(W0930-10-56) Leveraging Cross-Species Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling to Drive Discovery Efforts of a Novel Protein Degrader

Purpose: The appropriate use of Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is invaluable in the progression of new chemical entities. It can aid in modality choice and guide lead optimization and selection by ensuring the optimal study designs for both pre-clinical and clinical studies. For protein degraders, understanding target kinetics across species are critical in defining PD thresholds for efficacy and tolerability. This work highlights a compound that demonstrated robust anti-tumor efficacy in rodent xenografts but exhibited dose limiting toxicity in monkeys. A PK/PD model was developed that integrated preclinical data and informed dose selection and regimens for toxicology studies. PK/PD to efficacy translation across species was also used for projecting the efficacious dose in humans.

Methods: Dose ranging studies (0.3-10 mg/kg) in rodent xenograft models were used to establish a quantitative relationship between target degradation in tumors and efficacy. A mechanistic PK/PD model was developed to characterize the target degradation rate kinetics based on single dose PK/PD studies in rodent xenograft and cynomolgus monkey. PD in rodents was measured in tumors while in monkey it was measured in blood leukocytes. The PK/PD model incorporated target kinetics including resynthesis, degradation and turnover rates. Simulations were conducted to optimize the experimental design of key non-terminal toxicology studies in monkeys ensuring hazard identification in the context of pharmacologically relevant exposures. The PK/PD model was also used in projecting the efficacious human dose by establishing the PD/efficacy relationship in rodent xenograft models.

Results: Efficacy/PK/PD studies in rodent xenograft models suggested that 70% sustained target degradation was required for robust efficacy. Mechanistic PK/PD modeling demonstrated that target resynthesis rate kinetics was 5 fold slower in monkey compared to rodents. The PK/PD model was used in the selection of doses for exploratory monkey toxicology studies. Visual predictive check of observed vs predicted data from continuous and intermittent schedule toxicology studies demonstrated good prediction of monkey PK and PD profiles. The efficacious dose in humans projected to achieve 70% sustained target degradation using the PK/PD model was 1 mg QD.

Conclusion: Mechanistic PK/PD modeling was critical in understanding the species difference in target kinetics. It helped calibrate PD requirements for efficacy with the appropriate selection of doses for exploratory monkey toxicology studies and for projecting the human efficacious dose.

Figure 1: PD-Efficacy Relationship was established in Rodent Xenograft Models.

Figure 2: Target degradation kinetics are different between rodent xenografts and monkeys.

Figure 3: PK/PD model integrates drug PK parameters with target kinetics. PK is described by either a 1 compartment or a 2 compartment model based on the species.