Physiological effects of aging make the older population more susceptible to
adverse drug events and drug-drug interactions. We evaluated the impact of aging and gender on the pharmacokinetics (PK) of
atazanavir/
ritonavir (ATV/r) 300/100 mg once daily (qd) in 22 well-suppressed HIV-infected patients. This was a 24-h intensive PK study. Subjects were HIV-1-infected adults aged ≥18 years with HIV
RNA <50 copies/ml and treated with ATV/r 300/100 mg once daily plus two
nucleoside reverse transcriptase inhibitors (NRTIs) for at least 2 weeks.
Atazanavir and ritonavir plasma concentrations were measured by validated high-performance liquid chromatography (HPLC). Plasma PK parameters were calculated using noncompartmental methods. Since 50% of the patients were older than 42 years, age 42 was selected as the cut-off point for the older (>42 years) group. Gender, weight, duration of ATV/r
therapy, and proportion treated with
tenofovir disoproxil fumarate (TDF)-containing regimens did not differ between both groups. Patients from the aging group had a reduced
creatinine clearance (91 versus 76 ml/min). The older group had a higher
atazanavir exposure with median AUC(0-24) 71.2 vs. 53.1 mg·h/liter, C(max) 8.5 vs. 5.5 mg/liter, and C(trough) 1.17 vs. 0.78 mg/liter, and slower apparent clearance (3.5 vs. 4.8 liter/h). Ten patients (91%) from the older group and 36% from the younger group had ATV C(trough) levels higher than the proposed upper limit for toxicity of 0.85 mg/liter. Females had a lower
body weight (BW) (46 versus 63 kg) than the males, but
atazanavir concentrations in females were greater. However, in multivariate analysis, older age was the only significant predictor for higher
atazanavir concentrations. Parameter estimate for age and
atazanavir AUC after adjusting for gender and BW was 2.17 (95% CI 1.01-3.33). That is, for every year increase in age, AUC increases by approximately 2 mg·h/liter. Age seems to be an important factor influencing
atazanavir pharmacokinetics. Patients from the aging group appeared to have higher
atazanavir exposure compared to the younger group. Further PK explorations of ATV in the extremely aged population are warranted.