Effect of concomitantly administered rifampin on the pharmacokinetics and safety of atazanavir administered twice daily

Abstract

The potent induction of hepatic cytochrome P450 3A isoforms by rifampin complicates therapy for coinfection with human immunodeficiency virus (HIV) and Mycobacterium tuberculosis. We performed an open-label, single-arm study to assess the safety and pharmacokinetic interactions of the HIV protease inhibitor atazanavir coadministered with rifampin. Ten healthy HIV-negative subjects completed pharmacokinetic sampling at steady state while receiving 300 mg atazanavir every 12 h without rifampin (period 1), 300 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 2), and 400 mg atazanavir every 12 h with 600 mg rifampin every 24 h (period 3). During period 1, the mean concentration of drug in serum at 12 h (C(12 h)) was 811 ng/ml (range, 363 to 2,484 ng/ml) for atazanavir, similar to historic seronegative data for once-daily treatment with 300 mg atazanavir boosted with 100 mg ritonavir. During periods 2 and 3, the mean C(12 h) values for atazanavir were 44 ng/ml (range, <25 to 187 ng/ml) and 113 ng/ml (range, 39 to 260 ng/ml), respectively, well below historic seronegative data for once-daily treatment with 400 mg atazanavir without ritonavir. Although safe and generally well tolerated, 300 mg or 400 mg atazanavir administered every 12 h did not maintain adequate plasma exposure when coadministered with rifampin.

Figures

FIG. 1.

Steady-state plasma concentration curves for atazanavir. Mean values are shown. Error bars indicate standard deviations. Closed circles represent period 1 (300 mg atazanavir administered every 12 h without rifampin), open circles represent period 2 (300 mg atazanavir administered every 12 h with 600 mg rifampin every administered 24 h), and open squares represent period 3 (400 mg atazanavir every administered 12 h with 600 mg rifampin administered every 24 h). The 24-h time points for periods 2 and 3 represent the atazanavir C12 h following the second dose during the 24-h interval. The horizontal dashed line indicates 159 ng/ml, the historic mean C12 h for healthy volunteers given 400 mg atazanavir every 24 h (3).

FIG. 2.

Steady-state plasma concentration curves for rifampin and desacetyl rifampin. Mean values are shown. Error bars indicate standard deviations. Open circles represent period 2 (300 mg atazanavir administered every 12 h with 600 mg rifampin administered every 24 h), and open squares represent period 3 (400 mg atazanavir administered every 12 h with 600 mg rifampin administered every 24 h). Solid lines represent rifampin, and dashed lines represent desacetyl rifampin.

FIG. 3.

Steady-state plasma concentration curves for atazanavir in HIV-negative subjects. Mean values are shown. Error bars indicate standard deviations. Rifampin was not coadministered. Closed circles represent 300 mg atazanavir administered every 12 h without ritonavir (period 1 of the present study), open triangles represent historic data for 400 mg atazanavir administered every 24 h, and open squares represent historic data for 300 mg atazanavir and 100 mg ritonavir, both given every 24 h.