Background:  Mycobacterium tuberculosis is of concern in patients with HIV infection. Rifampin (RIF), an agent used for Mycobacterium tuberculosis, is contraindicated with most HIV protease inhibitors (PI). Atazanavir (ATV) is a potent once daily PI with comparable clinical efficacy to standard of care in naïve patients and, when boosted with ritonavir (RTV), to lopinavir/ritonavir boost (LPV/r) in treatment-experienced patients. The study’s objectives were to assess the safety and pharmacokinetics of ATV resulting from 3 regimens of ATV, RTV, and RIF.

Methods:  An open-label, randomized study was conducted in 71 healthy subjects. Pharmacokinetics for ATV and RTV were assessed after 6 and 10 days of dosing with ATV 400 mg (A) and ATV/RTV 300/100 mg (B), respectively. Steady-state pharmacokinetics for ATV, RTV, RIF, and desacetyl-RIF were measured after 10 days of dosing of:  ATV/RTV 300/100 mg + RIF 600 mg (C), ATV/RTV 300/200 mg + RIF 600 mg (D), or ATV/RTV 400/200 mg + RIF 600 mg (E). A RIF alone arm was enrolled to assess safety.

Results:  Final geometric means and ratios (90% CI) (both generated from a general linear model) for ATV/RTV/RIF vs ATV 400 mg are listed in the table. ATV AUC values were comparable, but C_min values lower, for Trt E relative to ATV alone. ATV exposures were substantially reduced for the other regimens relative to ATV alone and for all regimens relative to ATV/RTV alone. RIF and desacetyl-RIF exposures were comparable across different regimens of ATV/RTV, but were ~1.6- and 2.5-fold higher than with RIF alone. Incidence of grade 3/4 ALT/AST values was limited to 1 subject in both Trt D and E.

Conclusions:  Co-administration of ATV with RIF was safe and generally well-tolerated. As ATV exposures were reduced in all regimens, neither ATV nor RIF should be co-administered at the dosing regimens studied. Alternative dosing regimens will be explored.

Keywords: atazanavir; rifampin; ritonavir