1. POPULATION PHARMACOKINETICS RAYMOND MILLER, D.Sc. Pfizer Global Research and Development RAYMOND MILLER, D.Sc. Pfizer Global Research and Development

2. Population Pharmacokinetics Definition Advantages/Disadvantages Objectives of Population Analyses Impact in Drug Development

3. Population pharmacokinetics describe The typical relationships between physiology (both normal and disease altered) and pharmacokinetics, The interindividual variability in these relationships, and Their residual intraindividual variability. Sheiner-LB Drug-Metab-Rev. 1984; 15(1-2): 153-71 Definition

4. E.g.: A simple Pk model Ri = Cl·Cpss Cpss = Rate in / Rate out   Rate in = infusion rate Rate out = drug clearance  = measurement error, intra-individual error Drug Conc Time Definition

5. E.g.: A simple Pk model Cpss = Rate in / Rate out   Rate in = infusion rate Rate out = drug clearance  = measurement error, intra-individual error Drug Conc Time   N(0,  ) Definition

6. Cpss = Infusion rate / Cl CL = Infusion rate / Cpss Drug Conc Time Definition

7. Cl = metabolic clearance + renal clearance Cl =  1 +  2 CCr   Drug Clearance Creatinine Clearance Drug Conc Time Definition

8. Cl = metabolic clearance + renal clearance Cl =  1 +  2 CCr   Drug Clearance Creatinine Clearance   N(0,  ) Definition

9. Graphical illustration of the statistical model used in NONMEM for the special case of a one compartment model with first order absorption. (Vozeh et al. Eur J Clin Pharmacol 1982;23:445-451)

10. Mean, expected value, or some other point estimate: Variability among subjects around that mean: Residual (unexplained) variability and/or model misspecification: Definition

11. Responses on data input requirements from a questionnaire survey of producers of software for population pharmacokinetic-pharmacodynamic analysis Program Nature of input, Constraints Dosing histories specified in a flexible mannerHow is covariate information specified? BUGS ASCII, S-Plus data set User has to supply code Variable in data set MIXNLIN SAS data set User has to supply code Classified as inter- and intra-individual None, but must conform to covariates SAS conventions NLINMIX SAS data set User has to supply code Variables in the SAS data set NLME ASCII, spreadsheets and data basesUser has to supply code Variables in the data set NLMIX ASCII, user responsible for writing input routineUser has to supply code As for input NONMEM ASCII Yes (specified by the routine PREDPP)Variables in the data set None (some dimensions are initially set but these may be changed by the user) NPEM ASCII via USC*PACK programYes Either linked to a pharmacokinetic 99 days of time, 99 doses,or numerical value. Interpolation 99 values of dependentbetween covariate values is possible variables (maximum of 6) NPMLASCII User has to supply code Variables in the data set PPHARM Dedicated data base ASCIIYes Variables in data base or in ASCII file

12. Objectives 1. Provide Estimates of Population PK Parameters (CL, V) - Fixed Effects 2. Provide Estimates of Variability - Random Effects Intersubject Variability Interoccasion Variability (Day to Day Variability) Residual Variability (Intrasubject Variability, Measurement Error, Model Misspecification)

13. Objectives 3. Identify Factors that are Important Determinants of Intersubject Variability Demographic: Age, Body Weight or Surface Area, gender, race Genetic: CYP2D6, CYP2C19 Environmental: Smoking, Diet Physiological/Pathophysiological: Renal (Creatinine Clearance) or Hepatic impairment, Disease State Concomitant Drugs Other Factors: Meals, Circadian Variation, Formulations

14. Advantages Sparse Sampling Strategy (2-3 concentrations/subject) –Routine Sampling in Phase II/III Studies –Special Populations (Pediatrics, Elderly) Large Number of Patients –Fewer restrictions on inclusion/exclusion criteria Unbalanced Design –Different number of samples/subject Target Patient Population –Representative of the Population to be Treated

15. Disadvantages Quality Control of Data –Dose and Sample Times/Sample Handling/ Inexperienced Clinical Staff Timing of Analytical Results/Data Analyses Complex Methodology –Optimal Study Design (Simulations) –Data Analysis Resource Allocation Unclear Cost/Benefit Ratio

16. Drug Conc Time Models are critical in sparse sampling situations:

17. Drug Conc Time Models are critical in sparse sampling situations:

18. Drug Conc Time Models are critical in sparse sampling situations:

19. Drug Conc Time Models are critical in sparse sampling situations:

20. Drug Conc Time Models are critical in sparse sampling situations:

21. Drug Conc Time Models are critical in sparse sampling situations:

22. Study Objectives  To evaluate the efficacy of drug treatment or placebo as add on treatment in patients with partial seizures.

23. Data Structure

24. BaselinePlacebo

25. Count Model represents the expected number of events per unit time E(Yij)= i t ij The natural estimator of is the overall observed rate for the group.

26. Suppose there are typically 5 occurrences per month in a group of patients:- =5

27. The mean number of seizure episodes per month (λ) was modeled using NONMEM as a function of drug dose, placebo, baseline and subject specific random effects. Baseline = estimated number of seizures reported during baseline period Placebo = function describing placebo response Drug = function describing the drug effect  = random effect

28. Sub-population analysis  Some patients are refractory to any particular drug at any dose.  Interest is in dose-response in patients that respond  Useful in adjusting dose in patients who would benefit from treatment  Investigate the possibility of at least two sub- populations.

29. Population A (p) Population B (1-p) Mixture Model A model that implicitly assumes that some fraction p of the population has one set of typical values of response, and that the remaining fraction 1-p has another set of typical values

30. Final Model

33. Expected percent reduction in seizure frequency  Monte Carlo simulation using parameters and variance for Subgroup A  8852 individuals (51% female)  % reduction from baseline seizure frequency calculated  Percentiles calculated for % reduction in seizure frequency at each dose

35. Impact in Drug Development  Gabapentin was recently approved by FDA for post-herpetic neuralgia  Approved label states under clinical studies: “Pharmacokinetic- pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses”

36. PHN Study Designs  Used all daily pain scores  Exposure-Response analysis utilized titration data for within-subject dose response

37. Fits to Data Time Dependent Placebo Response, Emax Drug Response and Saturable Absorption,

39. Outcomes  Model and Data Provided with Submission FDA reviewers used model to test various scenarios Supported doses and conclusions of Pfizer Provided confidence to eliminate need for replicate doses FDA proposed language in the label on PK-PD modeling and clinical trials  FDA/Pfizer publication to discuss modeling and impact on regulatory decision-making clinical endpoints similar study design familiarity with drug class