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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
  • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
• • G—PHYSICS
  • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
  • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
  • G16H70/00—ICT specially adapted for the handling or processing of medical references
  • G16H70/40—ICT specially adapted for the handling or processing of medical references relating to drugs, e.g. their side effects or intended usage

Definitions

• the present invention generally relates to treating attention-deficit disorders (e.g.,
• ADHD by providing an effective amount of an ADHD-effective agent to a patient in need thereof
• the invention relates to the treatment of Attention Deficit Hyperactivity Disorder (ADHD) by providing an effective amount of a dosage form.
• ADHD Attention Deficit Hyperactivity Disorder
• the invention provides a method for determining an effective amount of a methylphenidate formulation for administration to an individual.
• ADD Attention Deficit Disorder
• ADHD ADHD
• ADDERALL® and RITALIN® are administered two or three times a day.
• WO 2015/188092 describes that "the recommended dosing regimen begins with a titration regimen, starting the patient at a low dose for seven days, followed by weekly upward adjustments until the optimal response is reached.” Additionally, the publication describes that "[i]t is known that clearance of methylphenidate is an important factor in reaching and maintaining therapeutically effective levels of MPH in a patient. However, it is also known that drug clearance in children and adults does not always correlate well with their total body weight.” While the publication describes a dosing regimen for the specific formulation utilized, there is still a need for dosing regimens for other formulations of methylphenidate products.
• the invention provides methods of treating a patient comprising administering an effective amount of a drug composition, wherein the effective amount of the drug composition is calculated based on a pharmacokinetic-pharmacodynamic correlation (PK-PD correlation).
• the invention provides for methods of treating a patient in need thereof (e.g., a child) with an effective amount of an oral composition that provides effective, prolonged treatment.
• the invention provides methods of establishing an effective amount of a drug formulation for treating an individual patient (e.g., a child) in need of treatment for a disease (e.g., ADHD or ADD).
• the effective amount of the oral composition can be calculated for any individual patient in need thereof (e.g., a child) based on the P -PD correlation.
• the PK-PD correlation for the drug formulation can be adjusted based on a predictive factor (e.g. the weight of the patient) as a representative adjustment factor to reduce error in the PK-PD correlation.
• the effective amount of the composition for the individual patient in need thereof may be administered once-a-day as a single or multiple unit dose.
• the effective amount of the drug formulation is calculated by:
• the calculation of the predicted serum concentration of the active component in the drug formulation in the second test population based on the generated pharmacokinetic equation and the measuring of the pharmacodynamic effect of the active component in the drug formulation are used to produce a PK-PD correlation.
• one or more predictive factors can be included in the PK-PD correlation of the drug formulation as a representative adjustment factor to reduce error in the PK- PD correlation.
• the predictive factor is the weight of the individual patient.
• the dosage chart is a printed or digital dosage chart that provides the effective amount of the dosage form for particular patients or groups of patients.
• a physician is able to predict the effective dosage for an individual patient by consulting a dosage chart.
• the in vivo serum profiles of the composition are correlated to the in vitro dissolution profile of the composition.
• a physician is able to predict the in vivo serum profile by the in vitro dissolution profile of the composition, when the weight of the patient is considered for dosing.
• an "ADHD effective agent” is any agent effective to treat ADHD or ADD in any patient population (e.g., children, adolescents, adults), wherein the agent includes stimulants such as methylphenidate, and its optical isomers, or any combination that comprises at least one of these agents. As discussed herein, ADHD effective agents may also be used in the effective treatment of other conditions such as fatigue, obesity and for imparting alertness.
• an "effective amount" of the ADHD effective agent e.g., methylphenidate
• an "effective amount" of the ADHD effective agent is an amount that, when administered to a patient in need, provides the desired effect on the disease pathophysiology.
• a "reference composition” is a product defined in any relevant example from WO 2013/003622, which is incorporated herein by reference.
• controlled release means the time course of drug appearance in medium surrounding the composition is modified compared to an immediate release composition.
• Controlled release encompasses "delayed release” and "extended release” formulations.
• delayed release means that appearance of drug in the medium surrounding the composition occurs after a time lapse.
• An example of a delayed release coating is a triggered- release coating.
• a "triggered-release coating” is a coating that degrades as a result of a triggering event, where the triggering event is a change in the physiological environment of surrounding the triggered-release coating.
