Tolerance and Pharmacokinetic Interactions of Rifabutin and Clarithromycin in Human Immunodeficiency Virus-Infected Volunteers

Abstract

This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically stable human immunodeficiency virus-infected volunteers with CD4 counts of <200 cells/mm 3 . Thirty-four subjects were randomized equally to either regimen A or regimen B. On days 1 to 14, subjects assigned to regimen A received clarithromycin and subjects assigned to regimen B received rifabutin, and then both groups received both drugs on days 15 to 42. Of the 14 regimen A and the 15 regimen B subjects who started combination therapy, 1 subject in each group prematurely discontinued therapy due to toxicity, but 19 of 29 subjects reported nausea, vomiting, and/or diarrhea. Pharmacokinetic analysis included data for 11 regimen A and 14 regimen B subjects. Steady-state pharmacokinetic parameters for single-agent therapy (day 14) and combination therapy (day 42) were compared. Regimen A resulted in a mean decrease of 44% (P ‫؍‬ 0.003) in the clarithromycin area under the plasma concentration-time curve (AUC), while there was a mean increase of 57% (P ‫؍‬ 0.004) in the AUC of the clarithromycin metabolite 14-OH-clarithromycin. Regimen B resulted in a mean increase of 99% (P ‫؍‬ 0.001) in the rifabutin AUC and a mean increase of 375% (P < 0.001) in the AUC of the rifabutin metabolite 25-O-desacetyl-rifabutin. The usefulness of this combination for prophylaxis of Mycobacterium avium infections is limited by frequent gastrointestinal adverse events. Coadministration of clarithromycin and rifabutin results in significant bidirectional pharmacokinetic interactions. The resulting increase in rifabutin levels may explain the increased frequency of uveitis observed with concomitant use of these drugs.

Pharmacokinetic Evaluation of Rifabutin in Combination with Lopinavir‐Ritonavir in Patients with HIV Infection and Active Tuberculosis

“…The relative contribution of rifabutin or the desacetyl-rifabutin metabolite (or other metabolites not measured here) to rifabutin-associated adverse drug reactions is not clear [2,12,19]. It is clear that exposure to the metabolite increases after the addition of lopinavir-ritonavir.…”

A Randomized, Double-Blind Trial Comparing Azithromycin and Clarithromycin in the Treatment of Disseminated Mycobacterium avium Infection in Patients with Human Immunodeficiency Virus

“…In this light, to uncover new advances in the treatment of opportunistic disease remains an important priority for HIV research. Although clarithromycin remains a well-established component of effective therapy for treatment of disseminated MAC, there remain clinically relevant concerns regarding its use [5,8,25]. On the basis of the collection of analyses performed on the data from this trial, azithromycin 600 mg taken every day, when given in combination with ethambutol, is an effective agent for the treatment of disseminated M. avium disease in HIV-infected patients.…”

Acute panuveitis with hypopyon in Crohn's disease secondary to medical therapy: a case report

“…A particular role for rifabutin has been noted in patients with proven evidence of Mycobacterium avium infection, although this was not the case in this subject[9]. Previous studies reported pharmacokinetic interactions when combining rifabutin and clarithromycin leading to an increase in rifabutin levels, resulting in an increase frequency of uveitis, this could explain the acute onset of uveitis in our case[10]. …”