2019 ACOP: A Semi-physiological Population Pharmacokinetic Model Developed Using Clinical Dose Escalation and Dose Confirmation Data for an Oral Fixed-Dose Combination of CDA Inhibitor Cedazuridine with Decitabine (ASTX727) in Subjects with Myelodysplastic Syndromes
Abstract
Objectives:
Cytidine deaminase (CDA) rapidly degrades decitabine (DAC), an approved treatment for myelodysplastic syndromes, resulting in poor and variable bioavailability. Low doses of oral DAC co-administered with a novel and potent CDA inhibitor, cedazuridine (E7727), have been shown in clinic to produce exposures similar to IV DAC with acceptable inter-patient variability. The objective of this work was to further develop a semi-physiological population PK model ([1]) to characterize the PK enhancement of oral DAC when co-administered with cedazuridine and to identify potential covariates that impact the PK of DAC and/or cedazuridine.
Methods:
Model development utilized serial cedazuridine and DAC plasma concentration observations of IV DAC, oral DAC, and cedazuridine monotherapies and DAC+cedazuridine combinations. Observations from Phase 1/2 Study ASTX727-01 included dose escalation data (n=43; cohorts of 40:20, 60:20, 100:20, 100:40, and 100:30 mg cedazuridine:DAC with n=6 per cohort), dose confirmation data (n=42; 35:100 mg cedazuridine:DAC), and an FDC formulation extension (n=26). R was used for data processing, exploratory analysis, and visual predictive checks, while model development and parameter estimation utilized NONMEM. Covariate effects were explored using a full model approach.
Results:
Mono- and combination therapy data were sequentially integrated into a semi-physiological population PK model. Semi-physiological structural modeling elements included an IV DAC depot, oral DAC and cedazuridine transit compartment absorption, and portal vein, liver, central, and peripheral compartments. CDA metabolism of DAC primarily occurs in the liver compartment, with additional extra-hepatic metabolism. A maximum effect (Emax) inhibition model, dependent on local cedazuridine concentrations, described the drug effect of the oral ASTX727 combination therapy on CDA metabolism of DAC. IV DAC data were used to parameterize distribution and metabolism of DAC, while oral DAC monotherapy data was used to parameterize oral absorption. cedazuridine mono- and combination therapy data were used to parameterize cedazuridine PK parameters. Stratified individual-level random effects did not demonstrate systematic biases for any covariates, including weight-based effects.
Conclusions:
A semi-physiological population PK model was sequentially developed from mono- and combination therapy observations of plasma concentrations from the ASTX727-01 dose escalation and confirmation study. The analysis characterized the PK enhancement of oral DAC when co-administered with cedazuridine across a range of dose regimens and found no significant covariate effects, including weight-based effects. The resulting model will be used to interpret outcomes from an ongoing Phase 3 study (FDC ASTX727 of 35 mg DAC / 100 mg cedazuridine), while simulations will quantitatively inform future clinical development of ASTX727.
