Pharmacokinetics and generic drug switching: a regulators view

Generics/Research | Posted 13/11/2020 post-comment0 Post your comment

Researchers from the Netherlands share their view on the pharmacokinetic aspects of generic drug switching, from a regulatory perspective. They argue that there is no reason to change the current average bioequivalence-based approval pathway for generics [1].

Pharmacokinetics 1 V13K15

Registration of a generic drug requires demonstration of bioequivalence – statistical proof of comparable bioavailability – to the originator. Requirements for bioequivalence have been in use since the 1970s but have been debated ever since. Particularly the width of the acceptance range for the confidence interval (usually 80%‒125%) is an issue for discussion. Also, the use of healthy subjects in bioequivalence studies is often seen as an argument against extrapolation of bioequivalence to the intended patient population. Such doubts on bioequivalence, and interchangeability of generics, are fueled by the observation of clinical discomfort following generic drug switches. Case reports of adverse drug reactions following a drug switch have been published, as well as bigger studies such as an article by Concordet et al. [2], in which the occurrence of more than 30,000 adverse drug reactions following a switch between levothyroxine drug products.

So, what causes these real-world observations, and could the explanation indeed be found in the pharmacokinetics aspects of generic drug approval?

Bioequivalence is based on study population averages. Nonetheless, individual subjects will often have an individual exposure ratio outside the acceptance criteria, which is frequently observed in bioequivalence studies filed for regulatory approval of generics as well. However, it is crucial to realize that the same phenomenon occurs when comparing the exposure of two repeated administrations of the same brand-name or generic drug; therefore, this finding is merely a reflection of the daily clinical situation upon treating a patient, with his or her inherent within-subject variability leading to different exposures per occasion, than a reflection of differences in the quality and/or exposure of a generic drug.

The authors indicate that the reported clinical discomfort during a bioequivalent drug switch could very well be caused by these different exposures to the active substance. However, these differences are not attributable to differences between the originator and switched drug but are merely due to the within-subject pharmacokinetic variability of the active substance involved. In other words, the variation in exposure following a switch from a brand-name drug to a generic drug is comparable to that observed upon repeated administration of either the brand-name drug or the generic drug.

The authors conclude that there is currently no evidence to support a change in the regulatory approach to the evaluation of bioequivalence, and it can safely be assumed that switching from a brand-name drug to an approved generic drug, or between different generics, will result in comparable exposure within boundaries determined by the within-subject variability of the pharmacokinetics of the active substance involved.

Conflict of interest
Some of the authors of the research paper [1] are full-time employees of the Medicines Evaluation Board in the Netherlands. The other authors declared that there was no conflict of interest. For full details of the authors’ conflict of interest, see the research paper [1].

Abstracted by Pieter Glerum from the Medicines Evaluation Board, CBG-MEB, Utrecht, The Netherlands and the Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Editor’s comment
Readers interested to learn more about bioequivalence and switching to generics are invited to visit to view the following manuscript published in GaBI Journal:

Interchangeability of gabapentin generic formulations in The Netherlands: summary of a comparative bioavailability study

GaBI Journal is indexed in Embase, Scopus, Emerging Sources Citation Index and more.

Readers interested in contributing a research or perspective paper to GaBI Journal – an independent, peer reviewed academic journal – please send us your submission here.

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1. Glerum PJ, Neef C, Burger DM, et al. Pharmacokinetics and generic drug switching: a regulator's view. Clin Pharmacokinet. 2020;59(9):1065-9.
2. Concordet D, Gandia P, Montastruc JL, Bousquet-Melou A, Lees P, Ferran A, et al. Levothyrox® new and old formulations: are they switchable for millions of patients? Clin Pharmacokinet. 2019;58(7):827-33.

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