p16^INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects

Abstract

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.

Pharmacogenetic Analysis of the Model‐Based Pharmacokinetics of Five Anti‐HIV Drugs: How Does This Influence the Effect of Aging?

“…No significant SNPs were found for the TFV‐DP CL out . The FTC‐TP CL in showed the same statistical results as the FTC CL/F, because during the model construction the FTC‐TP CL in was described as a fixed fraction of FTC CL/F . Therefore, TFV‐DP CL out and FTC‐TP CL in were excluded from further analysis.…”

“…FTC‐TP has higher CL out from the cells given an ABCC2 _c.1249G>A variant, which increases MRP2 function . The p16 INK4a expression remains a significant predictor, potentially related to effects of cellular aging on the transport of drugs and/or the catabolic and anabolic processes for the metabolites …”

“…Study conduct has been described in previous publications . Briefly, HIV‐infected patients were enrolled from the University of North Carolina HealthCare Infectious Diseases Clinic (Chapel Hill, NC) and the Cone Health Regional Center for Infectious Diseases (Greensboro, NC).…”

“…The phenotypes in this study were the post hoc PK parameters. The PK analysis was performed as previously described . Briefly, drug concentrations were measured in the University of North Carolina Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Laboratory.…”

“…Aging could change drug absorption, distribution, metabolism, and elimination, which could alter efficacy and safety profiles. In our previous studies, we have investigated the effects of chronological age and aging surrogates on the PK of five selected ARVs . Our analysis showed that the clearances of two renally eliminated drugs, tenofovir (TFV) and emtricitabine (FTC), demonstrated a significant association with creatinine clearance, which is strongly related to chronological age .…”