Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity

Abstract

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.

Keywords: drug-drug interaction; endogenous biomarker; ritlecitinib; rosuvastatin.

Fig. 1

Treatment flow diagram. *Day was relative to the first day of study medicine dosing in each period. Day 1 of Period 2 was the same as Day 5 of Period 1.

Fig. 2

Mean plasma rosuvastatin concentration-time profiles following a single dose of rosuvastatin (10 mg) alone and with ritlecitinib (200 mg QD) coadministration in (a) linear scale and (b) semi-log scale. Error bars show the standard deviation. QD, once-daily.

Fig. 3

Plasma concentration-time profiles for (a) PDA and (b) CP-I following a single dose of rosuvastatin (10 mg) alone and with ritlecitinib (200 mg QD) coadministration. Error bars show the standard deviation. QD, once daily.