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

Authors


Dr David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA.
Tel: +1 617 636 6997
Fax: +1 617 636 6738
E-mail: dj.greenblatt@tufts.edu

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.

AIMS We 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.

METHODS Thirteen 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).

RESULTS Ritonavir increased mean (±SE) total area under the curve (AUC) for midazolam by a factor of 28.4 ± 4.2 (P < 0.001), and reduced oral clearance to 4.2 ± 0.5% of control (P < 0.001). In contrast, ALT-2074 increased midazolam AUC by 1.25 ± 0.11 (P < 0.05), and reduced oral clearance to 88 ± 8% of control.

CONCLUSIONS Low-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.

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