Ritonavir Impairs Alprazolam and Triazolam Clearance
Abstract & Commentary
Synopsis: Contrary to some previous reports, ritonavir coadministration causes marked impairment of clearance of both triazolam (Halcion) and alprazolam (Xanax).
Source: Greenblatt DJ, et al. Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: The clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999;19:293-296.
The current article appears as an editorial and reports preliminary findings which suggest that the short-term administration of the protease inhibitor ritonavir (Norvir) causes a marked impairment of triazolam (Halcion) clearance. These findings, from a placebo-controlled drug interaction trial, support previous reports in which ritonavir has been implicated in causing increases in triazolam serum levels to an extent similar to that caused by the coadministration of ketoconazole. Further, additional preliminary, unpublished data are presented which show that the short-term administration of ritonavir given 200 mg twice daily greatly inhibited the clearance of alprazolam (Xanax), prolonging its half-life from 3.7 hours to 50 hours in one subject.
These findings are in contrast with at least one previously published report in which subjects were given ritonavir 500 mg twice daily for 10 days followed by a single oral dose of alprazolam. This study reported that ritonavir did not impair alprazolam clearance. Greenblatt and colleagues hypothesized that the conflicting reports may be explained by the ability of ritonavir to induce cytochrome P450 3A4 (CYP3A4) enzymes. Because induction requires new protein synthesis, it usually takes place only after repeated dosing of ritonavir. Thus, the short-term coadministration of ritonavir with CYP3A4 substrates such as alprazolam and triazolam will result in elevated serum levels; whereas long-term administration will induce the CYP3A4 system and somewhat offset the inhibition of the substrates, creating a virtual balance with a net effect of normal half-lives of drugs such as alprazolam and triazolam.
COMMENT BY Michael F. Barber, PharmD
Drug interactions involving the CYP3A4 system have gained much attention in recent years due to the unfortunate deaths involving terfenadine, astemizole, and cisapride. Although benzodiazepines such as alprazolam and triazolam are not cardiotoxic, the importance of a reduction in clearance of these agents should not be underemphasized. Accumulation of these agents would most likely result in a simple increase in the amount or incidence of somnolence; however, ataxia and impaired coordination could take place, resulting in increased likelihood of falls. Also, patients may be at higher risk for accidents involving heavy machinery. Further, patients with compromised respiratory functioning would be at higher risk for serious adverse reactions.
It is difficult for clinicians to interpret the literature regarding CYP3A4-mediated drug interactions. This is the result of conflicting data for various reasons. First, sometimes in vitro results are not replicated by in vivo findings. Second, the induction of hepatic isozymes such as CYP3A4 is not easily predicted in terms of onset and magnitude. Finally, there are differences in study design which make the results difficult to interpret. Clearly, in vitro studies should be verified by in vivo studies where possible. It would certainly be advisable to avoid certain agents or exercise caution when using known substrates of CYP3A4 in patients who are receiving CYP3A4 inhibitors such as ritonavir. (Dr. Barber is Assistant Professor of Clinical Sciences and Administration, University of Houston College of Pharmacy.)
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