How to Use a Reference-scaled Average Bioequivalence Approach for Narrow Therapeutic Index Drugs

The standard approach for approval of generic drugs is to run a bioequivalence study to demonstrate that a generic product is comparable to an approved (i.e., reference) drug in their rate and extent of absorption. The rate and extent of drug absorption are determined from the pharmacokinetic parameters: peak concentration (Cmax) and the area under the concentration-time curve (AUC) respectively. The approach is referred to as average bioequivalence (ABE) where the 90% confidence interval for the ratio of the average geometric means (test/reference) for AUC and Cmax must fall between preset regulatory bioequivalence limits from 80% to 125%.

Drugs with a narrow therapeutic index (NTIDs) have a narrow range between therapeutic and toxic dose levels. Traditional ABE methodology may be unacceptable for NTIDs because small differences in drug exposure may lead to serious therapeutic failures and/or adverse drug reactions. The usual average ABE limits are not considered sufficient for NTIDs, and several regulatory agencies have narrowed the limits for bioequivalence.

The US FDA guidance for warfarin sodium (2012) proposed a new bioequivalence methodology for NTIDs as an extension of reference-scaled average bioequivalence (RSABE) to scale bioequivalence limits to the within-subject variability of the reference product and to compare within-subject variabilities of test and reference products.

A Phoenix template workflow was created to analyze narrow NTIDs per the FDA’s Warfarin Guidance criteria. Watch this webinar to learn how RSABE for NTIDs can be performed in Phoenix WinNonlin using this reusable template. Because the template projects require minimal user input to be used with any input dataset from a replicated 4-period crossover design, they can provide significant time savings and increased efficiency to users!