Alprazolam-ritonavir interaction: Implications for product labeling

David J. Greenblatt, Lisa L. Von Moltke, Jerold S. Harmatz, Anna Liza B Durol, Johanna P. Daily, Jennifer A. Graf, Polyxane Mertzanis, Jonathan L. Hoffman, Richard I. Shader

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

Background: Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The vital protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms. Methods: The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo. Results: Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50% inhibitory concentration was 0.11 μmol/L (0.08 μg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 μg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41% of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. Conclusion: Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.

Original languageEnglish (US)
Pages (from-to)335-341
Number of pages7
JournalClinical Pharmacology and Therapeutics
Volume67
Issue number4
StatePublished - 2000
Externally publishedYes

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Product Labeling
Alprazolam
Ritonavir
Cytochrome P-450 CYP3A
Liver Microsomes
Therapeutics
Hydroxylation
Protease Inhibitors
Drug-Related Side Effects and Adverse Reactions
Benzodiazepines
Double-Blind Method
Inhibitory Concentration 50
Half-Life
Volunteers
Protein Isoforms
Pharmacokinetics
Placebos

ASJC Scopus subject areas

  • Pharmacology

Cite this

Greenblatt, D. J., Von Moltke, L. L., Harmatz, J. S., Durol, A. L. B., Daily, J. P., Graf, J. A., ... Shader, R. I. (2000). Alprazolam-ritonavir interaction: Implications for product labeling. Clinical Pharmacology and Therapeutics, 67(4), 335-341.

Alprazolam-ritonavir interaction : Implications for product labeling. / 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.

In: Clinical Pharmacology and Therapeutics, Vol. 67, No. 4, 2000, p. 335-341.

Research output: Contribution to journalArticle

Greenblatt, DJ, Von Moltke, LL, Harmatz, JS, Durol, ALB, Daily, JP, Graf, JA, Mertzanis, P, Hoffman, JL & Shader, RI 2000, 'Alprazolam-ritonavir interaction: Implications for product labeling', Clinical Pharmacology and Therapeutics, vol. 67, no. 4, pp. 335-341.
Greenblatt DJ, Von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA et al. Alprazolam-ritonavir interaction: Implications for product labeling. Clinical Pharmacology and Therapeutics. 2000;67(4):335-341.
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. / Alprazolam-ritonavir interaction : Implications for product labeling. In: Clinical Pharmacology and Therapeutics. 2000 ; Vol. 67, No. 4. pp. 335-341.
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abstract = "Background: Pharmacokinetic interactions involving antiretroviral therapies may critically influence the efficacy and toxicity of these drugs, as well as pharmacologic treatments of coincident or complicating diseases. The vital protease inhibitor ritonavir is of particular concern since it both inhibits and induces the activity of cytochrome P450 3A (CYP3A) isoforms. Methods: The inhibitory effect of ritonavir on the metabolism of alprazolam, a CYP3A-mediated reaction in humans, was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer subjects received 1.0 mg of alprazolam concurrent with low-dose ritonavir (four doses of 200 mg) or with placebo. Results: Ritonavir was a potent in vitro inhibitor of alprazolam hydroxylation. The 50{\%} inhibitory concentration was 0.11 μmol/L (0.08 μg/mL); this is below the usual therapeutic plasma concentration range (generally exceeding 2 μg/mL). In the clinical study, ritonavir reduced alprazolam clearance to 41{\%} of control values (P < .001), prolonged elimination half-life (mean values, 30 versus 13 hours; P < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. Conclusion: Consistent with in vitro results, administration of low doses of ritonavir for a short duration of time resulted in large impairment of alprazolam clearance and enhancement of clinical effects. Removal from product labeling of a warning against coadministration of ritonavir and alprazolam was based on a previous study only of extended exposure to ritonavir, in which CYP3A induction offset inhibition. Kinetic interactions involving antiretroviral therapies may be complex and time dependent. Product labeling should reflect this complexity.",
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AU - Harmatz, Jerold S.

AU - Durol, Anna Liza B

AU - Daily, Johanna P.

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AU - Mertzanis, Polyxane

AU - Hoffman, Jonathan L.

AU - Shader, Richard I.

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