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.

Autor: Wang X; Pfizer Inc., Groton, CT, USA., Dowty ME; Pfizer Inc., Cambridge, MA, USA., Wouters A; Pfizer Inc., Groton, CT, USA., Tatulych S; Pfizer Inc., Groton, CT, USA., Connell CA; Pfizer Inc., Groton, CT, USA., Le VH; Pfizer Inc., New York, NY, USA., Tripathy S; Pfizer Inc., Groton, CT, USA., O'Gorman MT; Pfizer Inc., Groton, CT, USA., Winton JA; Pfizer Inc., Groton, CT, USA., Yin N; Pfizer Inc., New York, NY, USA., Valdez H; Pfizer Inc., New York, NY, USA., Malhotra BK; Pfizer Inc., New York, NY, USA. bimal.k.malhotra@pfizer.com.
Jazyk: angličtina
Zdroj: European journal of drug metabolism and pharmacokinetics [Eur J Drug Metab Pharmacokinet] 2022 May; Vol. 47 (3), pp. 419-429. Date of Electronic Publication: 2022 Feb 28.
DOI: 10.1007/s13318-021-00745-6
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
Externí odkaz: