Abrocitinib is a Janus kinase-1–selective inhibitor under development for treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by cytochrome P450 (CYP)2C19 (53%), CYP2C9 (30%), CYP3A4 (11%), and CYP2B6 (6%) metabolism, and its pharmacologic activity is attributable to the unbound concentrations of the parent molecule and its 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. The objective of this study was to evaluate the effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety. Three phase 1, open-label, fixed-sequence studies in healthy adult volunteers examined the drug–drug interactions (DDIs) of fluvoxamine and fluconazole (NCT03634345), rifampin (NCT03637790), and probenecid (NCT03937258) with abrocitinib. Coadministration of abrocitinib with the strong CYP2C19 inhibitors, fluvoxamine and fluconazole, increased the area under the plasma concentration-time curve from time 0 to infinity (AUCinf) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin, a strong inducer of CYP enzymes, decreased unbound active moiety AUCinf by 56%. The OAT3 inhibitor, probenecid, increased the unbound active moiety AUCinf by 66%. Consideration of the abrocitinib active moiety is critical for quantifying DDIs and informing dose adjustments. A dose reduction by half is recommended if abrocitinib is coadministered with strong CYP2C19 inhibitors. Coadministration of abrocitinib with CYP2C19/2C9 inducers is not recommended. No adjustment is needed for coadministration with OAT3 inhibitors.

ESDR077 - Effect of Cytochrome P450 Inhibition and Induction and Organic Anion Transporter 3 Inhibition on the Pharmacokinetics of Abrocitinib Active Moiety in Healthy Individuals

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING