Short Communication: Aging Not Gender Is Associated with High Atazanavir Plasma Concentrations in Asian HIV-Infected Patients

Abstract

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.

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

“…In a study evaluating trough concentrations measured during therapeutic drug monitoring, their analysis suggested no changes in EFV concentrations with age, with increased concentrations of protease inhibitors, such as ATV and RTV, although only 16.5% of these participants were 50 years old or older 37. In a noncompartmental analysis of ATV/RTV PK in Thai patients with HIV, age >42 years was found to be significantly associated with increased ATV and RTV area under the curve and peak plasma concentration (C max ), however, the median age in this study was 42 years and the oldest subject was 57 years old 38. In the present work, 38% of EFV and 36% of ATV/RTV participants were 50 years of age or older, with the oldest subject in each group 73 and 61, respectively.…”

Plasma trough concentrations of darunavir/ritonavir and raltegravir in older patients with HIV‐1 infection

“…Moreover, 91% of the older subjects vs . 36% of the younger subjects had atazanavir C trough higher than the proposed upper limit for toxicity (0.85 mg/L), and the multivariate analysis found older age to be the only significant predictor for high atazanavir concentrations .…”

“…The geometric mean plasma C trough of darunavir and ritonavir was significantly higher in older subjects than in younger individuals, while the geometric mean plasma C trough of raltegravir was comparable between older and younger subjects. This increase in plasma concentrations of protease inhibitors in elderly people is comparable to that observed in other studies , and probably arises from pharmacokinetic changes which physiologically occur in older subjects, leading to a slower clearance of several drugs. However, raltegravir showed comparable plasma levels in younger and older subjects, as reported by other authors , and its metabolism and excretion are probably less affected by the pharmacokinetic changes occurring in older people.…”

Antiretroviral Treatment Efficacy and Safety in Older HIV‐Infected Adults

“…Three prospective studies assessing the PK effects of ARVs in older HIV‐infected patients were identified . A study evaluated the exposure of two alternative first‐line regimens in 12 HIV‐infected adults aged 55 years or older (mean age 59.7 ± 3.9 yrs) in an unblinded, intensive‐sampling PK study.…”

“…A groups of investigators evaluated the impact of age and gender on the PK of atazanavir (300 mg/day), ritonavir (100 mg/day), and two NRTIs (once/day) in a 24‐hour intensive PK study. Twenty‐two HIV‐infected adults were included and received ART for at least 2 weeks prior to the start of the study.…”