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

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 of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.).

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

BMS-626529 population PK model. AMT, administered treatment; CL, apparent oral clearance; DUR, estimated duration of BMS-663068 release from the extended-release formulation; F1, relative bioavailability; KA, first-order absorption rate constant; Q, intercompartmental clearance; V2, volume of distribution of the central compartment; V3, volume of distribution of the peripheral compartment.

FIG 2

Predicted fold change in PK parameters due to covariate effects. Categorical covariates were RTV coadministration and dry granulation formulation, where the diamonds represent the estimated change in the parameter due to the covariate and whiskers represent the 95% confidence interval of the estimate. Continuous covariates were LBM and the baseline CD8+ percentage, where the diamonds represent the reference values and whiskers represent the change in the parameter at the minimum and maximum value of the covariate (noted on plot). Dashed lines represent a 25% change in the parameter relative to the value for the reference individual who received the wet granulation formulation without RTV. 1, exponent for the effect of the median-normalized baseline LBM on CL; 2, exponent for the effect of the median-normalized baseline CD8+ percentage on CL; 3, change relative to the reference treatment (BMS-663068 dosed without RTV); 4, change relative to the reference formulation (the wet granulation). BL, baseline; CL, apparent oral clearance; DUR, estimated duration of BMS-663068 release from the extended-release formulation; F1, relative bioavailability; LBM, lean body mass; RTV, ritonavir.

FIG 3

Prediction-corrected visual predictive checks for the final population PK model. (A) Linear plot; (B) semilogarithmic plot. Solid black lines, 5th, 50th, and 95th percentiles of the prediction-corrected observations from bottom to top, respectively; gray bands, 90% confidence intervals for the 5th, 50th, and 95th percentiles of the prediction-corrected simulated values (500 replicates) from bottom to top, respectively.

FIG 4

Relationship between PBAIC50-adjusted Ctau and change in the HIV-1 RNA level from the baseline level (log10 copies/ml) after 7 days of BMS-663068 monotherapy. CI, confidence interval; Ctau, concentration at the end of a dosing interval; PBAIC50, protein binding-adjusted BMS-663068 half-maximal (50%) inhibitory concentration.

FIG 5

Model-predicted relationship between an HIV-1 RNA level of Ctau) at week 24 (observed population). The predicted probabilities of a value of 1 for the antiviral response variable for the observed population at a baseline log10 HIV-1 RNA level of 4.795 log10 copies/ml are shown. Ctau, concentration at the end of a dosing interval.

FIG 6

Probability of achieving a decline in the HIV-1 RNA level of >0.5 log10 copies/ml and >1 log10 copies/ml from the baseline level as a function of the BMS-626529 loge PBAIC50-adjusted Ctau. Closed squares at bottom and top for each dose, 5th and 95th percentiles, respectively; bottoms and tops of bars, 10th and 90th percentiles, respectively; bottoms and tops of large open squares, interquartile range; solid horizontal bars, medians; dotted lines, means; dashed lines, target change in viral loads. BID, twice daily; Ctau, concentration at the end of a dosing interval; PBAIC50, protein binding-adjusted BMS-663068 half-maximal (50%) inhibitory concentration; QD, once daily; log10 c/ml, log10 copies/ml.