Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy.

Cathy Connolly,Tracey Kellerman,Suhashni Naiker,Lubbe Wiesner,Alexander Pym,Anthony Harries,Helen Mcilleron,Christian Lienhardt,Tarylee Reddy

doi:10.1186/2050-6511-15-61

Abstract

BackgroundPharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity.Methods and resultsSixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0–48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0–48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations.ConclusionsA daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR.Trial registrationClinicalTrials.gov Identifier: NCT00640887

Highlights

Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis
Rifabutin and 25-O-desacetylrifabutin pharmacokinetic analysis The main pharmacokinetic parameters for rifabutin and d-RBT are summarized in Table 1 and shown graphically in Figures 2 and 3
The geometric mean ratios (GMR) for AUC0–48 was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for rifabutin 150 mg tiw compared with rifabutin 300 mg

Summary

Introduction

Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). Combining efavirenz-based first-line antiretroviral therapy (ART) with rifampicin based tuberculosis chemotherapy significantly reduces mortality in these patients [2,3,4] and is safe and efficacious. As public sector ART expands in developing countries, an increasing number of patients are developing virological failure and require second-line ART with protease inhibitors [5,6]. Combining rifampicin and protease inhibitor-based second-line ART is problematic as rifampicin significantly reduces the bioavailability and increases the clearance of protease inhibitors by accelerating their metabolism via induction of cytochrome 3A4 (CYP3A4) enzymes. Increasing the dose of the protease inhibitor or co-administering higher doses of a CYP3A4 inhibitor to ameliorate this adverse drugdrug interaction have been thwarted by hepatotoxicity and other problems with tolerability [7,8]

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