Proposed Scheme for Dosing Venetoclax in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships

M. Badawi and S. Gopalakrishnan equally contributed to this work Introduction: Venetoclax is a selective BCL2 inhibitor approved for patients with CLL and patients with newly diagnosed AML who are ineligible for induction chemotherapy. Venetoclax is currently being evaluated in other hematologic and solid tumors in both adult and pediatric populations. In this analysis, we characterized the pharmacokinetics and exposure response relationships of venetoclax to guide dose selection of venetoclax in combination with high dose cytarabine (HDAC) in pediatric patients with relapsed or refractory AML. Methods: A population PK model describing venetoclax PK in pediatric patients was developed using data from 121 subjects across three venetoclax studies that tested venetoclax at 400-800 mg doses across different tumors. The model accounted for the CYP3A4 developmental changes in early years of life using a maturation function and allometric scaling was also incorporated in the model to account for growth and body size effect. Individual subject average venetoclax plasma concentration (Cavg) up to the event of interest, determined based on the population PK analysis using the post-hoc empirical Bayesian parameter estimates, was used as an exposure metric to explore exposure-efficacy and exposure-safety relationships. Data from subjects with AML (database version 23-Mar-2020) who received venetoclax in combination with either azacitidine, decitabine, or cytarabine were included in the exposure-efficacy and exposure-safety analyses. The population PK model was then used to simulate venetoclax exposures in pediatric subgroups to guide dose selection for future trials. Results: Population PK estimates (clearance, volume of distribution, rate of absorption and peripheral volume of distribution) were comparable to previously reported estimates. Additionally, weight was identified as a statistically significant covariate on clearance and volume of distribution. Exposure-response analyses showed a flat relationship between venetoclax exposures and efficacy in patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine. Moreover, venetoclax exposures did not correlate with incidence of neutropenia. Specifically, in AML patients who received venetoclax in combination with HDAC (>500-2000 mg/m2/day, n=15), higher venetoclax exposures were not associated with better clinical response. A 600 mg dose of venetoclax was selected based on hig