Evaluation of the Impact of Ritlecitinib on Organic Cation Transporters Using Sumatriptan and Biomarkers as Probes

Abstract

Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration‐time curve (AUC). Coadministration of a single 400‐mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUCinf) by ≈30% relative to a single 25‐mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUCinf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl‐L‐carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N1‐methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults.

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

“…Therefore, the IC 50 approximates the inhibition constant (K i ) and supports determination of fraction inhibited [ 14 ]. c C max,u = maximal free plasma concentration (C max × f u ) of ritlecitinib (5.5 µM × 0.86) at 200 mg. [I] 2 = oral molar dose of ritlecitinib/250 mL (molecular weight = 285.34) d Etimated maximal free hepatic portal concentration of ritlecitinib I max,inlet,u = f u × [C max + (F a × F g × k a × Dose)/Q h /Rb], where maximal plasma concentration (C max ) = 5.5 µM, fraction absorbed × fraction surviving gut first pass (F a × F g ) = 0.89, absorption rate constant ( k a ) = 7.9 h −1 , liver blood flow (Q h ) = 97 L/hr, blood-to-plasma ratio (Rb) = 1.62, and fraction unbound in plasma (f u ) = 0.86 [ 10 ]. e R -value = 1 + (I max,inlet,u /IC 50 ).…”

“…d Etimated maximal free hepatic portal concentration of ritlecitinib I max,inlet,u = f u × [C max + (F a × F g × k a × Dose)/Q h /Rb], where maximal plasma concentration (C max ) = 5.5 µM, fraction absorbed × fraction surviving gut first pass (F a × F g ) = 0.89, absorption rate constant ( k a ) = 7.9 h −1 , liver blood flow (Q h ) = 97 L/hr, blood-to-plasma ratio (Rb) = 1.62, and fraction unbound in plasma (f u ) = 0.86 [ 10 ].…”

“…In the previously reported sumatriptan DDI study, ritlecitinib coadministration decreased the C max of sumatriptan by 13% even though AUC inf of sumatriptan was increased by 30% due to OCT1 inhibition. The authors hypothesized the potential inhibition of another transporter, e.g., OATP2B1, by ritlecitinib to explain this differential impact [ 10 ]. Compared to other transporters, little is known about the clinical relevance of OATP2B1 and guidance for DDI evaluation for OATP2B1 is also lacking [ 30 , 31 ].…”

“…It is noteworthy that ritlecitinib is one of the first compounds in development to assess drug transporter inhibition by leveraging four different endogenous biomarkers (PDA, CP-I, IBC, and NMN) integrated with a drug probe like rosuvastatin and sumatriptan [ 10 ]. Such an approach was warranted as ritlecitinib exceeded conservative regulatory DDI risk cutoffs for both renal (OAT1, OAT3, OCT 2, MATE1 and MATE2K) and hepatic (OCT1, OATP1B1, and OATP1B3) transporters.…”

“…In a recent study, inhibition of hepatic organic cation transporter (OCT) 1 by ritlecitinib was evaluated using sumatriptan as a probe substrate drug [ 10 ]. In the same study, the endogenous biomarker of N 1 -methylnicotinamide (NMN) was successfully used to de-risk the inhibition of renal multidrug and toxin extrusion proteins (MATE1 and MATE2K) and organic cation transporter (OCT) 2 by ritlecitinib, based on the lack of changes in NMN renal clearance with ritlecitinib coadministration.…”