PK-PD modelling to support go/no go decisions for a novel gp120 inhibitor
PLS Chan, E van Schaick, G Langdon, J Davis, T Parkinson, L McFadyen
Objectives: PF-00821385 is a specific inhibitor of HIV-1 gp120 mediated cell-cell fusion. Inhibitors of HIV-1 gp120 represent a novel mechanistic approach with the promise of activity against both CXCR4 and CCR5-using B-clade viruses. The aim of this analysis was to describe the population pharmacokinetics (PK) of PF‑00821385 in healthy subjects and to use this to update a Pharmacokinetic-Pharmacodynamic Disease (PK-PD-Disease) model based on preclinical data to predict a likely oral dose to achieve a 1.5 log drop in viral load (VL) following 10 days of treatment.
Methods: Single doses of PF-00821385 were dosed orally to 24 healthy male volunteers. The maximum tolerated dose was 1300 mg. A total of 969 concentrations were available for modelling and population PK parameters were estimated using NONMEM.Using only scaled preclinical data (animal PK and in vitro IC90 data) a PK-PD-disease model previously developed to describe viral load changes for CCR5 antagonists was adapted to evaluate, by simulation, possible clinical doses of PF‑00821385. Trial Simulator 2.2 (Pharsight Corp.) was used. Simulations for gp120 antagonists are complicated by high variability in assay sensitivity, thus two IC50 targets were utilised viz., low of 121 ng/mL and high of 489 ng/mL. These represent scaling of the median and upper limit of sensitivity of IC90 values for PF-00821285 in a panel of clinical virus isolates (Virologic Phenosense assay).New simulations were performed with the model updated with human PK data.
Results: A two-compartment disposition model with first-order absorption was used to fit the log-transformed plasma concentrations. The population estimated rate of absorption (ka) was 0.597 h-1 with an elimination half-life during the initial phase of 0.3 hours. If the "true" IC50 for PF-00821385 was low (121 ng/mL), the minimum predicted B.I.D. dose required for 1.5 log drop in VL was 319 mg. If the "true" IC50 was high (489 ng/mL), the minimum predicted Q.D. and B.I.D. doses were above 1300 mg. Further simulations were performed with theoretical assumptions on ka changes to predict likely doses for controlled-release formulations. A minimum predicted dose of 1000 mg was required for IC50 of 489 ng/mL.
Conclusions: The predicted dose required to target 70% of Clade B virus isolates was close to or above the maximum tolerated dose of PF-00821385. A controlled release formulation could improve the PK characteristics, but would only be of utility in the treatment of a narrow spectrum of viral sensitivities.
Based on this outcome, further development of PF-00821385 will not be pursued.
