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

• Published in: European journal of drug metabolism and pharmacokinetics Vol. 47; no. 3; pp. 419 - 429
• Main Authors: Wang, Xiaoxing, Dowty, Martin E., Wouters, Ann, Tatulych, Svitlana, Connell, Carol A., Le, Vu H., Tripathy, Sakambari, O’Gorman, Melissa T., Winton, Jennifer A., Yin, Natalie, Valdez, Hernan, Malhotra, Bimal K.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.05.2022
• Subjects: Adult; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Clinical Trials, Phase I as Topic; Cytochrome P-450 CYP2C19 - metabolism; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 Enzyme System - metabolism; Drug Interactions; Fluconazole - pharmacology; Fluvoxamine; Human Physiology; Humans; Medical Biochemistry; NCT; NCT03634345; NCT03637790; NCT03937258; Original; Original Research Article; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Pharmacy; Probenecid; Pyrimidines; Rifampin; Sulfonamides
• ISSN: 0378-7966; 2107-0180
• DOI: 10.1007/s13318-021-00745-6

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 (AUC inf ) of the unbound active moiety of abrocitinib by 91% and 155%, respectively. Co-administration with rifampin decreased the unbound active moiety AUC inf by 56%. The OAT3 inhibitor probenecid increased the AUC inf 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