title: Are plasma levels valid surrogates for cellular concentrations of antiretroviral drugs in HIV-infected patients?
abstract: Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients. TPC levels were analysed by high-performance liquid chromatography with ultraviolet detection and CC by LC-MS/MS from peripheral blood mononuclear cells. The best correlations between TPC and CC were observed for nelfinavir (NFV, slope=0.93, r=0.85), saquinavir (SQV, slope=0.76, r=0.80) and lopinavir (LPV, slope=0.87, r=0.63). By contrast, TPC of efavirenz (EFV) exhibited a moderate correlation with CC (slope=0.69, r=0.58), while no correlation was found for nevirapine (NVP, slope=-0.3, r=0.1). Interindividual variability in the CC/TPC ratio was lower for protease inhibitors (coefficients of variation 76%, 61%, and 80% for SQV, NFV and LPV, respectively) than for nonnucleoside reverse transcriptase inhibitors (coefficients of variation 101% and 318%, for EFV and NVP). As routine CC measurement raises practical difficulties, well-correlated plasma concentrations (ie, NFV, SQV and LPV) can probably be considered as appropriate surrogates for cellular drug exposure. For drugs such as EFV or NVP, there may be room for therapeutic drug monitoring improvement using either direct CC determination or other predictive factors such as genotyping of transporters or metabolizing enzyme genes.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital of Bern, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Colombo
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Belle L
authors.initials: BL
authors.lastname: Lee
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biollaz
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood* / Q000493:pharmacokinetics; D015331:Cohort Studies; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018894:Reverse Transcriptase Inhibitors / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors