Advancing Modeling of Hematologic Safety using a Semi-mechanistic Multivariate PK/PD Approach: Application to the ATR Inhibitor Tuvusertib in Early Phase Oncology Development

• DOI: 10.70534/uapn6715
• Publication Date: 2025-02-18T14:45:56Z
• Authors: Jatinder Kaur Mukker; Paul Diderichsen; Farina Hellmann; Ioannis Gounaris; Wei Gao; Rainer Strotmann; Karthik Venkatakr...

Background: The modeling of drug effects on myelopoiesis is widely used to inform dose and schedule optimization in development. While many examples exist for neutropenia, applications describing anemia are fewer, with delayed attainment peak effect hemoglobin (HGB) introducing additional complexity when analyzing short-term data early clinical Tuvusertib a potent, selective, orally administered ATR inhibitor currently phase1/2 Anemia has been reported as limiting toxicity during the escalation phase DDRiver Solid Tumors 301 study (NCT04170153), indicating exposure dependency. To provide quantitative metrics guide dosing regimen selection through model-based development, semi-mechanistic multivariate PK/PD model was developed link tuvusertib hematology data.Methods: Data analyzed from Phase 1 (Part A1) [1] patients advanced solid tumors (N&#3f55). A non-linear mixed describe PK tuvusertib, subsequently, relationship between individual predicted concentrations observed reticulocytes (RET), red blood cells (RBC), HGB levels. Both RET RBC were included dynamically reinforce reliable prediction long-term multi-cycle treatment, even if may not have escalation.Results: 2-compartment population (popPK) an estimated absorption lag clearance via “clearance compartment”. semi-mechanistic, consisted 3 serial cell systems, i.e., progenitor (PC), RET, [2] (each 4 transit compartments). EMAX PC production, two negative feedback mechanisms counts PC. scaled sum RBC. popPK adequately described profile tuvusertib. Estimated apparent central volume distribution 30.0 L; 55.7 L/h. In model, EC50 736 ng/mL. Models qualified based standard diagnostics, evaluated using pcVPC bootstrap, data. No statistically significant covariates identified. Multi-cycle simulations suggested that 180 mg QD 2w on/1w off allowed partial recovery one-week break; however, 130 showed no resulted lower levels than regimen.Conclusions: models joint allowing various continuous intermittent regimens strategy tuvusertib.Citations: 1. Yap TA, et al. Clin Cancer Res. 2024. doi: 10.1158/1078-0432.CCR-23-2409.2. Zhang X, CPT Pharmacometrics Syst Pharmacol. 2017 Dec;6(12): 804-13