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Evaluating Within‐Subject Variability for Narrow Therapeutic Index Drugs
Author(s) -
Jayachandran Priya,
Okochi Hideaki,
Frassetto Lynda A.,
Park Wansu,
Fang Lanyan,
Zhao Liang,
Benet Leslie Z.
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1293
Subject(s) - bioequivalence , warfarin , therapeutic index , medicine , pharmacology , cyp2c9 , pharmacokinetics , drug , cytochrome p450 , metabolism , atrial fibrillation
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.