• Triggering events include, but are not limited to, a pH change which occurs upon transit from one stage to another stage in a subject's gastrointestinal (GI) tract, an enzyme secreted in a particular region in a subject's GI tract, or enzymatic presence in digestion.
• extended release means that the rate of release is slower than the rate for an immediate release or delayed release composition from the initial point of release.
• immediate release means the initial period during which drug is released from the composition that does not involve delayed or extended release but may include taste- masking.
• a "subject” means any animal, but is preferably a mammal, such as, for example, a human.
• substantially all in the context of drug release, means 90% or more.
• substantially similar parameters have values within—20%/ +25% of each other.
• Measures of bioavailability well known in the art include the area under the plasma concentration-time curve (AUC), the concentration maximum (C max ), and the time to C max (T max ).
• AUC is a measurement of the area under the plasma concentration-time curve (e.g., serum concentration profile), and is representative of the amount of drug absorbed following
• C max is the maximum plasma concentration achieved after oral drug administration (see Remington, page 999).
• An oral drug administration results in at least one C max , but may result in more than one "peak plasma concentration” or "plasma concentration peak” (for example, following the administration of a pulsed dose formulation).
• T max is the amount of time necessary to achieve the C max after oral drug administration, and is related to the rate of absorption of a drug (see Remington, page 999).
• Bioequivalence can be measured by pharmacokinetic parameters such as, for example, AUC and C max .
• pharmacokinetic parameters such as, for example, AUC and C max .
• a product is bioequivalent to a reference product if the 90% confidence intervals of the relative mean AUC, C max , and T max of the test formulation are within 80% to 125% (-20%/ +25%) of the reference formulation drug when administered in the fasting state.
• bioequivalence is the absence of a significantly different rate and extent of absorption in the availability of the active ingredient when administered at the same dose under similar conditions.
• bioequivalence may be established by comparing a test drug to a reference drug by comparing partial AUCs (e.g., over statistically or clinically relevant time intervals).
• This bioequivalence measure based partial AUCs may be used alone or in combination with the bioequivalence measures discussed above.
• Pharmacokinetics describes the appearance and disappearance of a drug in the patient's body; pharmacodynamics correlates the drug concentration at the site of action to the physiological effect. For both concepts, the time course after dosing is important. However, determining the effective amount of a drug formulation for a child at a given stage in the growth and development period requires determining the pharmacodynamics of the drug formulation for the child at the given stage of growth and development. More specifically, the relationship, or a correlation, between the pharmacokinetics (PK) and pharmacodynamics (PD) of a given drug formulation for the patient at the given stage of growth and development must be determined.
• PK pharmacokinetics
• PD pharmacodynamics
• the present invention relates to generating a dosage chart for an individual patient (e.g., child) by determining the pharmacokinetics of a drug formulation in a group of patients and, from that data, generating a predictive formula based on the drug dosage and the pharmacokinetic measurement over time elapsed since administration of the drug formulation.
• pharmacodynamics of the drug formulation can then be measured for a group of patients, and the predictive formula for the pharmacokinetic measurement can be compared to the data from the pharmacodynamic measurements.
• the group of patients used to gather the pharmacokinetic data may be different from the group of patients used to gather the pharmacodynamic data.
• the group of patients used to gather the pharmacokinetic data may be the same group of patients used to gather the pharmacodynamic data as long as the pharmacokinetic data is gathered at a separate time from the pharmacodynamic data.
• the PK-PD correlation of the drug formulation can be determined based on this comparison of the predictive formula for the pharmacokinetic measurement and the measured pharmacodynamic data over the same elapsed time since drug administration.
• This PK-PD correlation of the drug formulation can be used to calculate the dosing regimen for an individual patient.
• the dosing regimen for an individual patient may be based on predictive factors for the individual patient, such as height, weight, body mass index (BMI), volume of the systemic circulation, age, gender, etc.
• the invention provides for methods of determining an effective amount of a pharmaceutical methylphenidate formulation for administration to an individual (e.g., a child). If the
• methylphenidate formulation is being administered to a child
• the ever-changing body volume of the child as the child grows can impact the effective amount of the methylphenidate formulation for that child at any given point in the growth period.
• the relative activities of various enzyme systems can change over the growth and development of the child. Accordingly, in response to these changes, the drug dosage must be changed as the child grows and develops, to continue administering an effective amount of the drug for the child over time.
