JAC Advance Access originally published online on April 27, 2009
Journal of Antimicrobial Chemotherapy 2009 64(1):109-117; doi:10.1093/jac/dkp132
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Original research |
Pharmacokinetic variability of antiretroviral drugs and correlation with virological outcome: 2 years of experience in routine clinical practice
1 Institute of Clinical Infectious Diseases, Catholic University, Rome, Italy 2 Institute of Pharmacology, Catholic University, Rome, Italy
Received 9 December 2008; returned 30 January 2009; revised 17 March 2009; accepted 18 March 2009
* Corresponding author. Istituto di Clinica delle Malattie Infettive, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168 Rome, Italy. Tel: +39-0630155366; Fax: +39-063054519; E-mail: massifab{at}alice.it
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/mm3). NNRTIs showed less inter-individual (CVinter 54.8% versus 84.3%) and intra-individual (CVintra 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.
Keywords: HIV , therapeutic drug monitoring , inter-individual and intra-individual variability