(T1330-05-27) Exposure-Response Relationships of Radotinib Assessed in Patients with Chronic Myeloid Leukemia

Purpose: Radotinib, a second-generation tyrosine kinase inhibitor, has been used to treat chronic myeloid leukemia in chronic phase (CML-CP). This study aimed to assess the pharmacokinetic (PK) characteristics and the exposure-response relationships of radotinib in patients with CML-CP after the first and repeated administrations. Such data would be valuable for optimizing the dosing regimen for the safe and effective use of radotinib in CML-CP patients.

Methods: Participants newly diagnosed with CML-CP were enrolled and given the repeated doses of radotinib 300 mg twice daily. Blood samples were collected from each participant’s arm vein pre-dose, and 1, 2, 3, 4, 6, 8 and 12 hours post-dose on Day 1 (first dose) and Day 14 (repeated dose). Additional blood samples were collected pre-dose at Months 1, 3, 6, 9 and 12 for measuring trough concentrations (C_trough). The achievement of major molecular response (MMR, BCR-ABL transcript level 0.1%) was assessed at baseline, and at Months 3, 6, 9 and 12, while adverse events were recorded as they occurred. The plasma concentrations of radotinib were measured using a high-performance liquid chromatographic method with tandem mass spectrometric detection. The PK parameter values of radotinib were determined using a noncompartmental method. The correlation between the C_trough and area under the plasma concentration-time curve within a dosing interval (AUC_τ) was evaluated using a Spearman correlation. Differences in C_trough were assessed using a Mann-Whitney U test, not only between patients who achieved MMR and those who did not, but also between patients who experienced adverse events and those who did not.

Results: The PK characteristics and exposure-response relationships of radotinib were evaluable in 24 Asian patients, consisting of thirteen males (54%) and eleven females (46%). On Day 1, the median (interquartile range, IQR) values of maximum concentration (C_max), time to C_max (t_max) and AUC_τ were 0.49 (0.36 – 0.73) μg/mL, 3.0 (2.0 – 4.0) hours and 3.43 (2.41 – 4.76) μg∙h/mL, respectively. On Day 14, the corresponding values were 1.60 (1.14 – 2.39) μg/mL, 2.5 (2.0 – 3.8) hours and 11.98 (9.66 – 21.16) μg∙h/mL, respectively. Hence, the median (IQR) value of accumulation ratio (R_ac) computed as dividing the AUC_τ of Day 14 by that of Day 1 was 3.59 (3.00 – 7.01). The median (IQR) value of terminal half-life based on the R_ac (t_1/2) was 25.5 (20.5 – 54.1) hours. A strong positive correlation (r = 0.974, p < 0.0001) exists between C_trough and AUC_τ. The median value of C_trough was significantly higher in patients who achieved MMR than in those who did not at Month 12 (1.58 versus 1.12 μg/mL, p = 0.037). C_trough was numerically higher in patients who experienced the adverse events of hyperbilirubinemia at Month 9 (1.55 versus 0.94 μg/mL, p = 0.146) or liver enzyme elevations at Month 12 (1.59 versus 1.33 μg/mL, p = 0.186), than in those who did not.

Conclusion: This is the first study that evaluated the PK characteristics and exposure-response relationships of radotinib in patients with CML-CP. The accumulation of radotinib was substantial at the 12-hour dosing interval with the half-life of 25.5 hours, which suggests that the dosing interval should be extended. C_trough may be used for dose adjustments in patients with CML-CP, considering that radotinib exposure was higher in patients who achieved MMR or those who experienced adverse events.

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 of Seoul National University, and the fourth phase of the Brain Korea 21 Program in 2025.