Academic Journal
Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity
| العنوان: | Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity |
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| المؤلفون: | Huh, Yeamin, Plotka, Anna, Wei, Hua, Kaplan, Julia, Raha, Nancy, Towner, Justin, Purohit, Vivek S., Dowty, Martin E., Wolk, Robert, Vourvahis, Manoli, King-Ahmad, Amanda, Mathialagan, Sumathy, West, Mark A., Lazzaro, Sarah, Ryu, Sangwoo, Rodrigues, A. David |
| المساهمون: | Pfizer |
| المصدر: | Pharmaceutical Research ; volume 40, issue 11, page 2639-2651 ; ISSN 0724-8741 1573-904X |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | Purpose Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. Methods In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. Results In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUC inf ) by ~ 13% and maximum concentration (C max ) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUC inf and C max for CP-I and PDA were also similar regardless of ritlecitinib coadministration. Conclusion Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1007/s11095-023-03564-3 |
| DOI: | 10.1007/s11095-023-03564-3.pdf |
| DOI: | 10.1007/s11095-023-03564-3/fulltext.html |
| الاتاحة: | http://dx.doi.org/10.1007/s11095-023-03564-3 https://link.springer.com/content/pdf/10.1007/s11095-023-03564-3.pdf https://link.springer.com/article/10.1007/s11095-023-03564-3/fulltext.html |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.34084325 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1007/s11095-023-03564-3 |
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