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Clin Pharmacol Ther. 2019 Feb;105(2):411-416. doi: 10.1002/cpt.1293. Epub 2019 Jan 16.

Evaluating Within-Subject Variability for Narrow Therapeutic Index Drugs.

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Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Silver Spring, Maryland, USA.


The US Food and Drug Administration (FDA) reference-scaled average bioequivalence approach scales the bioequivalence (BE) limits of narrow therapeutic index drugs (NTIDs) to the intrasubject or within-subject variability (WSV) of the reference-listed drug. A clinical study was conducted to evaluate the WSV of warfarin (Coumadin), 10 mg, administered to 10 healthy volunteers exhibiting similar cytochrome P450 2C9 and vitamin K epoxide reductase alleles on 3 study days. Individual intrasubject coefficients of variation for maximum plasma concentration and area under the curve (0-72 hour) ranged from 3.7-15% and from 4.3-16.2%, respectively (R-warfarin) and from 5.4-19.1% and from 2.5-11.9%, respectively (S-warfarin). Two BE tests were performed on a WSV distribution obtained by bootstrapping 1,000 replicates of the clinical data, yielding passing rates of 95-97% for the mean comparison and 84-87% for the variability comparison. The variability comparison passing rate was lower than expected for an NTID product tested against itself, but it may provide further assurance of BE.


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