• PK model for a PK model
• methylphenidate plasma concentrations of compositions comprising an immediate release component and a controlled release component Concentrations following administration of methylphenidate may be described by the following:
• the parameters are the dose fraction absorbed via the immediate release component of the formulation (Fl), the lag time of the controlled release component of the formulation (t hg ), the first- order rate constant for the immediate release component of the formulation (Ka Im ), the first-order rate constant for the controlled release component of the formulation (Ka Ext ), the apparent volume of methylphenidate distribution (V) and the apparent plasma clearance of methylphenidate (CL).
• the selection of parameters and calculation of values for the parameters can be determined by measuring a serum concentration for each individual in a test population, and then fitting the serum concentration time data to a PK model using a nonlinear mixed-effects modeling program with first-order conditional maximum likelihood estimation to find the best set of parameter values for the observed data.
• the pharmacodynamics of the formulation can be determined using methods known to one of ordinary skill in the art, such as determining S AMP, and/ or PERMP scores at various times after administration of the test formulation.
• SKAMP scores are described in Wigal et al, Effect of Reinforcement on Facial Responsivity and Persistence in Children with Attention-Deficit Hyperactivity Disorder, Behavior Modification (April 1998), Vol. 22, No. 2, pp. 143-166, incorporated herein in its entirety.
• PERMP scores are described in Wigal et al., Randomised, Double-Blind, Placebo-Controlled, Crossover Study of the Efficacy and Safety ofUsdexamfetamine D mesylate in Adults with Attention-Deficit/ 'Hyperactivity Disorder Novel Findings Using a Simulated Adult Workplace Environment Design, Behavioral and Brain Functions (2010), Vol. 6, p. 34, incorporated herein in its entirety.
• the determination of the pharmacokinetics and the determination of the pharmacodynamics of a drug formulation do not need to be done at the same time, or on the same patient population.
• the PK-PD correlation is not artificially skewed (e.g., by the sampling bias related to a needle producing artificial adrenaline responses).
• a dosing regimen can be generated based on a PK-PD correlation for any of the drug formulations described herein by: measuring serum concentration at various times after dose administration for each individual in a first test population for a pharmaceutical active component in a drug formulation, generating a pharmacokinetic equation describing the serum concentration profile for the drug formulation where the pharmacokinetic equation is characterized by several pharmacokinetic parameters determined by fitting the pharmacokinetic equation to the measured serum concentrations for the first test population, measuring a pharmacodynamic effect of the active component in the drug formulation at various times in a second test population, calculating a predicted serum concentration of the active component in the drug formulation in the second test population based on the generated pharmacokinetic equation, fitting the generated data of the pharmacodynamic effect and the predicted serum concentrations for each point in time to produce a PK-PD correlation, and generating a dosage chart describing the effective amount of the drug formulation.
• the drug formulation contains methylphenidate, and, optionally, an ion- resin.
• the first test population and the second test population comprise different individual subjects.
• the measurement of the serum concentration can be done at a different time than the measurement of the pharmacodynamic effect.
• the PK-PD correlation is further predictive of the effective amount of the composition for an individual patient in need thereof (e.g., a child) when a predictive factor is included in the calculation as a representative adjustment factor to reduce error in the PK- PD correlation.
• the predictive factor can be on or more of a patient's weight, a patient's sex, a patient's age, or systemic volume.
• the predictive factor of weight alone was sufficient to adequately reduce the error in the PK-PD correlation (without needing to factor in other covariates such as body-mass index (BMI), sex, age, etc.).
• the physician can establish a dosing regimen for an individual patient based on the PK-PD correlation, and, optionally, based on the predictive factor for the individual patient.
• the dosing regimen for an individual patient can be individualized by one or more predictive factors for that individual patient.
• the physician administers to a patient an effective amount of a formulation that provides the in vivo release profiles described herein, wherein the effective amount is based on the PK-PD correlation and a predictive factor, wherein the predictive factor is the patient's weight, the patient's age, or a combination of the patient's weight and sex.
• a dosage chart can be formulated using the methods described herein.
• a dosage chart can be formulated by determining the pharmacokinetics of a formulation (e.g., calculating Fl, t 13 ⁇ 4 , Ka Im , Ka E ,. t , V, and CL), determining the pharmacokinetics of a formulation (e.g., calculating Fl, t 13 ⁇ 4 , Ka Im , Ka E ,. t , V, and CL), determining the pharmacokinetics of a formulation (e.g., calculating Fl, t 13 ⁇ 4 , Ka Im , Ka E ,. t , V, and CL), determining the pharmacokinetics of a formulation (e.g., calculating Fl, t 13 ⁇ 4 , Ka Im , Ka E ,. t , V, and CL), determining the pharmacokinetics of a formulation (e.g., calculating Fl, t 13 ⁇ 4 , Ka Im , Ka E ,. t
• pharmacodynamics of the formulation e.g., measuring the SKAMP or PERMP scores
• generating a PK-PD correlation based on a predictive factor e.g., weight of the individual patient
• determining the effective dose for an individual patient based on the output e.g., measuring the SKAMP or PERMP scores
• the chart may describe the amount of methylphenidate
• the pharmacodynamic measurement is a psychological measurement, that may relate to measuring pain, sleep, attention, impotence, or measurements related to disorders of the central nervous system.
• a patient in need thereof e.g., a child
• an effective amount of an ADHD-effective agent in accordance with a dosage chart.
• the patient in need thereof e.g., the child
• an effective amount of the formulation based on the following table:
• a physician may prescribe a dose of methylphenidate for a patient in need thereof (e.g., a child) for the treatment of ADHD by: determining the body weight of the patient, referring to the chart above that correlates body weight ranges with a number of dosage amounts having a different level of methylphenidate, identifying the corresponding dosage amount to the body weight of the patient, and administering to the patient the dosage amount.
• the invention provides for methods of treating a patient in need thereof (e.g., a child) with an effective amount of an ADHD-effective agent (e.g., methylphenidate) where the ADHD- effective agent is formulated to provide the in vivo release profile described herein.
• an ADHD-effective agent e.g., methylphenidate
• Methylphenidate formulations which have in vivo release profiles suitable for the present invention are described in one or more of the following: U.S. Pat. Nos.
• the invention provides methods of treating a patient in need thereof (e.g., a child) with compositions having various drug (e.g., ADHD effective agent) release profiles.
• the compositions may be administered in the morning and have therapeutically effective activity throughout the course of the day.
• the composition is
• the ADHD effective agent e.g., methylphenidate
• the composition will continue to be therapeutically effective throughout the day including the mid- afternoon, when children tend to be fatigued.
• the compositions described herein typically have an escalating in vivo serum profile early in the therapeutic time course.
• the patient in need thereof is administered a composition having an in vivo serum profile bioequivalent to the profile of a reference composition.
• the composition has one or more parameters (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or eleven parameters) selected from AUC 0 . , AUC 0 _ 5 , AUC .12 , AUC 5.12 , AUC 5.T (AUC 5.HST ), AUC 0.12 , AUC Q ., , AUC 0.t , AUC Q. ⁇ , C RA X , and/ or T max which meet the bioequivalence conditions for a reference composition.
• the invention provides for methods of treating a patient in need thereof (e.g., a child) by providing compositions in which the rate of appearance of the ADHD effective agent (e.g., methylphenidate) in a dissolution medium increases after a period of decrease in the rate of appearance of the drug in the dissolution medium.
• the compositions typically contain an immediate release and delayed release portion. The immediate release portion, in an in vitro
• dissolution assay contributes to an initial release of ADHD effective agent (e.g., 30-60%) within an initial time period (e.g., 0.5, 1, 1.5, 2, or 2.25 hours from when the composition is introduced into the dissolution medium).
• an initial time period e.g., 0.5, 1, 1.5, 2, or 2.25 hours from when the composition is introduced into the dissolution medium.
• the release rate of ADHD effective agent will decrease or level off.
• the delayed release portion will release and the amount of ADHD effective agent released increases until, e.g., 80% or more of the ADHD effective agent is released.
• the first and second time points will vary depending on the ADHD effective agent, coatings used, and ratio of immediate and delayed release components of the composition.
• the drug e.g., ADHD effective agent such as methylphenidate
• the conditions of the dissolution assay may be an initial dissolution medium of 0.1 NHCL, and after 2 hours, the medium is adjusted to a pH which triggers the triggered release coating, e.g., pH of ⁇ 6.8; and dissolution testing is performed using a USP Apparatus 2.
• the pH is adjusted to e.g., pH 6.8, 7, etc.
• the invention also provides for methods of treating a patient in need thereof (e.g., a child) by providing compositions in which the composition achieves an ascending plasma concentration of the drug (e.g., methylphenidate during a time period) after a therapeutically effective level is reached.
