Human Population PK Model, Dose Selection and Target Attainment Simulations for CF-301 - a Novel Antibacterial Lysin
Tatiana Khariton (1), Joannellyn Chiu (1), Cara Cassino (2), Parviz Ghahramani (1)
(1) Inncelerex, Jersey City, NJ, (2) ContraFect Corporation, Yonkers, NY
Introduction: CF-301, a novel bacteriophage-derived lysin that has completed the first Phase 1 trial in the US, is being developed for treatment of S. aureus bacteremia, exhibits rapid S. aureus-specific bacteriolysis, anti-biofilm activity, has low propensity for resistance and pronounced synergy with antibiotics.
Objectives: To develop a population PK model for CF-301 in humans and to perform target attainment simulations to determine optimal clinical doses for Phase 2 study in patients.
Methods: Data from 13 healthy subjects (receiving single doses of CF-301, 0.04-0.4 mg/kg 2-hr infusion) were used to develop the population PK model. The clinical relevance of statistically significant covariates was assessed based on the magnitude of effect on the PK profiles. The final PK model was used to perform target attainment simulations for various IV dosing regimens to select optimal dose for the first study in patients.
Results: 200 CF-301 plasma concentrations were available for the analysis. Two-compartment model with proportional residual error described the data best. PK parameters were well estimated, CL=7 L/h (RSE=5.4%) and Vc=6.5 L (RSE=6.5%). Influence of weight, gender, age, race and dose was assessed on clearance and volume of distribution. Sex and weight were determined to be statistically significant covariates for CL. Based on these detectable covariate effects, females are expected to have ≤15% lower AUC or Cmax than males; impact of weight on AUC and Cmax was ≤25%. Dose was a statistically significant covariate on CL and Vc. The relationship between dose and AUC or Cmax was determined to be linear, but less than dose proportional with a slope of ~0.75. Target attainment simulations determined that doses 0.12-0.4 mg/kg (2-hr infusions) maintain AUC and Cmax above clinically relevant exposures.
Conclusions: The population model described the PK of CF-301 adequately. Weight and sex, although statistically significant covariates, were not clinically relevant (≤25% effect). PK of CF-301 was linear, but not dose-proportional with a 2-fold increase in dose resulting in a 1.75-fold increase in Cmax and AUC. Target attainment simulations predicted doses of 0.12-0.4 mg/kg (2-hr infusion) to be efficacious with almost all patients expected to achieve targets (AUC/MIC≥0.5), that are expected to be efficacious.