Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs

Pieter J Glerum; Walter M Yamada; Michael N Neely; David M Burger; Marc Maliepaard; Cees Neef

doi:10.1111/bcp.15629

Interchangeability of generic drugs for subpopulations: Bioequivalence simulation from a nonparametric PK model of gabapentin generic drugs

Br J Clin Pharmacol. 2022 Dec 8. doi: 10.1111/bcp.15629. Online ahead of print.

Authors

Pieter J Glerum^{1

2}, Walter M Yamada³, Michael N Neely³, David M Burger⁴, Marc Maliepaard^{1

5}, Cees Neef⁶

Affiliations

¹ Medicines Evaluation Board, Utrecht, The Netherlands.
² Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre+, Maastricht, The Netherlands.
³ Laboratory of Applied Pharmacokinetics and Bioinformatics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA.
⁴ Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁵ Department of Pharmacology and Toxicology, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁶ Department of Clinical Pharmacy and Toxicology, CARIM, Maastricht University, Maastricht, The Netherlands.

PMID: 36482842
DOI: 10.1111/bcp.15629

Abstract

Patients are often switched between generic formulations of the same drug, but in some cases generic interchangeability is questioned. For generic drugs to be approved, bioequivalence with the innovator drug should be demonstrated, but evidence of bioequivalence is not required in the intended patient population or relative to other approved generics.

Aim: We aim to identify pathophysiological pharmacokinetic subpopulations for whom there is a difference in comparative bioavailability compared to a healthy population.

Methods: We used simulated exposures from a nonparametric model of multiple generics and the originator gabapentin. Exposure was simulated for virtual populations with pharmacokinetic characteristics beyond those of healthy subjects with regard to rate of absorption, volume of distribution and reduced renal function. Virtual parallel design bioequivalence studies were performed using a random sample of 24 simulated subjects, with standard acceptance criteria.

Results: Results indicated increased pharmacokinetic variability for patient populations with a lower rate of absorption or a reduced renal function, but no change in the average comparable bioavailability ratio. This increased variability results in a reduced likelihood of demonstrating bioequivalence. Observations were similar for comparisons between all different formulations, as well as between subjects who received the identical formulation in a repeated fashion. No relevant effect was observed for simulations with increased volume of distribution.

Conclusion: Our simulations indicate that the reduced likelihood of demonstrating bioequivalence for subjects with altered pharmacokinetics is not influenced by a formulation switch, nor does the average comparable bioavailability ratio change, therefore these results support generic interchangeability and current approval requirements for generics.

Keywords: bioequivalence; gabapentin; generic drug; interchangeability; nonparametric model; simulation; switching.