Background: BMS-663068 is a prodrug of BMS-626529, an attachment inhibitor that binds to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+ T-cells. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling of Phase 2 data was performed to guide dose selection for subsequent studies.
Methods: PK/PD data from two Phase 2 studies (AI438006, AI438011) in HIV-1-infected subjects (N=244) were used to develop a population PK model for BMS-626529 using non-linear mixed effects modelling (NONMEM v.7.2.0). Subsequently, relationships between IC50-normalized BMS-626529 systemic exposure (Cmax, Cssavg, Ctau) and efficacy/safety variables during monotherapy or after 24/48 weeks of combination therapy, were investigated using linear models. Monte-Carlo methods were used to assess the probability of achieving a decline of >0.5 (per FDA draft guidance) or >1.0 log10 c/mL in HIV-1 RNA from baseline (BL) as a function of BMS-626529 systemic exposure after 7 days of BMS-663068 monotherapy for 5 proposed BMS-663068 doses (400mg/600mg [not studied clinically]/800mg BID and 600mg/1200mg QD).
Results: A 2-compartment model with 1st-order elimination from the central compartment, zero-order release into a hypothetical absorption compartment, and 1st-order absorption into the central compartment described the PK of BMS-626529. The categorical covariates (ritonavir co-administration, BMS-663068 formulation type) and the continuous covariates (lean body mass, BL CD8%) were significant in the model. After 7 days of BMS-663068 monotherapy, BL BMS-626529 protein-binding adjusted IC50 (PBAIC50) influenced HIV-1 RNA decline and a clear relationship was observed between loge-transformed PBAIC50-adjusted Ctau and change in HIV-1 RNA from BL (log10 c/mL). No trends were observed between BMS-626529 systemic exposure and other efficacy/safety variables during BMS-663068 monotherapy or after 24/48 weeks of combination therapy. After 7 days of simulated BMS-663068 monotherapy, the probability of achieving a decline in HIV-1 RNA of >0.5 log10 c/mL or >1 log10 c/mL as a function of loge PBAIC50-adjusted Ctau was predicted to be 99–100% and 57–73%, respectively across the doses (Table).
Conclusions: Simulations showed an advantage of BID over QD dosing and a similar probability of achieving a decline of >1 log10 c/mL across the 400, 600 and 800mg BID doses. Combined with clinical and safety observations, a 600mg BID dose of BMS-663068 was predicted to have the best benefit–risk profile and was selected for further study.
Predicted probability of achieving a decline in HIV-1 RNA of >0.5 or >1.0 log10 copies/mL after 7 days of BMS-663068 monotherapy, as a function of loge PBAIC50-adjusted Ctau