Proposal of a new limited sampling strategy to predict CYP3A activity using a partial AUC of midazolam

Abstract

Midazolam metabolic clearance to 1'-hydroxymidazolam is an accurate measure of CYP3A activity which requires extensive plasma and urine sampling. The objective of this study was to find a new limited sampling strategy (LSS) to predict midazolam metabolic clearance to 1'-hydroxymidazolam and subsequently CYP3A activity in an easy and reliable way, reducing costs and labour. The development of this LSS is based on data from an in vivo drug-drug interaction study carried out in our clinical research unit. Various partial AUCs of midazolam were calculated and correlated with metabolic clearance of midazolam to 1'-hydroxymidazolam by non-linear regression. The correlation with highest r (2) values was chosen to predict the midazolam metabolic clearance. Statistical significance of this method was verified by calculating the 95% confidence interval of the differences (%) between predicted and measured metabolic clearance of midazolam to 1'-hydroxymidazolam. The midazolam partial AUC from 2 to 4 h after oral administration correlated best with metabolic clearance of midazolam to 1'-hydroxymidazolam with r (2) = 0.9816. This partial AUC comprised four midazolam concentrations at 2, 2.5, 3 and 4 h after oral administration of a midazolam solution. The 95% confidence interval of the differences between predicted metabolic clearance and measured metabolic clearance of midazolam to 1'-hydroxymidazolam was -0.97 to +13.2. The determination of the partial AUC using four plasma samples from 2 to 4 h after oral administration of a midazolam solution is proposed to be an easy and reliable CYP3A phenotyping measure which of course needs to be validated in prospective clinical trials.