(T-021) Semi-physiological population pharmacokinetic (PPK) model using dose optimization data for ASTX030, an oral fixed-dose combination (FDC) of CDA inhibitor cedazuridine and azacitidine in MDS patients

Ahmed Elmokadem, PhD – Senior Scientist, Metrum Research Group; Yuri Sano, MD, PhD – Sr. Medical Director, Clinical Development, Taiho Oncology, Inc.; Harold Keer, MD, PhD – Chief Medical Officer, Taiho Oncology, Inc.; Aram Oganesian, PhD, DABT – VP, Clinical Pharmacology, Taiho Oncology, Inc.

Objectives: Cytidine deaminase (CDA) rapidly degrades azacitidine (AZA), an approved parenteral treatment for myelodysplastic syndromes (MDS), resulting in poor and variable bioavailability. ASTX030, an oral fixed-dose combination (FDC) of AZA with the CDA inhibitor cedazuridine (CED), produces systemic exposures similar to subcutaneous (SC) AZA with acceptable inter-patient variability. Here, a semi-physiological population pharmacokinetic (PPK) model was developed and qualified to assess the comparable bioavailability of SC AZA and ASTX030 at different AZA and CED dose level combinations.

Methods: A previously developed semi-physiological PPK model [1] that characterized the PK enhancement of oral decitabine when dosed with CED (ASTX727) was utilized and the parameters were updated using data from a phase 1 first-in-human dose optimization study for ASTX030 (NCT04256317). The model included semi-physiologic elements (SC AZA depot, oral AZA and CED transit compartment absorption and portal vein, liver, central and peripheral compartments) and a competitive inhibition model describing CED effect on AZA metabolism which was assumed to occur in the gut, liver, and systemic circulation. A sequential modeling approach was adopted where CED model parameters were fixed to the previously estimated values for ASTX727, assuming similar CED PK, then a simulation was run to obtain the CED concentrations in gut, liver, and systemic circulation. These concentrations were then used to influence the inhibitory effect on AZA clearance in these respective compartments. The model used height to scale physiological parameters. Pearson correlation (r) was used for data processing, exploratory analysis, and visual predictive checks (VPCs), while parameter estimation utilized NONMEM.

Results: The developed semi-physiologic model parameters were estimated using phase 1 ASTX030 data (n = 68). The model’s performance was evaluated using standard goodness-of-fit plots and visual predictive checks (VPCs) that compared model predictions to the observed data. Parameter uncertainty was quantified using bootstrapping (600 samples).

Conclusions: A semi-physiologic PPK model was sequentially developed using ASTX030 phase 1 trial data to characterize the PK enhancement of oral AZA when dosed with CED. Simulations will inform future clinical development of ASTX030 and evaluate the appropriate AZA:CED doses in FDC that would achieve a comparable exposure to the SC AZA dosing.

Citations: [1] Burroughs, E., Oganesian, A., Zhang, X. and Hoke, F. Development of a Semi-Mechanistic PK/PD Model of an Oral Fixed Dose Combination (FDC) of Cytidine Deaminase Inhibitor E7727 with Decitabine (ASTX727) in Subjects withMyelodysplastic Syndromes. ASCPT AnnualMeeting. 2017. Available: https://astx.com/wp-content/uploads/2017/03/2017_ASTX727_Poster_ASCPT_Oganesian_Final-web.pdf