Role of PBPK based virtual trials modeling in generic product development and regulation

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1 Role of PBPK based virtual trials modeling in generic product development and regulation Robert Lionberger, Ph.D. Director Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research, FDA AAPS Annual Meeting November 15, 2016

2 Need for Virtual BE Studies Predict what will happen In a specific study In a range of different regulatory and product development scenarios In a range of patient population or use scenarios Both FDA and industry would benefit from this capability 2

3 What is a Virtual BE Study? Use of model to compare test and reference formulations The model must have a formulation variable that can be adjusted to represent the difference between T and R The model generates a population for BE study, compares T and R in that population Simulate many studies to estimate probability of success or failure 3

4 Oral Absorption Models My scope today will be primarily for oral Although OGD needs this capability for non-oral The context for biopharmaceutics modeling and simulations in the generic drug framework is different than from modeling and simulation in drug discovery and development Much more knowledge about drug and human PK data often available 4 4

5 Models of formulation difference Simplest: use different ka for test and reference Example publications Concerns Ka has massive variability, cannot estimate it well in a poppk setting Ka pools formulation and physiology 5

6 Models of formulation difference More complex: ACAT to PBPK Separate absorption and formulation models Same absorption process Different drug release rates Current lack of confidence that in vitro dissolution provide the correct in vivo release rate Use virtual BE to simulate on potential differences of in vivo release 6

7 Factors Affecting Oral Absorption 7 7

8 Models of the Population Between subject variation is a common target of empirical population PK modeling (Nonmem) CL and its covariates Within subject variation is a rare target of empirical population PK modeling Ends up in residual variability Very limited repeated administration to the same subject To model a crossover BE study you need the within subject variability 8

9 Models of the Population Current approaches Ignore population and simulate the mean effect Create a virtual population of subject with different physiology and clearance In commercially available software Uncertainty on how to replicate the dose Use identical subjects Use subjects that have variability Add variation in all parameters 9

10 Don t Cross the Streams To do virtual BE studies you need to mix PBPK absorptions models Population models Traditionally separate areas of development Recent FDA grant award to Colorado 10

11 EXAMPLES OF VIRTUAL BE 11

12 FDA Uses Virtual BE Every guidance that has novel PK BE methodology For all of our own in vivo studies To evaluate sponsor submissions that propose alternative BE approaches 12

13 Novel BE Partial AUC for multiphasic MR products Locally acting GI drug bioequivalence Development of BE criteria for zolpidem tartrate ER tablets Steady state simulations for risperidone long acting injection Simulations for the development of BE criteria for complex drugs, HVDs and NTI drugs 13

14 FDA s Studies PK/PD modeling and simulation to determine the appropriate study design and evaluate BE between generic anti-epilepsy drugs and immunosuppressant drugs in patients. Warfarin BE 14

15 ANDA Review Examples BE standards for MR products (different mechanism between brand and generic) Waivers of lower strength products Risk of formulation changes (particle size, polymorphic form) Linkage from single dose to multiple dose Linkage from healthy subjects to patients 15

16 ANDA Review Examples PD modeling and simulation for budesonide nasal spray to support the selected dose for BE study. Simulation of in vivo alcohol dose dumping studies 16

17 Example BE Study Compare aged and properly stored product M&S predicts no impact on BE High risk drug (NTI) Conduct in vivo studies Pre study virtual BE prediction BE study results Drug has very low between subject variability 17

18 % Dissolved % Dissolved Do These Dissolution Differences Impact Bioavailability 2-stage ph Time (min) Time (min) 18

19 Pre-study Predictions Model predicts no significant impact to BE Pre-study estimated of BE results T vs R C max (%) AUC 0-72 (%) ABE RSABE ABE RSABE B vs C D vs C A vs C B vs D A vs B A vs D

20 In Vivo Study Results AUC 0-72 C max Primary Comparisons GMR 90% CI GMR 90% CI B vs. C (0.968, 1.030) (0.957, 1.059) C vs. D (0.965, 1.028) (0.941, 1.082) Secondary Comparisons A vs. C (0.979, 1.056) (0.906, 1.082) B vs. D (0.974, 1.056) (0.974, 1.056) A vs. B (0.990, 1.041) (0.916, 1.048) A vs. D (0.974, 1.056) (0.909, 1.116) 20

21 Future Use of Virtual BE Expand BCS class waivers Do we do too many fed BE studies? Describe what happens in steady state BE study Describe what would happen in a steady state BE study in patients Conclude risk in patient population that are not studied 21

22 WHAT DO WE NEED TO GET THERE? 22

23 Gaps for Oral Absorption Variability: For the generic drug program, simulation of a cross-over bioequivalence study is an important modeling and simulation application but current data sets and models of within subject variability for GI parameters lag the understanding of between subject variability. 23

24 Gaps for Oral Absorption Formulation: The interaction of formulation variables with physiological factors is important to the design of bioequivalent formulations. This includes improved prediction of food effect, prediction of bioavailability for complex formulations and solid dispersions, and prediction of bioavailability for nano-size formulations. 24

25 Gaps for Oral Absorption Physiology: Improving the modeling and simulation for colon absorption to fully account for the performance of modified release dosage forms. Improving knowledge of in vivo hydrodynamics is needed to improve the models and IVP dissolution 25

26 2013 GDUFA Research Prediction of In Vivo Performance for Oral Solid Dosage Forms Awarded to the University of Michigan (HHSF C) The purpose of this contract is to improve prediction of in vivo performance of oral solid dosage forms. The scope includes modeling of GI fluid hydrodynamics, sampling of GI tract fluids composition and ph, novel dissolution methods and in vivo PK studies to validate model predictions. Pharmacokinetic Study of Bupropion Hydrochloride Products with Different Release Patterns Awarded to University of Michigan (HHSF C) The objectives of this contract are to conduct healthy subject pharmacokinetic studies of bupropion HCl modified release products with different release patterns and different doses. This will help FDA understand how the release pattern of bupropion HCl products and the genotype of metabolic enzyme may affect the bioequivalence conclusions across different dose strengths within one product line due to the saturation of intestinal metabolism

27 2014 GDUFA Research Effect of Different Preparation Methods on the In Vitro and In Vivo Performance of Solid Dispersion Formulations Awarded to Purdue University, West Lafayette (1U01FD ). The study goal is to investigate the in vitro and in vivo performance of solid dispersion drug products originating from different manufacturing processes or polymer carriers and to assess performance consistency among batches and during storage. Study outcomes will identify critical process parameters and critical quality attributes for solid dispersion drug products originating from various preparation methods and will develop discriminating analytical methods for these drug products

28 2015 GDUFA Research Wireless Sampling Pill to Measure In Vivo Drug Dissolution in Gastrointestinal (GI) Tract and Computational Model Awarded to the University of Michigan (#HHSF ) The objective is to develop a wireless pharmaceutical analysis device (WPAD) that will acquire GI fluids directly at multiple sites throughout the GI tract in order to determine the in vivo drug dissolution profiles. Initial efforts focus on developing a prototype WPAD that will be tested in in vitro dissolution vessels and an in vivo canine model. The ability to determine GI drug concentrations will aid in the development of in vitro dissolution conditions that are in vivo predictive. The project will provide an innovative technological solution over traditional means (intubation studies) to measure GI drug concentrations and in vivo drug dissolution and provide concentration data through the entire GI tract including the colon. 28

29 2015 GDUFA Research In Vivo Predictive Dissolution (IPD) to Advance Oral Product Bioequivalence Regulation Awarded to the University of Michigan (#HHSF C) The objective of this project is to incorporate the most recent advances in gastroenterology, imaging technology, computational mass transport analysis, and development of in vivo predictive dissolution (IPD) methodologies into a gastrointestinal (GI) motility dependent (i.e. under fasted or fed conditions) predictive absorption method (i.e. oral absorption PBPK) for oral drug products. This project includes the use of MRI studies to measure water content in the GI tract. The study results will help the FDA determine the underlying GI variables in order to develop adequate in vitro dissolution methodologies that accurately represent the in vivo conditions. In addition, PBPK modeling and simulation can be improved for evaluating the BE of generic drug products, especially for locally GI-acting drugs. 29

30 2016 GDUFA Research Evaluation of formulation dependence of drug interaction with proton pump inhibitors (PPIs) Awarded to Biopharma Services USA Inc. (#HHSF I/HHSF T) The project aims to evaluate whether co-administration with PPIs/antacids will impact the bioequivalence of oral modified release products. PPIs/antacids are known to elevate gastric ph and potentially affect in vivo drug release, but there is minimal data on whether these effects are significant enough to impact conclusions of bioequivalence. The study results will help the Agency gain a better understanding of drug-drug interaction between oral modified release products and PPIs/antacids and establish =bioequivalence standards for generic oral extended release products. 30

31 2016 GDUFA Research Implementing population pharmacokinetic modeling algorithm in physiologically based pharmacokinetic (PBPK) models to allow parameter estimation at individual data level Awarded to Colorado State University (U01FD005838) The purpose of this project is to develop and implement a robust optimization algorithm that can be used to perform population-based statistical analysis in complex and computationally intensive PBPK models so that knowledge of parameter distributions in the population(s) of interest can be better informed. The developed models may be applied to generate improved predictions on the drug absorption and disposition from generic drug products to support generic drug development and regulatory reviews. 31

32 2016 GDUFA Research Integrating supersaturation-precipitation mechanisms in mechanistic oral absorption models for predicting in vivo performance Awarded to Simcyp Limited (1U01FD005862) The objectives of the study are to: 1) develop and establish a comprehensive mechanism-based absorption model to predict in vivo PK profiles of supersaturating formulations, and 2) to further establish an IVIVC for each of these drug products. The developed model will be used to gain mechanistic insights on the in vivo performance of oral supersaturating drug delivery systems. 32

33 Any Change in BE Standards should be evaluated by Virtual BE For FDA: Test sensitivity For Industry: Virtual BE studies could be submitted as a routine part of an request to use an alternative BE approaches. 33