title: Novel method to assess antiretroviral target trough concentrations using in vitro susceptibility data.
abstract: Durable suppression of HIV-1 replication requires the establishment of antiretroviral drug concentrations that exceed the susceptibility of the virus strain(s) infecting the patient. Minimum plasma drug concentrations (C(trough)) are correlated with response, but determination of target C(trough) values is hindered by a paucity of in vivo concentration-response data. In the absence of these data, in vitro susceptibility measurements, adjusted for serum protein binding, can provide estimations of suppressive in vivo drug concentrations. We derived serum protein binding correction factors (PBCF) for protease inhibitors, nonnucleoside reverse transcriptase inhibitors, and an integrase inhibitor by measuring the effect of a range of human serum concentrations on in vitro drug susceptibility measured with the PhenoSense HIV assay. PBCFs corresponding to 100% HS were extrapolated using linear regression and ranged from 1.4 for nevirapine to 77 for nelfinavir. Using the mean 95% inhibitory concentration (IC(95)) for ≥1,200 drug-susceptible viruses, we calculated protein-bound IC(95) (PBIC(95)) values. PBIC(95) values were concordant with the minimum effective C(trough) values that were established in well-designed pharmacodynamic studies (e.g., indinavir, saquinavir, and amprenavir). In other cases, the PBIC(95) values were notably lower (e.g., darunavir, efavirenz, and nevirapine) or higher (nelfinavir and etravirine) than existing target recommendations. The establishment of PBIC(95) values as described here provides a convenient and standardized approach for estimation of the minimum drug exposure that is required to maintain viral suppression and prevent the emergence of drug-resistant variants, particularly when in vivo concentration-response relationships are lacking.
authors.affiliation: Division of Clinical Pharmacology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA. eacosta@uab.edu
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Kay L
authors.initials: KL
authors.lastname: Limoli
authors.forename: Lan
authors.initials: L
authors.lastname: Trinh
authors.forename: Neil T
authors.initials: NT
authors.lastname: Parkin
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: King
authors.forename: Jodi M
authors.initials: JM
authors.lastname: Weidler
authors.forename: Ighovwerha
authors.initials: I
authors.lastname: Ofotokun
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
mesh_terms: D001681:Biological Assay; D001798:Blood Proteins / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019428:HIV Integrase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D011485:Protein Binding; D012044:Regression Analysis; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D001798:Blood Proteins; D019428:HIV Integrase Inhibitors; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors