Age-related changes in plasma concentrations of the HIV protease inhibitor lopinavir

Abstract

The advent of highly active antiretroviral therapy in the treatment of HIV disease has substantially extended the lifespan of individuals infected with HIV resulting in a growing population of older HIV-infected individuals. The efficacy and safety of antiretroviral agents in the population are important concerns. There have been relatively few studies assessing antiretroviral pharmacokinetics in older patients. Thirty-seven subjects aged 18-30 years and 40 subjects aged 45-79 years, naive to antiretroviral therapy, received lopinavir/ritonavir (400/100) bid, emtricitibine 200 mg qd, and stavudine 40 mg bid. Trough lopinavir concentrations were available for 44 subjects, collected at 24, 36, and 96 weeks. At week 24, older age was associated with higher lopinavir trough concentrations, and a trend was observed toward older age being associated with higher lopinavir trough concentrations when all time points were evaluated. In the young cohort, among subjects with two or more measurements, there was a trend toward increasing intrasubject trough lopinavir concentrations over time. Using a nonlinear, mixed-effects population pharmacokinetic model, age was negatively associated with lopinavir clearance after adjusting for adherence. Adherence was assessed by patient self-reports; older patients missed fewer doses than younger patients (p = 0.02). No difference in grade 3-4 toxicities was observed between the two age group. Older patients have higher trough lopinavir concentrations and likely decreased lopinavir clearance. Age-related changes in the pharmacokinetics of antiretroviral drugs may be of increasing importance as the HIV-infected population ages and as older individuals comprise an increasing proportion of new diagnoses.

FIG. 1.

Lopinavir trough con-centrations at week 24 by age group. Lopinavir trough concentrations were fitted in a linear regression model as described in Materials and Methods. At 24 weeks, the median trough plasma lopinavir concentration was 2700 ng/ml in the younger group compared to 7973 ng/ml in the older group (p = 0.0001 when controlled for adherence score). The model predicted an estimated increase in week 24 trough plasma lopinavir concentration of 163 ng/ml per year increase in age (95% CI = 89–238, p = 0.0002, R² = 0.50). (Color image can be found at www.liebertonline.com/aid).

FIG. 2.

Estimated lopinavir mean clearance rate by age. This figure displays the relationship between the mean lopinavir oral clearance (with the 95% confidence interval) and age (n = 77). Clearance was calculated as described in Materials and Methods.