Population Pharmacokinetic and Exposure-Response Analyses of Tasurgratinib in Subjects with Unresectable Advanced or Metastatic Cholangiocarcinoma with Fibroblast Growth Factor Receptor 2 Gene Fusion
Authors: Umetsu Yuko , Nomoto Maiko , Funasaka Setsuo , Hussein Ziad , Yasuda Sanae , Takenaka Osamu 
Published: February 2025

Objectives: Tasurgratinib is an oral tyrosine kinase inhibitor that selectively inhibits the kinase activities of fibroblast growth factor receptor (FGFR) 1-3. Population pharmacokinetic (PopPK) analysis was performed to characterize the PK of tasurgratinib and its pharmacologically active metabolite M2 in subjects with cholangiocarcinoma (CCA) and other solid tumors. Exposure-response (E-R) analyses were performed to evaluate the relationships between sum of model-predicted exposure (AUC at steady state [AUCss]) of tasurgratinib and M2 and blood biomarkers (phosphate, FGF23 and 1,25-(OH)2-Vitamin D [DHVD]) or efficacy (objective response and progression free survival), and between model-predicted exposure (AUCss or Cmax at steady state [Css,max]) of tasurgratinib or M2 and safety (treatment-emergent adverse events [TEAEs]). Methods: Data from two clinical studies (N&#3f93) [1-3] were used for PopPK analysis and E-R analyses for biomarkers and safety, and the data from one of these studies (N&#3f63, CCA only) [3] were used for E-R analysis for efficacy. The PopPK, conducted separately for tasurgratinib and M2, and E-R analyses for biomarkers were performed using NONMEM. The relationships between exposure and efficacy or safety were evaluated graphically. Results: The PK of tasurgratinib was best described by a 2-compartment model with simultaneous zero and first order absorption and linear elimination from the central compartment. No statistically significant covariates were identified. The PK of M2 was best described by a 2-compartment model with simultaneous zero and first order formation with lag time and linear elimination from the central compartment. Apparent clearance of M2 in subjects with CCA was 41% higher compared to other solid tumors. No other statistically significant covariates were identified. The E-R relationships for phosphate, FGF23 and DHVD were best described by Emax or sigmoid Emax models. No statistically significant covariates were identified in any of the E-R models. At the sum of AUCss of tasurgratinib and M2 at the clinical recommended dose of 140 mg once daily (QD), both the increase in phosphate and FGF23 almost reached their model-predicted maximums. However, the increase in DHVD was slightly lower than the model-predicted maximum. There was no clear relationship between sum of AUCss of tasurgratinib and M2 and efficacy. Subjects with higher hyperphosphatemia grade tended to have higher tasurgratinib or M2 exposure (AUCss or Css,max) than those without hyperphosphatemia. No clear relationship was observed for other TEAEs. Conclusions: The PopPK models described the PK of tasurgratinib and M2 adequately. The E-R models well described the relationships between the sum of AUCss of tasurgratinib and M2 and each biomarker. Based on these E-R models, the approximately maximum increase in biomarkers can be expected at the dose of 140 mg QD; which supports the dosage is optimal as clinical recommended dose of tasurgratinib.Citations: [1] Koyama T, et al. Cancer Sci. 2020;111(2):571-579. [2] Morizane C, et al. Ann Oncol. 2020;31:S1287-S1318. (Poster) [3] Furuse J, et al. J Clin Oncol. 2024;42:3_suppl:471. (Poster)