p16INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV-Infected Subjects.

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

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

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.