Pre-clinical Population PK Model of CF-301 - a Novel Antibacterial Lysin
Joannellyn Chiu (1) Tatiana Khariton (1) Parviz Ghahramani (1) Paula Lapinskas (2) Cara Cassino (2) Teresa Carabeo (2)
(1) Inncelerex, Jersey City, New Jersey (2) ContraFect Corporation, Yonkers, New York
Background: CF-301 is a lysin with rapid S. aureus-specific bacteriolysis that completed Phase 1 trial [1].
Objectives: To develop a pre-clinical population PK model (PPK) for CF-301 in animal species (rats and dogs) and apply interspecies scaling to predict human exposures over a range of doses.
Methods: Data was pooled from 10 PK studies in rats and dogs with various infusion regimens. 1, 2 and 3-compartmental models with zero-order infusion were evaluated using interspecies scaling on PK parameters. Covariates sex, age, formulation, total daily dose were assessed. The PPK model was validated with bootstrap and VPC. The animal PK model was allometrically scaled to predict human exposures (AUC and Cmax) over the dose range 0.12 to 1.6 mg/kg 2-hour IV infusion. The predicted human exposures from animal PPK model were compared to predicted exposures from human PPK model [1].
Results: Data included 393 animals (78 dogs, 315 rats), 2083 observations. A 3-compartment linear model with zero-order absorption adequately described the animal PK data. All fixed effect parameters were estimated with good precision (%RSE<11%). Sex was a primary predictor of V2. For a given weight of 0.304 kg, male and female rats were predicted to have comparable Cmax and AUC0-24. Total daily dose was found to be a predictor of CL and V1. For example, CL and V1 were estimated to be 3% and 4% higher for 2.5 mg dose vs 5 mg dose, respectively. Model validations support that the animal PPK model adequately describes the data. There was no significant effect of age or formulation on PK parameters. When comparing predicted human exposures from the animal PK model to exposures predicted from a human PK model, the difference in AUC0-24 and Cmax were <40% for doses ranging 0.12-0.8 mg/kg in human, which indicates a reasonable agreement between the two models. The predicted exposures from animals for a human dose of 1.6 mg/kg overestimated exposures by approximately 2-fold.
Conclusion: The population PK model parsimoniously described the data for both animal species and was deemed to be suitable for simulations to predict PK profiles in rats and dogs at various doses. Total daily dose was found to be statistically significant on CL and V1, but not clinically meaningful (<%5 effect). No meaningful effect of sex was detected on PK parameters. The allometric scaling of animal PPK model adequately predicted the exposures of CF-301 in humans within the dose range 0.12-0.8 mg/kg 2-h IV infusion.
References:
[1] Khariton T, Chiu J, Cassino C, Ghahramani P (2017) Human Population PK Model, Dose Selection and Target Attainment Simulations for CF-301 - a Novel Antibacterial Lysin, PAGE, Budapest.