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 language | English (US) |
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Pages (from-to) | 920-927 |
Number of pages | 8 |
Journal | British Journal of Clinical Pharmacology |
Volume | 68 |
Issue number | 6 |
DOIs | |
State | Published - Dec 2009 |
Externally published | Yes |
Keywords
- Cytochrome P450-3A
- Drug interaction
- Midazolam
ASJC Scopus subject areas
- Pharmacology
- Pharmacology (medical)