Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals

Abstract

Background and objective: Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 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. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety.

Methods: Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid.

Results: Co-administration of abrocitinib with fluvoxamine or 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 decreased the unbound active moiety AUCinf by 56%. The OAT3 inhibitor probenecid increased the AUCinf of the unbound active moiety by 66%.

Conclusions: It is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors.

Clinical trials registration ids: NCT03634345, NCT03637790, NCT03937258.

Conflict of interest statement

All authors are employees and stockholders of Pfizer Inc.

© 2022. The Author(s).

Figures

Fig. 1

Study treatment schedule. Abrocitinib was administered 3 h after fluvoxamine, 1 h after fluconazole, 1 h after rifampin, and 2 h after probenecid; BID twice daily

Fig. 2

Median plasma concentration–time curves (semilog scale) for the abrocitinib parent drug in the presence and absence of fluvoxamine (a), fluconazole (b), rifampin (c), and probenecid (d); BID twice daily, QD once daily, SD single dose

Fig. 3

Median plasma concentration–time curves (semilog scale) for abrocitinib metabolites M1 (a), M2 (b), and M4 (c) in the presence and absence of probenecid; BID twice daily, SD single dose

Fig. 4

Mean (SD) plasma concentrations of abrocitinib and metabolites prior to dosing on Days 1–4, and at 24 h following dosing on Day 4 following 4 days of abrocitinib 200 mg once-daily dosing to assess the steady state of abrocitinib M1, M2, and M4