) according to example 2.
• Upper and lower panels are linear and semi-logarithmic plots, respectively.
• the invention relates to a method of treating HIV in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of nelfinavir in a pharmaceutical composition with food and the food comprises more than 800 kcal.
• the food may comprise more than about 900 kcal or more than about 1000 kcal.
• the mammal preferably is a human.
• HIV is treated by administering nelfinavir at least once daily for at least two weeks. More preferably, nelfinavir is administered at least twice daily. Other preferable conditions of treatment include nelfinavir administration three times daily. Preferably, nelfinavir therapy continues for at least two weeks. More preferably, nelfinavir is administered for at least four weeks. Other durations of treatment that are preferred are at least three months, at least six months, and at least one year. Administration of nelfinavir should be with food. Preferably, nelfinavir is administered between 30 minutes prior to and two hours after consumption of food. More preferably, nelfinavir is administered between 30 minutes prior to and one hour after consumption of food.
• nelfinavir occurs at about the same time as the consumption of food.
• nelfinavir is administered at least once a day with one of the meals described herein. More preferably, nelfinavir is administered at least twice a day with each administration of nelfinavir being with one of the meals described herein. Also preferable is administration of nelfinavir three times a day with each administration of nelfinavir being with one of the meals described herein.
• One of the preferred meals of the invention is at least 800 kcal.
• nelfinavir is administered with food of at least 800 kcal and one of the following ranges of fat content as measured by percentage of energy content: between about 40% fat and about 50% fat, between about 50% fat and about 60% fat, between about 60% fat and about 70% fat, between about 70% fat and about 80% fat, between about 80% fat and about 90% fat and between about 90% fat and about 100% fat. Also preferable is administration of nelfinavir with a meal of at least 800 kcal and at least one of the following levels of fat content as measured by percentage of energy content: more than 40% fat, more than 50% fat, more than 60% fat, more than 70% fat, more than 80% fat and more than about 90% fat. Also, nelfinavir may be administered with food comprising at least 800 kcal and an amount of fat from the following list: from 36 g to 55 g fat, from 40 g to 55 g fat and at least about 55 g fat.
• Another method of the invention is treating human immunodeficiency virus (HIV) in a mammal comprising administering orally to a mammal in need thereof a therapeutically effective amount of nelfinavir in a pharmaceutical composition taken with food, wherein the food comprises at least about 500 kcal and at least about 50% fat by energy content.
• the food comprises at least about 500 kcal and has a fat content as measured by percentage of energy content from one of the following ranges: between about 50% fat and about 60% fat, between about 60% fat and about 70% fat, between about 70% fat and about 80%> fat, between about 80% fat and about 90% fat, and between about 90% fat and about 100% fat.
• nelfinavir may be administered with food comprising at least about 500 kcal and an amount of fat from the following list: from 36 g to 55 g fat, from 40 g to 55 g fat and at least about 55 g fat.
• nelfinavir with food wherein the food comprises at least about 50% fat by energy content and at least 600 kcal, at least 700 kcal, at least 800 kcal, at least 900 kcal, or at least 1000 kcal.
• administration of a pharmaceutical composition of nelfinavir with food results in an increase in plasma concentration of nelfinavir.
• the plasma concentration can be measured as AUC.
• the inventive methods result in an increase in the area under the curve from time zero extrapolated to infinite time (AUC(0-°°)) after nelfinavir administration with food that is at least about 3-fold greater than the AUC(0- M ) after administration in the fasted state and, more preferably, is at least about 5-fold greater than the AUC(O- ⁇ ) after administration in the fasted state.
• the plasma concentration can be measured as C max .
• the method can further comprise increasing C max values at least about 3-fold compared to a fasted subject.
• administration of the nelfinavir composition with food as described herein increases plasma concentration of a metabolite of nelfinavir, hydroxyl-f-butylamide, also called M8.
• the method can further comprise increasing AUC values of M8 at least about 3-fold compared to a fasted subject and more preferably at least 5-fold.
• the amount of the nelfinavir administered can be any therapeutically effective amount. For example, for an adult a dose of 1250 mg twice daily or 750 mg three times daily is recommended.
• Nelfinavir can be administered in any pharmaceutically acceptable form, such as a salt, stereoisomer, solvate or prodrug of nelfinavir.
