Evaluating Within-Subject Variability for Narrow Therapeutic Index Drugs

Area of Science:

• Pharmacokinetics and Bioequivalence Studies
• Drug Regulatory Science
• Pharmacogenomics

Background:

• The US FDA uses a reference-scaled average bioequivalence (RSABE) approach for narrow therapeutic index drugs (NTIDs).
• This method scales bioequivalence (BE) limits based on the within-subject variability (WSV) of the reference-listed drug.
• Understanding WSV is crucial for assessing drug product interchangeability, especially for NTIDs.

Purpose of the Study:

• To evaluate the within-subject variability (WSV) of warfarin (Coumadin) 10 mg.
• To assess the impact of WSV on bioequivalence testing using the FDA's RSABE approach.
• To determine the passing rates for mean and variability comparisons in bioequivalence tests for warfarin.

Main Methods:

• A clinical study administered 10 mg of warfarin to 10 healthy volunteers with similar CYP2C9 and VKORC1 alleles over 3 days.
• Individual intrasubject coefficients of variation for Cmax and AUC(0-72h) were calculated for R- and S-warfarin enantiomers.
• Two bioequivalence tests were performed using bootstrapped WSV distributions (1,000 replicates).

Main Results:

• Intrasubject CVs for R-warfarin ranged from 3.7-15% (Cmax) and 4.3-16.2% (AUC).
• Intrasubject CVs for S-warfarin ranged from 5.4-19.1% (Cmax) and 2.5-11.9% (AUC).
• Bioequivalence tests yielded passing rates of 95-97% for mean comparison and 84-87% for variability comparison.

Conclusions:

• The variability comparison passing rate was lower than anticipated for an NTID tested against itself.
• The observed passing rates suggest that the RSABE approach may offer additional assurance of bioequivalence for warfarin.
• Further evaluation of the RSABE method's sensitivity to variability is warranted for NTID drug products.