Evaluation of the Effect of Abrocitinib on Drug Transporters by Integrated Use of Probe Drugs and Endogenous Biomarkers

Manoli Vourvahis, Wonkyung Byon, Cheng Chang, Vu Le, Annette Diehl, Daniela Graham, Sakambari Tripathy, Nancy Raha, Lina Luo, Sumathy Mathialagan, Martin Dowty, A David Rodrigues, Bimal Malhotra, Manoli Vourvahis, Wonkyung Byon, Cheng Chang, Vu Le, Annette Diehl, Daniela Graham, Sakambari Tripathy, Nancy Raha, Lina Luo, Sumathy Mathialagan, Martin Dowty, A David Rodrigues, Bimal Malhotra

Abstract

Abrocitinib is an oral Janus kinase 1 (JAK1) inhibitor currently approved in the United Kingdom for the treatment of moderate-to-severe atopic dermatitis (AD). As patients with AD may use medications to manage comorbidities, abrocitinib could be used concomitantly with hepatic and/or renal transporter substrates. Therefore, we assessed the potential effect of abrocitinib on probe drugs and endogenous biomarker substrates for the drug transporters of interest. In vitro studies indicated that, among the transporters tested, abrocitinib has the potential to inhibit the activities of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3), organic cation transporter 1 (OCT1), and multidrug and toxin extrusion protein 1 and 2K (MATE1/2K). Therefore, subsequent phase I, two-way crossover, open-label studies in healthy participants were performed to assess the impact of abrocitinib on the pharmacokinetics of the transporter probe substrates dabigatran etexilate (P-gp), rosuvastatin (BCRP and OAT3), and metformin (OCT2 and MATE1/2K), as well as endogenous biomarkers for MATE1/2K (N1 -methylnicotinamide (NMN)) and OCT1 (isobutyryl-L -carnitine (IBC)). Co-administration with abrocitinib was shown to increase the plasma exposure of dabigatran by ~ 50%. In comparison, the plasma exposure and renal clearance of rosuvastatin and metformin were not altered with abrocitinib co-administration. Similarly, abrocitinib did not affect the exposure of NMN or IBC. An increase in dabigatran exposure suggests that abrocitinib inhibits P-gp activity. By contrast, a lack of impact on plasma exposure and/or renal clearance of rosuvastatin, metformin, NMN, or IBC suggests that BCRP, OAT3, OCT1, and MATE1/2K activity are unaffected by abrocitinib.

Trial registration: ClinicalTrials.gov NCT03742336 NCT03806101 NCT03796182.

Conflict of interest statement

All authors are employees and stockholders of Pfizer Inc.

© 2022 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Treatment schedule for clinical pharmacokinetic studies. All studies were randomized, with a two‐way crossover design. In each study, participants were randomized 1:1 into 1 of 2 treatment sequences, in which treatment A was followed by treatment B or vice versa, with a washout period between treatments.
Figure 2
Figure 2
Mean (+ SD) plasma concentration‐time curves for (a) dabigatran, (b) rosuvastatin, and (c) metformin alone and with abrocitinib, with semi‐log scale plasma concentration‐time curves inset in top right corners. QD, once‐daily.
Figure 3
Figure 3
Mean (+ SD) plasma concentration‐time curves for (a) NMN and (b) IBC.a Panel (c) shows a scatterplot of individual ratios for metformin CLr vs. NMN CLr.b CLr, renal clearance; IBC, isobutyryl‐l‐carnitine; NMN, N1‐methylnicotinamide; QD, once daily. aLog plots were not generated as NMN and IBC are endogenous compounds; bOnly 10 of the 12 study participants are included in this figure and contributed to the Pearson correlation coefficient calculation due to missing metformin CLr or NMN CLr values for metformin + abrocitinib treatment period.

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