• a composition comprising nelfinavir is administered to a subject to whom no other HIV medications are administered.
• a composition comprising nelfinavir is administered to a subject who is not receiving ritonavir, saquinavir or Iopinavir or a stereoisomer, solvate, salt, or prodrug thereof.
• nelfinavir is administered to a subject suffering from an HIV infection who is receiving at least one other HIV medication including, but not limited to a protease inhibitor, a nucleoside analogue reverse transcriptase inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleotide analogue reverse transcriptase inhibitor, or a viral fusion inhibitor.
• the additional HIV medication can be, but is not limited to, one or more of the following drugs: Retrovir® (3'-azido-2',3'-dideoxythymidine or AZT), Epivir® (2',3'- dideoxy-3'-thiacytidine or 3TC), Combivir® (AZT in combination with 3TC), Videx® (2',3'- dideoxyinosine or didanosine or ddl), Hivid® (2',3'-dideoxycytidine or ddC), Zerit® (stavudine or 2',3'-didehydro-3'-deoxythymidine or 3'-deoxythymidin-2'-ene or d4T), Ziagen® (abacavir), Viramune® (nevirapine), Rescriptor® (delavirdine), Sustiva® (efavirenz), Preveon® (adefovir dipovoxil), Crixivan® (indinavir), Angen
• the invention also relates to a kit comprising a therapeutically effective oral dose of nelfinavir and printed material comprising instructions for administering the dose with food according to one of the methods of the invention.
• the printed material may comprise instructions that nelfinavir be administered with food comprising at least 800 kcal in a high-fat meal.
• the high-fat meal preferably is instructed to comprise at least 40% fat by energy content.
• the printed material may instruct that nelfinavir be administered with food comprising at least 500 kcal and 50% fat by energy content.
• the printed material may instruct that the food comprise more than about 36 g of fat.
• the invention relates to a therapeutic composition for the treatment of HIV comprising fat and a therapeutically effective amount of nelfinavir in a weight ratio of at least about 25 fat: 1 nelfinavir. Also preferred is a composition in which the weight ratio is greater than about 30 fat: 1 nelfinavir. Preferably, the amount of nelfinavir is between about 100 mg and about 1500 mg, more preferably between 250 mg to 625 mg inclusive.
• Plasma concentrations of nelfinavir and its active hydroxy-t-butylamide metabolite (M8) were measured by validated high performance liquid chromatography (HPLC) methods. Pharmacokinetic parameters were determined from plasma concentration-time data using standard methods.
• nelfinavir area under the concentration-time profile was the primary parameter analyzed to determine the effect of caloric and fat content of meals on nelfinavir pharmacokinetics.
• Secondary parameters included were nelfinavir T 1 2 , time to maximum observed plasma concentration (T max ), and log transformed C max , as well as M8 pharmacokinetic parameters.
• Parameter values were evaluated by Analysis of Variance (ANOVA) using a model incorporating sequence, subject within sequence, period and treatment effects. Statistical tests were performed using the Type III sum of squares derived using WinNONIin Pro Version 2.1. Least squares treatment mean values were determined for each parameter.
• Nutrient composition data is from the USDA Nutrient Database for Standard Reference, Release 14 and select manufacturer's data for specific brands.
• Nelfinavir was administered as five 250-mg tablets with 240 mL of water. All subjects received a standardized snack the evening they were admitted to the in-patient facility. For the fasting evaluation, subjects were required to complete an overnight fast of at least 10 hours prior to dosing in the morning. For the fed pharmacokinetic evaluations, subjects were required to complete an overnight fast of at least 10 hours, prior to receiving the protocol- specific standardized breakfast meal (that is, Meal 1 , Meal 2, or Meal 3). Subjects were given 30 minutes to complete their standardized breakfast meal. Dosing was performed in the morning, immediately following the subject's completion of the standardized breakfast meal and after the subject's pre-dose pharmacokinetic specimen had been collected. Subjects could not ingest water 1 hour prior to or 1 hour after dosing. A standardized lunch was given at least 4 hours after the morning dose and a standardized dinner was given at least 10 hours after the morning dose.
• subjects were to refrain from consuming alcohol, starting 48 hours before each dose and continuing 12 hours following each dose and abstain from grapefruit and products containing grapefruit for 7 days prior to study entry (Day 1) and continuing through study completion.
• heparinized vacuum tubes green top tubes
• the actual time of each collection was recorded on the source document.
• the timing of each sample collection was as follows: predose and at 0.5, 1 , 2, 3, 4, 6, 8, and 12 hours postdose on Days 1 , 8, 15, and 22.
• Plasma samples All blood samples were kept at 4° C (using either ice or cryoblock) until centrifugation. Blood samples were centrifuged within 1 hour of collection, at approximately 1000 x g for 15 minutes, to separate the plasma. The plasma samples were split evenly into 2 aliquots and stored in appropriately labeled polypropylene transport tubes. Plasma was stored frozen at -
• Nelfinavir 0.0500 ⁇ g/mL 10.0 ⁇ g/mL ⁇ 7.31 % 2.94 to + 3.91 % M8 0.0500 ⁇ g/mL 10.0 ⁇ g/mL ⁇ 4.23% 4.07 to 5.55%
• AUC(O-tlqc) Area under plasma concentration-time Linear trapezoidal method profile from time zero to time for the last quantifiable concentration (Iqc)
• AUC(O- ⁇ ) Area under plasma concentration-time AUC(0-tlqc) + lqc / ⁇ z profile from time zero extrapolated to infinite time
• Ratio Ratio of treatment mean values, expressed as a percentage
• nelfinavir C 12 values in subjects receiving the dose with the high calorie/ high fat meal were higher than Cmax values in fasting subjects. Additionally, administration with meals decreases variability in nelfinavir plasma concentrations.
• the mean and coefficient of variation (%CV) nelfinavir C 2 values were as follows:
• Table 5 reports a summary of the pharmacokinetic results. Table 5. Summary of Pharmacokenetic Results
• Figure 2 depicts individual Cmax and AUC(0-°°) values following administration of an 1250 mg oral dose of nelfinavir, as a function of the energy content of the accompanying meal, if any.
• the average nelfinavir plasma concentration is depicted in Figure 3 as a function of the caloric value of the accompanying meal.
• the solid line represents AUC(0- ⁇ )(r 2 > 0.97) and the dashed line represents Cmax (r 2 ⁇ 0.95).
• the average nelfinavir plasma concentration is depicted in Figure 4 as a function of the protein content of the accompanying meal, if any.
• the solid line represents AUC(0- ⁇ )(r 2 > 0.99) and the dashed line represents Cmax (r 2 ⁇ 0.95).
• This example shows that food intake has a marked effect on nelfinavir pharmacokinetics with the highest levels achieved after the greatest food intake.
• AUC values increased 3-5-fold over those in the fasting state by administering nelfinavir with meals containing 500-1000 kcal and 20-50% fat.
• the metabolite, M8, plasma concentrations generally tracked those of nelfinavir. Based on the area under the plasma concentration-time profile from time zero extrapolated to infinite time (AUC (0-°°)) values, the bioavailability of M8 was 1.3-, 1.8 and 4.1 -fold higher with increasing caloric intake relative to fasting. In the fed state the M8 AUC/nelfinavir AUC ranged from 15-21%.
• EXAMPLE 2 Evaluation of Fat on Nelfinavir Bioavailability A study was conducted as a phase 1 , randomized, open-label, crossover 3x3 study, designed to evaluate the impact of a fixed kilocalorie meal at 20% and 50% fat content on single-dose pharmacokinetic parameters of the nelfinavir 250 mg tablet formulation in normal, healthy volunteers.
• Subjects were dosed with 1250 mg of nelfinavir 3 times at one-week intervals and 24- hour PK profiles were collected following each of the doses.
• Each subject was assigned three meals with different fat contents prior to dosing (fasting, 500kcal with 20% fat, 500 kcal with 50% fat) using a Latin square design.
• the moderate calorie/low fat meal consisted of 500 Kcal with 20% fat (11.3 grams of fat).
• the moderate calorie/high fat meal consisted of 500 Kcal with 50% fat (27.8 grams of fat).
• Subjects were administered nelfinavir 1250-mg (five 250-mg tablets) on the morning of the pharmacokinetic evaluations.
• the nelfinavir terminal half-life (t >) in plasma is typically 3.5 to 5 hours.
• PK evaluations were performed on Days 1 , 8 and 15 such that there would be a 7-day washout between doses.
• Subjects participated on an outpatient basis; however, subjects were admitted to the in- patient facility the evening prior to each PK evaluation and remained in the in-patient facility for approximately 16 hours post-dosing. The subjects returned the next morning (8 hours later) for their last 24 hr. pharmacokinetic blood draw. All pharmacokinetic evaluations were performed in the in-patient facility. Blood samples were collected and analyzed for plasma concentrations of nelfinavir and M8.
• subjects were required to complete an overnight fast of at least 10 hours prior to dosing in the morning.
• subjects were required to complete an overnight fast of at least 10 hours, prior to receiving the protocol- specific standardized breakfast meal. Subjects were given 30 minutes to complete their standardized breakfast meal. Dosing was performed in the morning, immediately following the subject's completion of the standardized breakfast meal and after the subject's predose PK specimen had been collected. Subjects could not ingest water 1 hour prior to or 1 hour after dosing. A standardized lunch was given at least 4 hours after the morning dose and a standardized dinner was given at least 10 hours after the morning dose. Actual sampling times were used for all data evaluation.
• Mean Cmax and AUC values were calculated as the antilogs of least-squares mean log-transformed values (analogous to geometric means). Ratios and confidence intervals for Cmax and AUC values are also based on log-transformed values. Mean values for all other pharmacokinetic parameters are least-squares means. Ratios and confidence intervals for these parameters are based on untransformed values.
• Example 1 healthy volunteers of any race and either gender, 18 to 60 years of age (inclusive), were used in the study. Volunteers were chosen who had a body mass index (BMI) between 18 to 31 kg/m 2 (inclusive), and who were seronegative for human immunodeficiency virus (HIV) -1/HIV -2. Females were required to be not pregnant and be using a reliable barrier method of birth control, have been surgically sterilized, or be postmenopausal. Pharmacokinetics
• Blood samples 5 mL each, were collected as in Example 1. The timing of each sample collection was as follows: Predose and at 0.5, 1 , 2, 3, 4, 6, 8, 12, 16 and 24 hours postdose on Days 1 , 8, and 15. All blood samples were kept at 4 s C (using either wet ice or cryoblock) until centrifugation. Blood samples were centrifuged within 1 hour of collection, at 3000 rpm (approximately 2619 x g) for 15 minutes, to separate the plasma. The plasma samples were split evenly into 2 aliquots and stored in appropriately labeled polypropylene transport tubes. Plasma was stored frozen at 20 s C or lower until analysis.
• Pharmacokinetic parameter values were calculated from plasma nelfinavir and M8 concentration-time data using standard noncompartmental pharmacokinetic methods as in Example 1.
• Log-transformed nelfinavir AUC was the primary parameter used in the evaluation of the potential effect of fat content of the meals on nelfinavir pharmacokinetics. Secondary parameters included in this analysis were nelfinavir terminal half-life (t 1 /2), time to maximum plasma concentration (tmax), and log-transformed Cmax, as well as M8 pharmacokinetic parameters. Parameter values were evaluated by analysis of variance (ANOVA) using a model incorporating sequence, subject within sequence, period, and treatment effects. Statistical tests were performed using the Type III sum of squares derived using WinNonlin Pro Version 2.1.
• Least-squares treatment mean values were determined for each parameter. Results from ANOVA were used to calculate 90% confidence intervals for the ratio (test/reference) least-squares treatment mean values, where administration of single nelfinavir doses fasting was the reference treatment. Confidence intervals were calculated using WinNonlin Pro Version 2.1. Confidence intervals were used as an aid in data interpretation. Descriptive statistics of nelfinavir Cmax and AUC were examined to determine the effect of meals of various fat content on the variability of these parameter values. Plasma concentrations of nelfinavir and M8 were measured by validated high- performance liquid chromatography (HPLC) methods. Pharmacokinetic parameters were determined from plasma concentration-time data using standard noncompartmental methods. Statistical Methods
• Log-transformed nelfinavir area under the plasma concentration-time profile (AUC) values was the primary parameter analyzed to determine the effect of fat content of meals on nelfinavir pharmacokinetics.
