A Novel Study Design Using Continuous Intravenous and Intraduodenal Infusions of Midazolam and Voriconazole for Mechanistic Quantitative Assessment of Hepatic and Intestinal CYP3A Inhibition

Abstract

The extent of a drug‐drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4‐period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg/h from 8 to 16 hours and of 15 mg/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography‐tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed‐effects modeling. A model including mechanism‐based inactivation of the metabolizing enzymes (maximum inactivation rate constant kinact, 2.83 h−1; dissociation rate constant , 9.33 μM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration‐time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver.

Pharmacokinetic drug–drug interactions of JBPOS0101 mediated by cytochrome P450 3A4 and UDP‐glucuronosyltransferases

“…MDZ was used as a sensitive index substrate for CYP3A4, which metabolizes MDZ to 1‐hydroxy MDZ (60%–80%) and much lesser extent to 4‐hydroxy MDZ (5%). 4 , 17 When MDZ and JBPOS0101 were co‐administered after multiple doses of JBPOS0101, the decrease for C max of MDZ was not clinically significant because of its IV administration and bypassing the first‐pass intestinal CYP3A4 metabolism. 18 , 19 However, the AUC of MDZ was reduced by 30% compared to that when MDZ was administered alone, and it was attributed to the induction of hepatic CYP3A4 by JBPOS0101.…”

Differential expression and activities of cytochrome P450 3A in the rat brain microsomes and mitochondria

“…Additionally, MDZ is a short-acting benzodiazepine used therapeutically for anesthesia induction and as a sedative [33]. In humans, 1 0 -OH-MDZ and 4-OH-MDZ constitute approximately 60% to 80% and 5%, respectively, of the systemic (i.e., primarily liver) biotransformation products of MDZ [34]. In the current study, we showed that CYP3A activity, as demonstrated by MDZ hydroxylation, is present in both rat brain MT and MC (Figure 4).…”