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Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and

Yeamin Huh1, Anna Plotka2, Hua Wei3

  • 1Pfizer Inc, Groton, CT, USA. YeaMin.Huh@pfizer.com.

Pharmaceutical Research
|August 10, 2023
PubMed
Abstract

Insights

Ritlecitinib does not significantly impact key drug transporters like BCRP, OATP1B1, and OAT3, indicating a low risk of clinical drug interactions. This study confirms the utility of endogenous biomarkers in assessing transporter function.

Area of Science:

  • Pharmacology
  • Drug Metabolism and Pharmacokinetics
  • Immunology

Background:

  • Ritlecitinib, a Janus kinase inhibitor, is under development for inflammatory conditions.
  • Understanding its interaction with drug transporters is crucial for safe clinical use.

Purpose of the Study:

  • To evaluate the in vitro and in vivo impact of ritlecitinib on major drug transporters.
  • To assess potential drug-drug interactions mediated by breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3).

Main Methods:

  • In vitro assessment of ritlecitinib and its metabolite on transporter substrates.
  • A clinical study in healthy adults involving coadministration with rosuvastatin, a probe drug for BCRP, OATP1B1, and OAT3.
  • Measurement of endogenous biomarkers coproporphyrin I (CP-I) and pyridoxic acid (PDA) to assess OATP1B1 and OAT1/3 function.

Main Results:

  • In vitro studies indicated potential inhibition of BCRP, OATP1B1, and OAT1/3 by ritlecitinib.
  • Clinical study showed a modest decrease in rosuvastatin exposure (AUCinf ~13%, Cmax ~27%) with ritlecitinib coadministration.
  • No significant changes in CP-I and PDA levels were observed, suggesting no clinically relevant inhibition of OATP1B1 and OAT1/3.

Conclusions:

  • Ritlecitinib does not appear to inhibit BCRP, OATP1B1, or OAT3 to a clinically relevant extent.
  • The risk of clinically significant drug interactions mediated by these transporters is low.
  • CP-I and PDA are validated as useful endogenous biomarkers for evaluating OATP1B1 and OAT1/3 activity.
Keywords:
drug-drug interactionendogenous biomarkerritlecitinibrosuvastatin

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