PI-026 - EFFECT OF CYP2D6 PHENOTYPE ON PHARMACOKINETICS OF DWN12088, A NOVEL PROLYL-TRNA SYNTHETASE INHIBITOR, IN A FIRST-IN HUMAN STUDY.
Wednesday, March 22, 2023
5:00 PM – 6:30 PM EDT
S. Bae1, M. Park2, J. Oh3; 1Seoul National University, Seoul, South Korea, 2Daewon Pharmaceutical Co., Ltd., Seoul, South Korea, 3Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea.
Resident Seoul National University Jongno, Seoul-t'ukpyolsi, Republic of Korea
Background: DWN12088, a novel first-in-class glutamyl-prolyl-tRNA-synthetase inhibitor being currently under clinical development, was shown to exert an anti-fibrotic effect through the down-regulation of collagen synthesis in various pulmonary fibrosis models. DWN12088 is metabolized by various Phase I and Phase II enzymes and genetic polymorphism of CYP2D6 may affect systemic exposure to DWN12088. Based on these understanding, a clinical study was performed to evaluate the effect of CYP2D6 phenotype on pharmacokinetic (PK) characteristics of DWN12088. Methods: A Phase I clinical study of DWN12088 was performed in healthy adults. A total of 24 subjects received 25 mg to 200 mg dose of DWN12088 tablet for 14 days and PK were evaluated after the first and the last dose. Subjects were categorized into either CYP2D6 poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), or ultra-rapid metabolizer (UM). Logarithmic transformed dose normalized area under curve during dosing interval (AUCtau) were compared between the CYP2D6 phenotype groups by Kruskal-Wallis test. Results: Among the 24 subjects, there were 1 CYP2D6 PM, 10 IMs, 11 NMs, and 2 UMs. The plasma concentration of DWN12088 were higher in CYP2D6 PM subjects than other groups. The mean± standard deviation of dose-normalized AUCtau were 12.75, 4.11±2.40, 3.42±1.21, and 2.59±0.64 ng/mL*h/mg after first dose (P = 0.1725) and 45.24, 12.95±9.22, 7.53±4.34, and 4.22±0.13 ng/mL*h/mg after last dose for PM, IMs, NMs, and UMs respectively (P = 0.0775). Conclusion: In conclusion, the systemic exposure to DWN12088 were higher in CYP2D6 PMs than other phenotype subjects but we failed to show its statistical significance.