Limitations of Using a Single Postdose Midazolam Concentration to Predict CYP3A‐Mediated Drug Interactions

Abstract

Midazolam is a common probe used to predict CYP3A activity, but multiple blood samples are necessary to determine midazolam's area under the concentration-time curve (AUC). As such, single sampling strategies have been examined. The purpose of this study was to assess the ability of single midazolam concentrations to predict midazolam AUC in the presence and absence of CYP3A modulation by Ginkgo biloba extract (GBE). Subjects received oral midazolam 8 mg before and after 28 days of GBE administration. Postdose blood samples were collected during both study periods and midazolam AUC determined. Linear regression was used to generate measures of predictive performance for each midazolam concentration. The geometric mean ratio (90% confidence intervals) of midazolam AUC 0-∞ post-GBE/AUC 0-∞ pre-GBE was 0.66 (0.49-0.84) (P = .03). Before and after GBE administration, optimal midazolam sampling times were identified at 3.5 to 5 hours and 2 to 3 hours, respectively. Single midazolam concentrations between 2 and 5 hours correctly predicted the reduction in midazolam AUC following GBE exposure, but confidence intervals were generally wide. Intersubject variability in CYP3A activity (either inherent or from drug administration) alters the prediction of optimal midazolam sampling times; therefore, midazolam AUC is preferred for assessing CYP3A activity in drug-drug interaction studies. Keywords Midazolam; Ginkgo biloba extract; drug interactions; CYP3ACytochrome P 450 (CYP) is a large group of enzymes responsible for phase I oxidative metabolism. CYP enzymes are located in various tissues throughout the body, with the liver being the largest source. Two intestinal CYP isoforms that account for approximately 70% of total intestinal CYP activity include CYP3A4 and CYP3A5. Because >50% of CYPmetabolized drugs are substrates for CYP3A, modulation of this enzyme is the source of numerous drug-drug interactions. 1 However, it is not practical to study each CYP3A substrate to determine its interaction potential with CYP3A-modulating medications. As such, various CYP3A probe drugs have been identified to detect and quantify potential CYP3A-mediated drug-drug interactions. 2Midazolam has been used extensively as a probe for determining CYP3A4 and 3A5 catalytic activity in vivo; it is metabolized by CYP3A4 and CYP3A5 to its primary metabolite, 1′- The purpose of this healthy volunteer study was to assess the ability of single postdose midazolam concentrations to independently predict CYP3A activity as determined by midazolam area under the concentration-time curve (AUC), in the presence and absence of a newly described CYP3A-modulating compound, and to assess potential limitations associated with this approach. This study was a nested substudy of a larger investigation that examined the influence of Ginkgo biloba leaf extract (GBE) on the pharmacokinetics of the HIV protease inhibitor combination lopinavir/ritonavir. NIH Public Access METHODS Study SubjectsTo be considered for study inclusion, subjects had to be 18 to 50 y...

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

“…The purpose was to assess the ability of one single midazolam concentration for predicting midazolam AUC in the presence and absence of CYP3A modulation by Gingko biloba inducing CYP3A. The study showed that optimal midazolam sampling times to predict AUC were different before or after Gingko biloba [12]. This approach is not useful for prospective clinical trials where CYP3A activity is to be determined.…”

Evaluation of partial area under the concentration time curve to estimate midazolam apparent oral clearance for cytochrome P450 3A phenotyping

“…Individual midazolam plasma concentrations were available during CYP3A baseline (n = 116), inhibition (n = 75), and induction or activation (n = 66) conditions from seven published studies (Table 1) [5,6,11,[21][22][23][24]. The data were from healthy adults, as determined by medical history, physical examination, and blood and urine laboratory tests, who were administered various single doses of oral midazolam alone or with the known CYP3A inhibitors: ketoconazole or doublestrength grapefruit juice or the known CYP3A inducers/activators: Ginkgo biloba extract, pleconaril, or rifampin.…”

“…The lower limit of quantitation ranged from 0.025 ng/ mL to 1 ng/mL, while inter-and/or intra-assay precision and accuracy was < 12%. Details of each assay are specified elsewhere [5,6,11,[21][22][23][24].…”

“…Midazolam single-point concentration measurements have been suggested as an alternative method, but they vary in terms of the optimal timepoint (e.g., 4, 5, or 6 h) to predict CYP3A activity [7,10]. Another research group reported wide confidence intervals (CIs) with single points ranging from 2 to 5 h and do not recommend use of single-point sampling [11]. Metabolic ratios of 1-hydroxymidazolam to midazolam is another proposed alternative, but it has been reported to poorly correlate with total CL [12].…”

Midazolam Limited Sampling Strategy With a Population Pharmacokinetic Approach to Simultaneously Estimate Cytochrome P450 (CYP) 3A Constitutive, Inhibition, and Induction/Activation Conditions in Healthy Adults

“…Institutional Review Board exemption was obtained from the University of California, San Diego, Human Research Protections Program. Midazolam plasma concentration data from 9 studies and serum concentration data from a single study were pooled from previously published studies of healthy subjects . Because the majority of studies consisted of plasma concentrations, a conversion factor was not used for the single study (n = 13) that used serum concentrations.…”