Assessment of the Effects of Abrocitinib on the Pharmacokinetics of Probe Substrates of Cytochrome P450 1A2, 2B6 and 2C19 Enzymes and Hormonal Oral Contraceptives in Healthy Individuals

Eur J Drug Metab Pharmacokinet. 2024 May;49(3):367-381. doi: 10.1007/s13318-024-00893-5. Epub 2024 Mar 30.

Abstract

Background and objective: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated.

Methods: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives).

Results: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax.

Conclusions: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives.

Clinical trials registration: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Area Under Curve
  • Contraceptives, Oral, Combined / administration & dosage
  • Contraceptives, Oral, Combined / pharmacokinetics
  • Contraceptives, Oral, Hormonal / pharmacokinetics
  • Cytochrome P-450 CYP1A2 / metabolism
  • Cytochrome P-450 CYP2C19 / metabolism
  • Drug Combinations
  • Drug Interactions*
  • Ethinyl Estradiol / pharmacokinetics
  • Female
  • Healthy Volunteers
  • Humans
  • Levonorgestrel / administration & dosage
  • Levonorgestrel / pharmacokinetics
  • Male
  • Middle Aged
  • Pyrimidines* / administration & dosage
  • Pyrimidines* / pharmacokinetics
  • Sulfonamides*
  • Young Adult

Substances

  • abrocitinib
  • Pyrimidines
  • Cytochrome P-450 CYP1A2
  • Ethinyl Estradiol
  • Contraceptives, Oral, Hormonal
  • Cytochrome P-450 CYP2C19
  • Levonorgestrel
  • CYP1A2 protein, human
  • Contraceptives, Oral, Combined
  • CYP2C19 protein, human
  • ethinyl estradiol, levonorgestrel drug combination
  • Drug Combinations
  • Sulfonamides

Associated data

  • ClinicalTrials.gov/NCT03662516
  • ClinicalTrials.gov/NCT03647670
  • ClinicalTrials.gov/NCT05067439