Background:  Safe and effective strategies are needed to treat HIV and Mycobacterium tuberculosis co-infection. Rifampin (RIF) is a cornerstone of antituberculous therapy, but its induction of hepatic cytochrome CYP3A lowers plasma concentrations of HIV protease inhibitors. To test the hypothesis that adequate plasma concentrations of atazanavir (ATV) can be maintained if given at higher than approved doses with concomitant RIF, steady state pharmacokinetics and safety of ATV and RIF were determined in healthy, HIV^– volunteers.

Methods:  HIV^– adults were enrolled into an open-label pharmacokinetics interaction study involving 3 sequential periods of ATV±RIF. Pharmacokinetics sampling was done on the last day of each period. ATV was taken orally with food every 12 hours; RIF was taken with the morning ATV dose. Period 1, ATV 300 mg every 12 hours for 8 to 11 days; period 2, ATV 300 mg every 12 hours and RIF 600 mg every 24 hours for 11 to 15 days; period 3, ATV 400 mg every 12 hours and RIF 600 mg every 24 hours for 8 to 11 days. Plasma was collected serially between 0 and 12 hours, and again at 24 hours after the morning dose. ATV was assayed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection (lower limit of quantification [LLQ] 25 ng/mL). RIF and desacetyl RIF were assayed by liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) (LLQ 50 ng/mL). Concentrations <LLQ were assigned values one-half the LLQ. AUC were estimated using the linear trapezoidal rule.

Results:  We studied 15 subjects, of whom 7 were female; 10 completed all 3 pharmacokinetics visits; 4 discontinued for protocol nonadherence and 1 for grade 3 fatigue. Compared with period 1, mean plasma ATV C_min values during periods 2 and 3 were 97% (p = 0.001) and 91% (p = 0.002) lower, respectively. Mean ATV AUC_0-12h values were 77% (p = 0.001) and 53% (p = 0.002) lower, respectively. The geometric mean plasma C_min during period 3 was 55 ng/mL, significantly less than the historic geometric mean C_min for ATV 400 mg every 24 hours (159 ng/mL, p = 0.002). RIF C_max and AUC_0-24h values were similar to historic data from individuals receiving RIF alone (p = 0.23 and 0.08, respectively); values for desacetyl RIF were significantly higher than historic data (p <0.01). There were no abnormal ALT, creatinine, or hemoglobin values.

Conclusions:  Although safe and generally well tolerated, ATV 300 mg or 400 mg every 12 hours does not maintain adequate plasma exposure to effectively treat HIV infection when co-administered with RIF 600 mg every 24 hours. Study is warranted of twice-daily ATV boosted with twice-daily ritonavir in individuals receiving RIF.