Inhibition of oral midazolam clearance by boosting doses of ritonavir, and by 4,4‐dimethyl‐benziso‐(2H)‐selenazine (ALT‐2074), an experimental catalytic mimic of glutathione oxidase

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The viral protease inhibitor ritonavir is known to inhibit clearance of intravenous midazolam.• ALT-2074, a catalytic mimic of glutathione oxidase, inhibits human cytochrome P450 3A (CYP3A) isoforms in vitro. WHAT THIS STUDY ADDS• Short-term administration of low-dose ritonavir increases area under the plasma concentration curve following oral midazolam by a factor of 28.• Therefore ritonavir is an appropriate positive control inhibitor for clinical drug interaction studies involving CYP3A substrates.• Midazolam clearance is weakly inhibited by ALT-2074, consistent with its in vitro profile. AIMSWe evaluated whether 'boosting' doses of ritonavir can serve as a positive control inhibitor for pharmacokinetic drug-drug interaction studies involving cytochrome P450 3A (CYP3A). The study also determined whether 4,4-dimethyl-benziso-(2H)-selenazine (ALT-2074), an investigational organoselenium compound that acts as a catalytic mimic of glutathione oxidase, inhibits CYP3A metabolism in vivo. METHODSThirteen healthy volunteers received single 3-mg oral doses of midazolam on three occasions: in the control condition, during co-treatment with low-dose ritonavir (three oral doses of 100 mg over 24 h), and during co-treatment with ALT-2074 (three oral doses of 80 mg over 24 h). RESULTSRitonavir increased mean (ϮSE) total area under the curve (AUC) for midazolam by a factor of 28.4 Ϯ 4.2 (P < 0.001), and reduced oral clearance to 4.2 Ϯ 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 Ϯ 0.11 (P < 0.05), and reduced oral clearance to 88 Ϯ 8% of control. CONCLUSIONSLow-dose ritonavir produces extensive CYP3A inhibition exceeding that of ketoconazole (typically 10-to 15-fold midazolam AUC enhancement), and is a suitable positive control index inhibitor for drug-drug interaction studies. ALT-2074 inhibits CYP3A metabolism to a small degree that is of uncertain clinical importance.

Pharmacokinetic Interaction Between Prasugrel and Ritonavir in Healthy Volunteers

“…These results are in agreement with previous studies demonstrating that ritonavir is a very potent CYP3A inhibitor [11,18]. A previous study assessing the effect of ketoconazole on prasugrel pharmacokinetics and pharmacodynamics demonstrated a decrease in prasugrel AM C max while AUC and platelet aggregation were not affected [5].…”

Complex Drug Interactions of HIV Protease Inhibitors 1: Inactivation, Induction, and Inhibition of Cytochrome P450 3A by Ritonavir or Nelfinavir

“…First, this study was begun when this higher dose was more widely used, and second, some of the paradoxical DDIs and autoinduction were observed at this higher dose. Nevertheless, our results are also applicable at the lower dose of 100 mg. Others have shown profound increases in the AUC of MDZ (28-fold) (Greenblatt et al, 2009) and triazolam (40-fold) (Culm-Merdek et al, 2006) after short-term treatment (2 days) and a 20-fold increase in triazolam AUC after extended treatment (10 days) with low-dose RTV (100 mg b.i.d.). Therefore, we predict that RTV, even at the lower dose (100 mg b.i.d.)…”

Predicting Clearance Mechanism in Drug Discovery: Extended Clearance Classification System (ECCS)

“…Inhibitors for metabolizing enzymes have a significant impact on the plasma exposure of Class 2 molecules, given the predominance of this clearance mechanism. For example, the CYP3A substrate midazolam, increased plasma exposure by 2541% when co-administered with the potent CYP3A4 inhibitor ritonavir [166]. A total of 172 of the compounds investigated are classified as Class 2 compounds, of which 95% are cleared by metabolism (Fig.…”