Nonnucleoside reverse transcriptase inhibitor pharmacokinetics in a large unselected cohort of HIV-infected women

J Acquir Immune Defic Syndr. 2009 Apr 15;50(5):482-91. doi: 10.1097/qai.0b013e31819c3376.


Background: Small intensive pharmacokinetic (PK) studies of medications in early-phase trials cannot identify the range of factors that influence drug exposure in heterogenous populations. We performed PK studies in large numbers of HIV-infected women on nonnucleoside reverse transcriptase inhibitors (NNRTIs) under conditions of actual use to assess patient characteristics that influence exposure and evaluated the relationship between exposure and response.

Methods: Two hundred twenty-five women on NNRTI-based antiretroviral regimens from the Women's Interagency HIV Study were enrolled into 12-hour or 24-hour PK studies. Extensive demographic, laboratory, and medication covariate data were collected before and during the visit to be used in multivariate models. Total NNRTI drug exposure was estimated by area under the concentration-time curves.

Results: Hepatic inflammation and renal insufficiency were independently associated with increased nevirapine exposure in multivariate analysis: crack cocaine, high fat diets, and amenorrhea were associated with decreased levels (n = 106). Higher efavirenz exposure was seen with increased transaminase, albumin levels, and orange juice consumption; tenofovir use, increased weight, being African American, and amenorrhea were associated with decreased exposure (n = 119). With every 10-fold increase in nevirapine or efavirenz exposure, participants were 3.3 and 3.6 times likely to exhibit virologic suppression, respectively. Patients with higher drug exposure were also more likely to report side effects on therapy.

Conclusions: Our study identifies and quantitates previously unrecognized factors modifying NNRTI exposure in the "real-world" setting. Comprehensive PK studies in representative populations are feasible and may ultimately lead to dose optimization strategies in patients at risk for failure or adverse events.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Alkynes
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Area Under Curve
  • Benzoxazines / adverse effects
  • Benzoxazines / pharmacokinetics*
  • Benzoxazines / therapeutic use
  • Cohort Studies
  • Cyclopropanes
  • Dose-Response Relationship, Drug
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / metabolism*
  • Humans
  • Linear Models
  • Middle Aged
  • Multivariate Analysis
  • Nevirapine / adverse effects
  • Nevirapine / pharmacokinetics*
  • Nevirapine / therapeutic use
  • Prospective Studies
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / pharmacokinetics*
  • Reverse Transcriptase Inhibitors / therapeutic use
  • Time Factors
  • Young Adult


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • efavirenz