title: Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Clinical Infectious Diseases, Catholic University, Rome, Italy. massifab@alice.it
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Fabbiani
authors.forename: Simona
authors.initials: S
authors.lastname: Di Giambenedetto
authors.forename: Laura
authors.initials: L
authors.lastname: Bracciale
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bacarelli
authors.forename: Enzo
authors.initials: E
authors.lastname: Ragazzoni
authors.forename: Roberto
authors.initials: R
authors.lastname: Cauda
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Navarra
authors.forename: Andrea
authors.initials: A
authors.lastname: De Luca
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D002851:Chromatography, High Pressure Liquid; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors