Shinsuke Inoue: No financial relationships to disclose
Objectives: The objective of this population pharmacokinetic and pharmacodynamic (PKPD) analysis was to characterize PKPD relationship of MT-4561 and identify the bromodomain-containing protein 4 (BRD4) reduction that exerts the drug effect.
Methods: Two nonclinical studies in xenograft mice were performed and used for the analysis: One is PKPD study to characterize the time course of MT-4561 concentrations in plasma and tumor, and BRD4 protein levels in tumor. Another is a pivotal nonclinical efficacy study to verify the efficacy based on the reduction in tumor size. Based on the PKPD study, a population PKPD model for MT-4561 was developed to predict average BRD4 reduction from baseline over a week in mice in the pivotal efficacy study. Population PKPD model was developed sequentially. A plasma PK model was developed, and tumor compartments were added to describe the PK profile in the tumor. Then, an indirect model was used to describe BRD4 time course. Based on the mechanism of inducing degradation of proteins, an indirect model promoting degradation was selected. Finally, the average BRD4 reduction from baseline was used to explore the exposure-response relationship between reduction in BRD4 and tumor size in xenograft mice to guide the target threshold for exerting efficacy.
Results: The nonclinical PKPD study showed a large difference in the elimination between plasma and tumor concentrations. Elimination from plasma was completed in approximately 24 hours while sustained exposure in the tumor was observed for 168 hours. This unique PK profile in plasma and tumor was described by 2-compartment model with an effect compartment. An indirect response model well described BRD4 expression in tumor. Finally, tumor regression was observed with increasing BRD4 reduction. When a linear model was fitted, the slope was -2.46 %/% and the intercept was 182%.
Conclusions: Despite rapid elimination from plasma, concentrations in tumor and BRD4 reduction are sustained, justifying the once weekly intravenous dosing in a first in human trial. Tumor regression effect of MT-4561 was expected at 74% of the average reduction of BRD4 protein in tumor.
Citations: None
Keywords: Protein degrader, bromodomain-containing protein 4, oncology
