Novel Method To Assess Antiretroviral Target Trough Concentrations Using In Vitro Susceptibility Data

• Type of Material: Article
• Authors: Edward P. Acosta, University of Alabama Birmingham; Kay L. Limoli, Monogram Biosciences, Inc.; Lan Trinh, Monogram Biosciences, Inc.; Neil T. Parkin, Data First Consulting Inc; Jennifer R. King, University of Alabama Birmingham; Jodi M. Weidler, Monogram Biosciences, Inc.; Ighoverha Ofotokun, Emory University; Christos J. Petropoulos, Monogram Biosciences, Inc.
• Language: English
• Date: 2012-11-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2012, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.00691-12
• Title of Journal or Parent Work: Antimicrobial Agents and Chemotherapy
• ISSN: 0066-4804
• Volume: 56
• Issue: 11
• Start Page: 5938
• End Page: 5945
• Grant/Funding Information: Development of the Monogram PhenoSense and GeneSeq integrase assays was supported by a grant from the NIH/NIAID, SBIR-AT 5 R44 AI057074.; E.A. is the recipient of NIH grant R01 AI05869.
• Keywords: BOOSTED PROTEASE INHIBITORS; PHARMACOLOGY & PHARMACY; INHIBITOR-EXPERIENCED PATIENTS; PHENOTYPIC SUSCEPTIBILITY; Science & Technology; Microbiology; VIROLOGICAL RESPONSE; HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-1-INFECTED PATIENTS; WILD-TYPE; Pharmacology & Pharmacy; ANTIVIRAL ACTIVITY; MICROBIOLOGY; TREATMENT-NAIVE; Life Sciences & Biomedicine; DRUG SUSCEPTIBILITY
• Research Categories: Health Sciences, Pharmacology

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, nonnucleo-side 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 nevirap ine 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. Copyright