Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice

J Antimicrob Chemother. 2009 Jul;64(1):109-17. doi: 10.1093/jac/dkp132. Epub 2009 Apr 27.

Abstract

Objectives: To assess the inter-individual and intra-individual plasma concentration variabilities of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) in routine clinical practice and to investigate their relationships with virological failure.

Methods: We retrospectively enrolled HIV-infected patients undergoing therapeutic drug monitoring (TDM) of NNRTIs and PIs during routine outpatient visits. Plasma drug concentrations were measured by HPLC-UV and were considered therapeutic if above the proposed minimum efficacy trough concentration. Inter-individual and intra-individual variabilities were evaluated through the coefficient of variation (CV).

Results: A total of 457 PI and 172 NNRTI plasma concentrations were measured from 363 patients (HIV-RNA <50 copies/mL in 70.8%, median CD4 count 434 cells/mm(3)). NNRTIs showed less inter-individual (CV(inter) 54.8% versus 84.3%) and intra-individual (CV(intra) 19.0% versus 38.1%) pharmacokinetic variabilities than PIs. Intra-individual variability was constantly lower than inter-individual variability for each drug. Subtherapeutic drug concentrations were observed in 106 samples (16.9%). Older age (P = 0.020) and higher viral load (P = 0.013) were associated with subtherapeutic levels. Patients with therapeutic levels had a viral load of <50 copies/mL more frequently than those with subtherapeutic levels (74.8% versus 63.2%, P = 0.020). The estimated proportion with virological failure at 24 weeks was 0.21 in patients with suboptimal baseline drug levels and 0.08 in those with optimal levels (P < 0.001). In the multivariate analysis, therapeutic drug levels showed an independent negative association with virological failure (P = 0.004).

Conclusions: A wide inter-individual and limited intra-individual pharmacokinetic variabilities, together with the demonstration of a concentration-response relationship, suggest that TDM is a useful tool for the clinical management of patients treated with NNRTIs or PIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use*
  • CD4 Lymphocyte Count
  • Chromatography, High Pressure Liquid
  • Female
  • HIV Infections / drug therapy*
  • HIV Protease Inhibitors / pharmacokinetics*
  • HIV Protease Inhibitors / therapeutic use*
  • Humans
  • Male
  • Middle Aged
  • Plasma / chemistry
  • Retrospective Studies
  • Reverse Transcriptase Inhibitors / pharmacokinetics*
  • Reverse Transcriptase Inhibitors / therapeutic use*
  • Treatment Outcome
  • Viral Load

Substances

  • Anti-HIV Agents
  • HIV Protease Inhibitors
  • Reverse Transcriptase Inhibitors