• a therapeutically effective level is reached within one, two, or three hours after ingestion of the composition.
• the plasma concentration of drug increases due to additional release of drug from the composition to a peak drug concentration level.
• clearance of drug will result in a decrease in plasma level between these two releases, resulting in two successive peak drug levels.
• the timing of the two releases is close enough that no decrease is observed.
• the in vivo plasma concentration profile is preferably bimodal with two peaks.
• the first peak may be achieved, between 1 to 3, 1 to 2.5, or 1 to 2 hours after ingestion of the composition.
• the second peak may be achieved 4 to 7, 4 to 6, or 4 to 5 hours after ingestion of the composition.
• the first or second peak may be the C max .
• the composition may have an in vivo serum profile that reaches a therapeutically effective level fairly rapidly (1-3 hours) and them continues to increase more slowly up to a maximum serum level between 4 hours and 7 hours after ingestion. It will be appreciated that the therapeutic and peak drug concentration level will vary depending on the subject, drug, coatings used, and ratio of coatings.
• compositions administered to the patient in need thereof may include various coatings and components (e.g., particles coated with a delayed release coating, particles coated with an extended release coating, particles coated with an sustained release coating, etc.).
• the formulation that provides the in vivo release profiles described herein may include components of any of the following: a delayed release component (e.g., contains delayed release coating), an immediate release component (e.g, an uncoated component), an extended release component, a sustained release component (e.g., comprising a water-insoluble, water-impermeable, pH independent, barrier coated ion-exchange resin complex), a modified release component (e.g., comprising a matrix), or combinations thereof.
• a delayed release component e.g., contains delayed release coating
• an immediate release component e.g, an uncoated component
• an extended release component e.g., a sustained release component (e.g., comprising a water-insoluble, water-impermeable, pH independent, barrier coated ion-exchange resin complex), a modified release component (e.g., comprising a matrix), or combinations thereof.
• a sustained release component e.g., comprising a water-insoluble, water-imper
• a physician is assisted in prescribing a dose of methylphenidate for the treatment of attention deficit hyperactivity disorder (ADHD) in an individual patient by a method comprising: determining the body weight of said individual patient; referring to a chart or reference tool that correlates a plurality of body weight ranges with a corresponding number of dosage amounts, each having a different level of methylphenidate; identifying a single dosage amount corresponding to a particular weight range in which said individual patient's weight falls in the chart or reference tool; and administering to said individual patient the identified dosage amount.
• the individual dosage amount can be based on the following chart:
• This example describes the development of a pharmacokinetic -pharmacodynamic model for the therapeutic effect of a particular methylphenidate formulation and its testing on a population of pediatric patients with ADHD.
• the drug formulation tested in this example is designated MPH X -ODT and described in U.S. Publication No. 2014/0030348, which is incorporated herein by reference.
• the fast release depot represents the immediate release portion of the formulation that is readily absorbed into the plasma using a first-order rate constant (Kalm).
• Kalm first-order rate constant
• Fr relative bioavailability parameter
• the slow release depot represents an extended release core that slowly releases drug following water permeation into the product core.
• the slow release was presumed to follow first- order absorption kinetics (KaExt).
• KaExt first- order absorption kinetics
• tlag lag time
• the fraction of dose released from an extended release core was estimated as 1-Fl.
• V t tvV * Weight 0 670 Equation 2
• CL, and V are the clearance and volume of distribution parameters for individual "i”
• tvCL and tvV are the typical population clearance and volume of distribution parameters
• weight is body weight in kg.
• Model parameters were determined using nonlinear mixed-effects modeling with first-order conditional maximum likelihood estimation using Phoenix NLME (Version 6.3).
• E BSL - DE + PE Equation 3
• E the observed SKAMP total score
• BSL the SKAMP total score just prior to dose administration under the classroom setting on Day 7 (Visit 8)
• DE the reduction in SKAMP total score due to the presence of methylphenidate
• PE the increase in SKAMP total score due to the placebo or classroom procedures.
• Equation 4 The drug effect (DE) was modeled using an E max equation as shown below: Equation 4
• E max is the maximum decrease in SKAMP total score
• C p is the plasma methylphenidate concentration
• EC 50 is the concentration of methylphenidate required to eiicit 50% of the maximal reduction in SKAMP total score.
• PE Slope * t Equation 5 where Slope is the rate of change in SKAMP total score with time, and t is the time after dose administration. While a variety of models were evaluated, this linear model was adequate to fit the observed data from the patients assigned to the placebo treatment.