• the 90% confidence intervals for the ratios of test (with test meal) to reference (fasting) least-squares mean AUC as well as maximum observed plasma concentration (Cmax) values were calculated using log-transformed data and expressed as a percentage of the reference mean. The relationship between nelfinavir exposure and fat content of the meals was examined.
• Nelfinavir pharmacokinetic parameter values following administration of 5 x 250-mg nelfinavir tablets to fasting subjects (reference), during a moderate calorie/low fat meal, and during a moderate calorie/high fat meal are summarized in the following Table 8. 0 Table 8. Nelfinavir Pharmacokinetic Parameter Values, Example 2
• nelfinavir administered with meals of similar caloric content and 20% and 50% fat content resulted in longer time to maximum plasma concentration (tmax) values and higher Cmax values.
• Mean tmax values were approximately 2 hours longer when administered with meals of 20% and 50% fat content, relative to that in fasting subjects.
• Mean Cmax values were approximately 2.5- and 3.8-fold higher in meals of 20% and 50% fat content, respectively.
• AUC(O- ⁇ ) area under the plasma concentration-time profile from time zero extrapolated to infinite time
• the bioavailability of nelfinavir was approximately 3- and 5-fold higher following administration of meals containing 20% and 50% fat content, respectively, relative to that in fasting subjects. Fat content did not have a profound effect on nelfinavir terminal half-life (V/z) values.
• Nelfinavir elimination t 1 /2 values following administration to fasting subjects and with test meals were similar, averaging approximately 4 hours.
• Figure 8 Mean nelfinavir pharmacokinetic parameter values in the comparison of nelfinavir administration with test meals relative to those to fasting subjects are presented in Table 9, along with ratios and confidence intervals. Individual Cmax and AUC values are illustrated in
• Ratio Ratio of treatment mean values expressed as a percentage (100%. x test/reference)
• This example indicates that fat intake has a marked effect on nelfinavir pharmacokinetic parameters after a single dose exposure.
• AUC values increased 3.2 fold with a 500 kcal, 20% fat breakfast and 5.2 fold with the same Kcal but 50% fat when compared to the fasting AUC. These values were similar to the values previously determined for a 500 Kcal, 20% fat breakfast and a 1000 Kcal, 50% fat breakfast.
• fat content in meals affects nelfinavir PK in addition to its Kcal content suggesting a plateau effect for Kcal content.
• a 500kcal/50% fat meal can be delivered as 3.5-4 ounces of roasted peanuts, less than one cup of canned coconut cream, or a variety of American breakfast fast foods. Also, the fat dependence allows the development of a formulation of nelfinavir with fat that would enhance compliance with optimal administration of the medication.
• the 90% confidence interval (90% CI) is calculated for the ratio above the CI.
• the ratio of plasma levels of nelfinavir metabolite to nelfinavir is expressed as "M8 AUC ⁇ /nelfinavir AUC ⁇ (x 100).

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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2004
  • 2004-01-29 CA CA002515095A patent/CA2515095A1/en not_active Abandoned
  • 2004-01-29 MX MXPA05008425A patent/MXPA05008425A/es unknown
  • 2004-01-29 EP EP04706250A patent/EP1605942A1/en not_active Withdrawn
  • 2004-01-29 JP JP2006502411A patent/JP2006517221A/ja active Pending
  • 2004-01-29 WO PCT/IB2004/000313 patent/WO2004069251A1/en not_active Application Discontinuation
  • 2004-01-29 BR BR0407174-3A patent/BRPI0407174A/pt not_active IP Right Cessation
  • 2004-02-05 CL CL200400202A patent/CL2004000202A1/es unknown
  • 2004-02-09 AR ARP040100399A patent/AR043133A1/es unknown
  • 2004-02-09 PE PE2004000146A patent/PE20040948A1/es not_active Application Discontinuation
  • 2004-02-09 PA PA20048595301A patent/PA8595301A1/es unknown
  • 2004-02-09 TW TW093102921A patent/TW200423922A/zh unknown
  • 2004-02-10 UY UY28183A patent/UY28183A1/es not_active Application Discontinuation
  • 2004-02-10 NL NL1025449A patent/NL1025449C2/nl not_active IP Right Cessation

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