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

Abstract

Background: 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}). 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 results: Sixteen 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.

Conclusions: A 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 registration: ClinicalTrials.gov Identifier: NCT00640887.

Figures

Figure 1

Diagram showing the timings of clinical trial visits and study regimens to tuberculosis (TB) treatment. Patients were screened after 5 weeks of standard TB chemotherapy administered as a fixed dose combination (Rmp – rifampicin, Inh – isoniazid, Pza – pyrazinamide, Emb – ethambutol). If patients met all eligibility criteria they were enrolled after 6 weeks of TB chemotherapy and switched to rifabutin 300 mg daily in place of rifampicin. At the end of the intensive phase (8 weeks of TB treatment) they continued with rifabutin 300 mg daily and isoniazid 300 mg daily. This was followed by the first pharmacokinetic visit (PK1) at which the bioavailability of rifabutin in the absence of LPV/r was assessed. The patients then initiated antiretroviral therapy (ART) and altered their dose of rifabutin based on the randomization to either 150 mg tiw of 150 mg daily. After a month of ART a second pharmacokinetic evaluation (PK2) was completed. Patients then switched doses of rifabutin from 150 mg tiw to daily, or vice versa, and after a further month of treatment a third pharmacokinetic evaluation was completed (PK3). Patients then continued with rifabutin at the dose they were on at PK3, in combination with ART and isoniazid until a total of 24 weeks of TB treatment had been completed. Patients continued ART after stopping TB treatment.

Figure 2

Rifabutin median concentration-time profiles. Median rifabutin (RBT) concentrations for the three pharmacokinetic evaluations in 14 patients. The orange line corresponds to the dosing of RBT at 300 mg without ART; the blue line to RBT dosing at 150 mg tiw with ART and the purple line to dosing with 150 mg of RBT daily with ART. The bars represent interquartile range (IQR).

Figure 3

25-O-desacetylrifabutin median concentration-time profiles. Median 25-O-desacetylrifabutin (d-RBT) concentrations for the three pharmacokinetic evaluations in 14 patients. The bars represent interquartile range (IQR). The blue line corresponds to the dosing of RBT at 300 mg without ART; the red line to RBT dosing at 150 mg tiw with LPV/r based ART and the purple line to dosing with 150 mg of RBT daily.

Figure 4

Median concentration-time profile of boosted lopinavir administered with two different doses of rifabutin. The median lopinavir (LPV) concentrations for 14 patients administered 2 different concentrations of rifabutin (RBT). Blue line corresponds to a RBT dose of 150 mg daily and the purple line to 150 mg tiw. LPV/r corresponds to boosted lopinavir. The bars represent interquartile range (IQR).

Pre-publication history