Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529

Antimicrobial Agents and Chemotherapy
Ishani Savant LandryRichard Bertz

Abstract

BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4(+) T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8(+) T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level ...Continue Reading

References

Apr 25, 2015·AIDS Research and Therapy·Weerawat ManosuthiUNKNOWN Adults and Adolescents Committee of the Thai National HIV Guidelines Working Group

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Citations

Mar 12, 2020·The Journal of Antimicrobial Chemotherapy·Yagai BoubaMaria Mercedes Santoro
Mar 4, 2020·Pharmaceuticals·Alexej Dick, Simon Cocklin
May 18, 2020·British Journal of Clinical Pharmacology·Morris Muliaditan, Oscar Della Pasqua
Feb 7, 2021·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Elias B Chahine
Dec 23, 2017·Journal of Medicinal Chemistry·Nicholas A MeanwellJohn F Kadow

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