title: Characterizing Class-Specific Exposure-Viral Load Suppression Response of HIV Antiretrovirals Using A Model-Based Meta-Analysis.
abstract: We applied model-based meta-analysis of viral suppression as a function of drug exposure and in vitro potency for short-term monotherapy in human immunodeficiency virus type 1 (HIV-1)-infected treatment-naïve patients to set pharmacokinetic targets for development of nonnucleoside reverse transcriptase inhibitors (NNRTIs) and integrase strand transfer inhibitors (InSTIs). We developed class-specific models relating viral load kinetics from monotherapy studies to potency normalized steady-state trough plasma concentrations. These models were integrated with a literature assessment of doses which demonstrated to have long-term efficacy in combination therapy, in order to set steady-state trough concentration targets of 6.17- and 2.15-fold above potency for NNRTIs and InSTIs, respectively. Both the models developed and the pharmacokinetic targets derived can be used to guide compound selection during preclinical development and to predict the dose-response of new antiretrovirals to inform early clinical trial design.
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: Y F
authors.initials: YF
authors.lastname: Li
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dockendorf
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tetteh
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Rizk
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Grobler
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: M-T
authors.initials: MT
authors.lastname: Lai
authors.affiliation: Center of Translational Science, University of Maryland School of Pharmacy, Baltimore, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gobburu
authors.affiliation: Merck Sharp & Dohme Corp, Kenilworth, New Jersey, USA.
authors.forename: W
authors.initials: W
authors.lastname: Ankrom
mesh_terms: D019380:Anti-HIV Agents / Q000145:classification* / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D019428:HIV Integrase Inhibitors / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D019562:Viral Load / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D018894:Reverse Transcriptase Inhibitors