Clinical CYP2D6-Mediated Pharmacokinetic Drug-Drug Interactions of DA-8010 with Paroxetine or Mirabegron in Healthy Korean Participants.

BACKGROUND AND

OBJECTIVE

DA-8010 is a selective M3 muscarinic receptor antagonist under development for overactive bladder (OAB). This study examined potential CYP2D6-mediated pharmacokinetic interactions between DA-8010 and paroxetine or mirabegron.

METHODS

An open-label, single-sequence, 2-part clinical study was conducted in healthy volunteers. In Part 1, the effect of paroxetine on the PK of DA-8010 was evaluated. Single-dose administration of DA-8010 5 mg was performed in both periods, with paroxetine 20 mg given once daily for 11 days in the second period. For PK characterization of DA-8010, plasma samples were obtained over a 48-hour period following dosing. Part 2 was designed to characterize reciprocal PK interactions between DA-8010 and mirabegron under multiple-dose conditions. Participants received DA-8010 at a 5 mg dose for five days during the initial phase. Subsequently, mirabegron 50 mg was administered alone for 10 days, after which coadministration with DA-8010 was continued for an additional five days. PK sampling for both DA-8010 and mirabegron was performed over 24 hours after dosing. PK parameters including maximum plasma concentration (Cmax) and area under the curve (AUC) were estimated using non-compartmental analysis. CYP2D6 genotyping was performed for all participants.

RESULTS

Eighteen participants completed Part 1, while seventeen completed Part 2. Exposure to DA-8010 increased following concomitant administration with paroxetine, with increases of 22.3% in Cmax and 55.4% in AUClast. When administered with mirabegron, Cmax,ss and AUCtau,ss of DA-8010 increased by 42.1% and 45.2%. In contrast, coadministration with DA-8010 produced little change in the Cmax,ss, although a 20.1% increase in AUCtau,ss was observed. All participants were classified as CYP2D6 extensive or intermediate metabolizers, and the magnitude of PK interactions varied according to CYP2D6 phenotype.

CONCLUSION

Systemic exposure to DA-8010 increased mildly with paroxetine or mirabegron, while the pharmacokinetics of mirabegron were largely unaffected. The magnitude of interaction was within the mild range and varied according to CYP2D6 metabolic activity.