Pharmacokinetic Drug–Drug Interactions of DA-8010 with Clarithromycin or Rifampicin: Influence of CYP2D6 Phenotype on the Extent of These Interactions

Sujong Lee,1,2 Heejae Won,1,2 Kyung-Sang Yu,1,2 Dae Young Lee,3 SeungHwan Lee1 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; 3Dong-A ST Research Institute, Yongin, Republic of KoreaCorrespondence: SeungHwan Lee, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea, Email leejh413@snu.ac.krPurpose: This study aimed to evaluate the pharmacokinetic (PK) drug–drug interactions (DDIs) of DA-8010 with clarithromycin or rifampicin, and to assess the influence of cytochrome P450 (CYP) 2D6 phenotype on the extent of these interactions.Methods: An open-label, fixed-sequence, three-period crossover study was conducted in healthy participants. Participants received a single dose of DA-8010 5 mg alone on Day 1 (Period 1); clarithromycin 500 mg twice daily from Day 6 to 11, with a concomitant single dose of DA-8010 5 mg on Day 10 (Period 2); and rifampicin 600 mg once daily from Day 16 to 25, with a concomitant single dose of DA-8010 5 mg on Day 25 (Period 3). Each treatment period was separated by a five-day washout. Serial blood samples for PK assessments of DA-8010 were collected up to 48 h post-dose. CYP2D6 genotyping was performed retrospectively, and phenotypes were assigned based on activity score.Results: Sixteen participants completed the study: eleven were classified as CYP2D6 extensive metabolizers (EMs) and five as CYP2D6 intermediate metabolizers (IMs). Co-administration of DA-8010 with clarithromycin had no significant effect on the PKs of DA-8010. In contrast, co-administration with rifampicin reduced the systemic exposure of DA-8010 by approximately 50% compared with DA-8010 alone. Across all treatment conditions, DA-8010 exposure was approximately two-fold higher in IMs than in EMs.Conclusion: DA-8010 showed no clinically meaningful PK interaction with clarithromycin, while rifampicin significantly reduced DA-8010 exposure. Although the CYP2D6 phenotype affected overall DA-8010 exposure, it did not alter the extent of the PK interaction observed with clarithromycin or rifampicin.Keywords: muscarinic receptor antagonist, drug interactions, CYP3A4 modulation, CYP2D6 polymorphism, pharmacokinetics