• the PK and PD structural models were linked using a direct effect model.
• a direct effect model the effect direcdy correlated to the measured plasma concentrations of the drug.
• Plasma sampling for determination of methylphenidate concentrations was not performed, due to the potential impact of multiple venipunctures on the efficacy outcomes.
• the addition of plasma sampling procedures is expected to cause anxiety for the pediatric patients, and it would negatively affect the SKAMP Combined score.
• a modeling and simulation analysis was conducted in place of blood sampling in the pediatric patients. Therefore, the plasma methylphenidate concentration-time profile was simulated for each patient in the study using the previously described pediatric PK model, and the final PK model parameter estimates.
• the simulated methylphenidate concentrations were then used to estimate the SKAMP Combined score using the PD structural model described above. As this was an integrated PKPD model, the simulation of plasma methylphenidate concentrations and the estimation of the PD parameters occurred during a single minimization procedure.
• the PK/PD mixed-effects model has two components:
• ⁇ 1 ⁇ the difference between the true value for individual I and the typical value for the population, with a mean of 0 and a variance of ⁇ 2'
• Cij Cij + e-iij Equation 8
• Cij A * (l + e 2 ij) Equation 9
• Sj, the additive residual error for the jth concentration for individual I, and is normally distributed with a mean of 0 and a variance of ⁇ , 2 .
• E 2l the proportional residual error for the jth measurement for individual I, and is normally distributed with a mean of 0 and a variance of ⁇ .
• the final analysis dataset for the PKPD model contained 640 SKAMP total score measurements from 81 pediatric patients. There were 53 (65.4%) male patients in the analysis dataset, and 42 (51.9%) patients received the formulation and the remaining 39 (48.1%) patients received placebo during the Day 7 classroom evaluation. The distribution of patients across the formulation dose range is shown in Table 1. [0076] Table 1 : Number of Patients at Each Dose Level and Treatment
• the integrated PKPD model with the PK and PD structural models was fit to the SKAMP total score measurements.
• the base PKPD model consists of 4 structural parameters, 3 between individual variability parameters, and a residual error parameter. These parameters are described below, respectively:
• EC50 is the concentration of methylphenidate required to achieve 50% of the maximal reduction in SKAMP total score
• Emax is the maximum reduction in SKAMP total score with administration of
• %CV percentage coefficient of variation calculated as standard deviation/estimate * 100
• %Shrinkage percentage shrinkage to mean parameter estimate calculated as 1- standard deviation/ estimate*100
• the objective of this analysis is to model the effect of methylphenidate on the SKAMP total score. While the finding that baseline SKAMP total scores are lower in older and heavier pediatric patients is statistically significant, the inclusion of a covariate on a baseline parameter does not provide additional information about the effects of methylphenidate. Therefore, these covariates were not included, and the Base PKPD model was considered the Final PKPD model. Posteriot Predictive Check of Final PKPD Model
• the posterior predictive check suggests that the final PKPD model can accurately predict the SKAMP total score over the 13-hour classroom test period.
• the final PKPD model was used to perform simulations of SKAMP total scores in pediatric patients. At each dose strength, 500 separate simulated profiles were produced across the weight range 15— 80 kg. Simulated SKAMP total score data was divided by dose level and body weight as shown in Table 3: Table 3: MPH XR-ODT Dose Levels and Patient Body Weight Groups
• Body weight groups are defined by the median of the range of body weights.
• the 20 kg group includes individuals between 17.5 kg and ⁇ 22.5 kg
• the 25 kg group includes individuals between 22.5 and ⁇ 27.5 kg.
• the mean baseline SICAMP total score was approximately 22 (E0 estimate of 21.99, Table 2). Therefore a decrease of 20 points in the SKAMP total score would represent a near complete reversal of the symptoms for the average patient, as measured by SKAMP.
• the data in Table 4 clearly show that patients who are heavier generally require a larger MPH XR-ODT dose.
• the beneficial effects of methylphenidate appear to plateau at higher doses in subjects such that increasing the MPH XR-ODT dose may not provide increased symptom control in some patients.
• the optimal MPH XR-ODT doses by body weight can be determined. A linear regression of those optimal doses versus body weight from the simulations was performed. The optimal doses for a range of body weights from 7-100 kg is presented in Table 5. Table 5: Optimal MPH XR-ODT Dose by Body Weight

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