Determining the Time Course of CYP3A Inhibition by Potent Reversible and Irreversible CYP3A Inhibitors Using A Limited Sampling Strategy

Abstract

We established a new limited sampling strategy to assess CYP3A activity and evaluated the time course of reversible (voriconazole) and irreversible (ritonavir) CYP3A inhibition. In this randomized trial, two groups, each with eight healthy participants, received CYP3A inhibitors voriconazole or ritonavir orally for 9 days, with 3 mg midazolam (MDZ) administered before the inhibitor treatment, on days 1, 2, 3, 5, 8, and 9 during inhibitor treatment, and on days 10, 11, and 12 (3 days) after discontinuation. Plasma MDZ area under the curve (AUC) between 2 and 4 h after oral administration in the form of a solution strongly correlated with MDZ clearance. Using this parameter, maximum inhibition of voriconazole and ritonavir was calculated to have occurred only 48 h after starting of the inhibitor (percentage of baseline MDZ clearance, voriconazole: 10.6%; ritonavir: 8.4%). Recovery of CYP3A activity occurred with a half-life of 24 h after voriconazole, whereas ritonavir inhibition was still strong 3 days after discontinuation. These findings underscore the substantial and gradual alterations in dose requirements in the first days of and after such combination therapies.

Effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites: exploration of a novel CYP2B6 phenotyping index

“…Interestingly, the 8,14-OH-EFV concentration-time curve in the clopidogrel phase developed a second peak at 48 h after EFV administration in all subjects, possibly due to the recovery of CYP2B6 activity. This phenomenon would be similar to that described previously for CYP3A4 [22]. In addition, not all EFV is metabolized through 8-hydroxylation.…”

“…One likely reason for this less than expected inhibition of EFV metabolism is that the preinactivated CYP2B6 recovered its activity during the long (120 h) sampling time. This recovery probably would not occur if the inhibition was maintained throughout the trial [22]. Interestingly, the 8,14-OH-EFV concentration-time curve in the clopidogrel phase developed a second peak at 48 h after EFV administration in all subjects, possibly due to the recovery of CYP2B6 activity.…”

Ritonavir and Efavirenz Significantly Alter the Metabolism of Erlotinib—an Observation in Primary Cultures of Human Hepatocytes That Is Relevant to HIV Patients with Cancer

“…This can be explained by the potent CYP3A inhibitory effects of ritonavir (Katzenmaier et al, 2011). The inhibition of erlotinib depletion was more pronounced than the inhibition of desmethyl erlotinib formation/clearance.…”

Effect of the CYP3A inhibitor ketoconazole on the PXR-mediated induction of CYP3A activity

“…In both study phases, participants received 3×300 mg St John's wort [JARSIN ® dragée, LI 160; Casella-med GmbH & Co., Cologne, Germany] over 8 days (day 2 until day 9). To assess CYP3A activity, midazolam exposure was determined using a limited sampling strategy after the oral administration of 3 mg midazolam (Dormicum ® V 5 mg/5 mL solution for injection; Roche, Grenzach-Wyhlen, Germany) using four blood samples drawn at 2, 2.5, 3, and 4 h after administration [10,11]. Midazolam clearance was measured at baseline (day 1), after co-administration of ketoconazole and St John's wort (day 9) and after their discontinuation (days 10, 11 and 12).…”

“…5.03 (GraphPad Software, La Jolla, CA). Midazolam partial metabolic clearance was calculated by the following established equation, which covers conditions from inhibition to induction [10,11]:…”