(T1130-02-09) Pharmacokinetic Characteristics of Radotinib Assessed in Asian Patients with Chronic Myeloid Leukemia

Purpose: Radotinib, a second-generation tyrosine kinase inhibitor (TKI), was approved for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). This study was performed to determine the pharmacokinetic (PK) characteristics of radotinib in patients with CML-CP following single and repeated doses.

Methods: The concentration-time data of radotinib and its metabolites, M1 and M2, were obtained from Asian patients who were newly diagnosed with CML-CP. The participants received the repeated doses of radotinib 300 mg twice daily from Day 1 to 14. On Days 1 (single dose) and 14 (multiple doses), serial blood samples were collected at pre-dose, and 1, 2, 3, 4, 6, 8 and 12 hours after the morning dose of radotinib. The plasma concentrations (Cp) of radotinib were measured using a high-performance liquid chromatographic method with tandem mass spectrometric detection. The PK parameter values of radotinib, M1 and M2 were determined using a noncompartmental method. The area under the concentration-time curve within a dosing interval (AUC_τ) was estimated using a linear-log trapezoidal rule. The ratios of metabolite-to-parent drug concentration (MR) for M1 and M2 were calculated in terms of AUC_τ and maximum concentration (C_max), by dividing the values for metabolites by those for the parent drug. The accumulation ratio (R_ac) for each analyte was calculated in terms of AUC_τ and C_max, by dividing the values of Day 14 by those of Day 1. The values of half-life calculated from R_ac (t’_1/2) were compared with those from the terminal rate constant (t_1/2).

Results: The time-concentration data obtained from a total of twenty-four participants was used to determine the PK parameters of radotinib. The participants consisted of thirteen males (54%) and eleven females (46%) with a median (range) age of 38 (18 – 72) years. On Day 1, the median (interquartile range, IQR) values of C_max, time to C_max (t_max), AUC_τ, terminal t_1/2 and mean residence time (MRT) of radotinib were 491 (357 – 730) ng/mL, 3.0 (2.0 – 4.0) hours, 3,434 (2,406 – 4,756) ngžh/mL, 8.9 (7.0 – 13.5) hours and 14.3 (12.1 – 22.0) hours, respectively. On Day 14, the median (IQR) values were 1,595 (1,143 – 2,393) ng/mL, 2.5 (2.0 – 3.8) hours, 11,984 (9,657 – 21,163) ngžh/mL, 10.9 (9.4 – 12.7) hours and 15.9 (14.2 – 18.3) hours, respectively. For M1, the median (IQR) values of C_max and AUC_τ on Days 1 and 14 were 9.1 (5.0 – 12.6) ng/mL and 70 (44 – 110) ngžh/mL, and 36.6 (25.6 – 46.9) ng/mL and 378 (254 – 473) ngžh/mL, respectively. For M2, the values were 136 (86 – 170) ng/mL and 825 (508 – 1,113) ngžh/mL, and 293 (222 – 391) ng/mL and 2,488 (1,920 – 3,117) ngžh/mL, respectively. The median (IQR) values of MR for M1 and M2 were 0.022 (0.019 – 0.029) and 0.208 (0.170 – 0.254), respectively, when computed using AUC_τ. The median (IQR) values of R_ac computed using the AUC_τ of radotinib, M1 and M2 were 3.59 (3.00 – 7.01), 4.62 (2.96 – 8.62) and 3.08 (1.84 – 5.12), respectively. The corresponding median (IQR) values of t’_1/2 were 25.4 (22.3 – 52.6), 34.1 (23.3 – 56.9) and 21.2 (10.9 – 35.1) hours, respectively.

Conclusion: This abstract reports, for the first time, the PK parameter values of radotinib that were determined in humans. The exposure of M2 was approximately 20% of the parent drug, suggesting that M2 is the major metabolite of radotinib. The accumulations of radotinib and M2 were substantial at the dosing interval of twelve hours, which may mean the dosing interval to be lengthened. The t’_1/2 estimated from the R_ac appears to be more reliable than the terminal t_1/2 for deciding the dosing frequency.

Acknowledgements: This study was approved by the Institutional Review Board of Peking University People’s Hospital (IRB number: 2018PHA053). This work was supported by IL-YANG Pharmaceutical Co., the Research Institute of Pharmaceutical Sciences, Seoul National University, and the fourth phase of the Brain Korea 21 Program in 2024.