| |
A Pharmacokinetic (PK) Study of Intermittent Rifabutin (RB) Dosing with a Combination of Ritonavir (RT) and Saquinavir (SQ) in HIV Patients K. GALLICANO1*, Y. KHALIQ1, I. SEGUIN1, K. FYKE1, G. CARIGNAN1, A. TSENG2, S. WALMSLEY2, and D. W. CAMERON1.
1Ottawa Gen. Hosp.; and 2Toronto Gen. Hosp., ON, Canada Background: Concurrent therapy of HIV and TB is important but problematic owing to bidirectional PK interactions between protease inhibitors (PIs) and rifamycins. Concomitant RB and SQ is not recommended when SQ is a sole PI. Intermittent RB has been proposed but not yet evaluated for concurrent therapy of RB and RT.
Purpose: To evaluate the effect of RB (150 mg q3d or 300 mg q7d) on the PK of a RT/SQ combination (400/400 mg bid), compare the PK of RB and its active desacetyl metabolite (D-RB) within and between the RB regimens over 8 wk of co-administration with RT/SQ, and observe safety of the regimens.
Methods: 24 HIV patients without TB on RT/SQ (400 mg bid > 2 wk) were randomized to receive RB 300 mg q7d (Gp A) or 150 mg q3d (Gp B) for 8 wk. Blood samples were collected over the dosing intervals at baseline for RT/SQ (P1) and after 4 wk (P2) and 8 wk (P3) of concomitant dosing with RB.
Results: 19 patients (10 Gp A, 9 Gp B) completed the study. RB significantly increased GGT enzyme levels in P2 and P3 (p<.003), which is consistent with induction of CYP3A isoenzymes. However, mean SQ and RT total (AUC) and peak (Cmax) exposures averaged over P2 and P3 increased nonsignificantly by 7-19% compared to those in P1, with 90% CIs for differences ranging from -7% to 26% for RT and -2% to 38% for SQ. RB and D-RB total and peak exposures were stable over the 8 wk, with intraindividual CVs of 12-19%. Oral clearance of RB was similar in both groups [321 (Gp B) vs 372 (Gp A) mL/min, p³.34]. RB Cmax values were significantly lower in Gp B [310 vs 496 ng/mL; p³.004]. RB and D-RB trough levels were significantly higher in Gp B (RB: 54 vs 17, D-RB: 55 vs 28 ng/mL; p<.002). D-RB/RB AUC ratios averaged 78% (Gp A) and 63% (Gp B). Low incidence of mild to moderate adverse events (malaise, paraesthesia) was similar in each group. Mild rash developed in 3 patients (2 Gp A, 1 Gp B).
Conclusions: RB exposures were similar at 4 and 8 wk, and had minimal effect on RT and SQ exposures. Peak and trough RB levels in both groups were comparable to but D-RB exposures were much higher than those reported for HIV patients taking RB 300 mg daily in the absence of PIs. Clinical consequences of lower RB and D-RB troughs in Gp A remain to be evaluated, but the high D-RB exposures may compensate for lower RB exposures. Over 8 wk, intermittent RB dosing (150 mg q3d or 300 mg q7d) provides a safe and manageable regimen for concurrent therapy with RT/SQ, which is highly relevant to treatment and prophylaxis of MAC and TB in HIV.
Key Words: Rifabutin, Ritonavir, Saquinavir
|
