A study of the pharmacokinetics and safety of rifabutin 150 mg once daily versus rifabutin 300 mg thrice weekly with Lopinavir/ritonavir based HAART in HIV/TB co-infected patients

Abstract

Introduction: Rifampicin is a potent cytochrome P450 inducer that can markedly reduce serum lopinavir level. Rifabutin based anti TB is an alternative when boosted protease inhibitors are in need, however recommended doses of rifabutin may be subtherapeutic. The primary aim of this study was to compare pharmacokinetics parameters of rifabutin 150 mg once daily, versus rifabutin 300 mg thrice weekly in combination with LPV/r 400/100 mg based HAART in HIV/TB infected patients in Thailand.

Method: This was a randomized, open-label, 2- arm, intensive pharmacokinetic study, as well as a 48 week efficacy study, conducted in Thai HIV and TB coinfected patients. Rifabutin pharmacokinetics were evaluated before and between week 2 to week 8 after coadministration of lopinavir/ritonavir. We used a high performance liquid chromatography (HPLC) technique to determine rifabutin and lopinavir/ritonavir concentrations.

Results: Twenty one patients were enrolled in the study. Ten patients were randomized to rifabutin 150 mg daily and eleven patients received rifabutin 300 mg thrice weekly. AUC of rifabutin 150 mg once daily combined with lopinavir/ritonavir is moderately higher than rifabutin alone for 41.9%. By contrast, AUC in patients with rifabutin 300 mg thrice weekly combined with lopinavir/ritonavir is markedly higher than rifabutin alone for 145.2%. After week 2 to week 8 of rifabutin and lopinavir/ritonavir concurrent administration, pharmacokinetic parameters of rifabutin included peak concentrations (Cmax), and area under the curve (AUC) were studied. Geometric mean Cmax (CV) of rifabutin 150 mg daily and 300 mg thrice weekly were similar [0.65 (36%) vs. 0.82 (30%) mg/L]. Geometric mean AUC (CV) of rifabutin 300 mg thrice weekly was higher than 150 mg daily for 72.7% [15.5 (43%) vs 8.97 (37%) mg.h/L]. Pharmacokinetic parameters of lopinavir/ritonavir are in therapeutic level [trough concentration (C0), peak concentrations (Cmax), minimum concentrations (Cmin) and average concentrations (Cave)] and were similar in both arms [mean C0 of rifabutin 150 mg daily and of rifabutin 300 mg three times weekly were 8.709 vs. 10.473 µg/mL, mean Cmax was 13.455 vs. 14.027µg/mL, mean Cmin was 5.287 vs. 4.155 µg/mL and mean Cave was 9.695 vs.10.252]. Uveitis which isassociated to rifabutin developed in two patients who received rifabutin 300 mg three times weekly.

Conclusion: Our study suggests that rifabutin 150 mg daily should be recommended in Thai patient who concurrently use lopinavir/ritonavir because of optimal pharmacokinetic parameters and clinical safety. Moreover, this study shows that lopinavir/ritonavir 400/100 mg BID can give adequate lopinavir levels in HIV and TB coinfected patients who were treated with rifabutin both 150 mg daily and 300 mg thrice weekly.

Rifabutin, lopinavir/ritonavir, pharmacokinetics