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Differential Impairment of Triazolam and Zolpidem Clearance by Ritonavir

Greenblatt David J.; von Moltke, Lisa L.; Harmatz, Jerold S.; Durol, Anna Liza B.; Daily, Johanna P.; Graf, Jennifer A.; Mertzanis, Polyxane; Hoffman, Jonathan L.; Shader, Richard I.
JAIDS Journal of Acquired Immune Deficiency Syndromes: June 1st, 2000
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Background:The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases.

Methods:The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo.

Results:Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir.

Conclusion:Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.

Address correspondence and reprint requests to David J. Greenblatt, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, U.S.A.; email:

Manuscript received January 25, 2000; accepted March 9, 2000.

© 2000 Lippincott Williams & Wilkins, Inc.