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

Clin Transl Sci. 2018 Mar;11(2):226-236. doi: 10.1111/cts.12525. Epub 2017 Dec 3.


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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adult
  • Age Factors
  • Aged
  • Aging / genetics*
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cytochrome P-450 CYP2B6 / genetics
  • Drug Combinations
  • Drug Therapy, Combination / methods
  • Female
  • Frail Elderly
  • HIV Infections / drug therapy*
  • HIV Infections / genetics
  • Humans
  • Male
  • Middle Aged
  • Multidrug Resistance-Associated Proteins / genetics
  • Pharmacogenomic Testing / methods*
  • Prospective Studies
  • Young Adult


  • ABCB1 protein, human
  • ABCC4 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Anti-HIV Agents
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Drug Combinations
  • Multidrug Resistance-Associated Proteins
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6