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

Abstract

Analysis of aging and pharmacogenetics (PGx) on antiretroviral pharmacokinetics (PKs) could inform precision dosing for older human HIV‐infected patients. Seventy‐four participants receiving either atazanavir/ritonavir (ATV/RTV) or efavirenz (EFV) with tenofovir/emtricitabine (TFV/FTC) provided PK and PGx information. Aging‐PGx‐PK association and interaction analyses were conducted using one‐way analysis of variance (ANOVA), multiple linear regression, and Random Forest ensemble methods. Our analyses associated unbound ATV disposition with multidrug resistance protein (MRP)4, RTV with P‐glycoprotein (P‐gp), and EFV with cytochrome P450 (CYP)2B6 and MRP4 genetic variants. The clearance and cellular distribution of TFV were associated with P‐gp, MRP2, and concentrative nucleoside transporters (CNTs), and FTC parameters were associated with organic cation transporters (OCTs) and MRP2 genetic variants. Notably, p16INK4a expression, a cellular aging marker, predicted EFV and FTC PK when genetic factors were adjusted. Both age and p16INK4a expression interacted with PGx on ATV and TFV disposition, implying potential dose adjustment based on aging may depend on genetic background.

Pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid

“… 14 ABCB1 rs3213619 was associated with increased tenofovir bioavailability in a predominantly African-American patient population ( n = 45) and thought to be a result of decreased P-glycoprotein function. 21 A genome-wide and candidate gene association analyses with tenofovir pharmacokinetics showed that SLC17A1 rs12662869 was associated with an increase in tenofovir clearance ( p = 7.1 × 10 −9 ) but failed to show significant associations in candidate genes (including ABCC4, ABCC10, ABCB1, ABCC2, SLC22A11, AK2 and AK3 ) after correction for multiple comparisons. 15 …”

Endogenous Hormones and Antiretroviral Exposure in Plasma, Cervicovaginal Fluid, and Upper-Layer Packed Cells of Malawian Women Living with HIV

“… 9 Increased CYP2B6 (or other hepatic enzyme) activity would explain lower systemic efavirenz exposure with increasing estradiol concentrations. Similarly, efavirenz is a substrate for efflux drug transporter MRP4, 10 , 11 which like CYP2B6 may also be induced by estradiol. Increased expression of efflux drug transporter in the gut epithelium may point to decreased efavirenz absorption and is consistent with our findings of lower efavirenz concentrations with increased estradiol.…”