The ratio of 1-hydroxymidazolam (1-OH MDZ) to midazolam (MDZ) plasma concentrations is not an accurate measurement for CYP3A activity when using oral (PO) MDZ

Abstract

Background The ratio of 1-OH MDZ to MDZ plasma concentrations has been proposed as an index to reduce sampling when measuring CYP3A activity. The aims of this study were to 1) assess if this ratio can be used to predict MDZ AUC when used as a CYP3A probe and 2) determine an optimal sampling strategy for the use of this ratio. Methods Data from 3 previous studies in 41 healthy adults were used. Subjects abstained from any drugs known to affect CYP3A. Plasma samples were collected at specified time points (Chr) after PO MDZ (0.075mg/kg) administration. 1-OH MDZ and MDZ concentrations were analyzed by LC/MS/MS. MDZ AUC0-∞ was determined by non-compartmental analysis. 20 subjects were randomly selected for the training set and the remaining 21 subjects for the validation set. The ratios of 1-OH MDZ to MDZ C0.5, 1, 2, 4, and 6 and AUC0-∞ were log-transformed. Stepwise multiple linear regression was used to derive equation models to predict MDZ AUC (AUCpred). Results One equation using C2 was statistically significant but had a low regression coefficient (R2=0.32): Log(AUCpred)=4.43–0.75[log(1-OH MDZ C2/MDZ C2)]. This equation did not meet the acceptable limits of bias and precision (Mean prediction error=−9.8%, Root mean square error=52.3%). Conclusions The ratio of 1-OH MDZ to MDZ plasma concentrations does not correlate with MDZ AUC and cannot be used to accurately predict MDZ exposure when PO MDZ is used as a CYP3A biomarker. Clinical Pharmacology & Therapeutics (2005) 77, P32–P32; doi: 10.1016/j.clpt.2004.12.016