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

David J. Greenblatt, Diane E. Peters, Lauren E. Oleson, Jerold S. Harmatz, Malcolm W. MacNab, Noah Berkowitz, Miguel A. Zinny, Michael H. Court

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)920-927
Number of pages8
JournalBritish Journal of Clinical Pharmacology
Volume68
Issue number6
DOIs
StatePublished - Dec 2009
Externally publishedYes

Keywords

  • Cytochrome P450-3A
  • Drug interaction
  • Midazolam

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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