Comprehensive Pharmacokinetic Analysis of Brepocitinib Using a 14C-Microtracer Approach in Healthy Male Subjects: A Phase 1 ADME Study

Brepocitinib is a novel dual inhibitor of tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1). These enzymes are key components of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, which plays a critical role in the pathogenesis of various autoimmune and inflammatory diseases. Given its potential therapeutic applications, comprehending its pharmacokinetic behavior in humans is essential for further drug development. A new study now published in British Journal of Clinical Pharmacology and conducted by Dr. Ruolun Qiu, Dr. Raman Sharma, Dr. Hua Wei, Dr. Leonid Kirkovsky, Dr. Yifan Zhou, Dr. David Martin, Dr. Christopher Banfield, and Dr. Martin Dowty from Pfizer Inc., the authors investigated the absorption, distribution, metabolism, and excretion (ADME) profile of brepocitinib. The study employed a ¹⁴C-microtracer approach, which allowed for the precise measurement of the drug and its metabolites in the human body with minimal radiation exposure. The clinical study was structured as a phase 1, open-label, non-randomized, fixed-sequence, two-period, single-dose investigation with six healthy male participants enrolled to receive a single oral dose of ¹⁴C-labeled brepocitinib in Period A, followed by an unlabeled oral dose and an intravenous microdose of ¹⁴C -labeled brepocitinib in Period B. By administering the microtracer with a therapeutic dose of the drug, it’s possible to study the pharmacokinetics of the drug under clinically relevant conditions without impacting its safety profile. The authors used accelerator mass spectrometry (AMS) for the detection of ¹⁴C in biological samples. They collected blood, urine, and feces samples at various intervals post-dosing to measure the concentration of brepocitinib and its metabolites and then they calculated PK parameters such as absorption rate, distribution, half-life, clearance, and volume of distribution. Additionally, they quantified the total recovery of the administered dose by measuring the cumulative excretion of brepocitinib and its metabolites in urine and feces.

The Pfizer research team found that Brepocitinib to be rapidly absorbed following oral administration, with an absolute oral bioavailability of approximately 75% which indicates that a significant portion of the drug reaches systemic circulation when administered orally. The total recovery of the administered dose was high, at 96.7%, with the majority (88.0%) excreted in urine and a smaller fraction (8.7%) in feces which suggests efficient elimination of the drug and its metabolites from the body. Moreover, a small fraction of the orally administered dose was recovered unchanged in urine which indicates that brepocitinib undergoes extensive metabolism before excretion. According to the authors, brepocitinib’s metabolism primarily involved hepatic cytochrome P450-mediated pathways, with renal excretion as metabolites being the major route of elimination. Additionally, brepocitinib was well tolerated by the participants, with no serious adverse events, or discontinuations due to adverse events reported.

It is noteworthy to mention the key innovation on the application of the ¹⁴C microtracer approach and AMS technology in this ADME study exemplifies an advanced and sensitive method to study drug pharmacokinetics, minimizing participants’ exposure to radiation while providing comprehensive data on the drug’s behavior in the human body. This methodological approach, aligned with European recommendations for AMS analysis, emphasizes the study’s innovative nature and its compliance with contemporary scientific standards. In conclusion, the Pfizer study provided a detailed and robust pharmacokinetic profile of brepocitinib, demonstrating its favorable absorption, bioavailability, metabolism, and excretion characteristics in healthy male subjects. These findings are important and support further development and clinical application of brepocitinib in the treatment of autoimmune diseases, offering a strong foundation for phase 2 and 3 clinical trials.  Moreover, the authors’ use of a ¹⁴C microtracer approach sets a new methodological benchmark for ADME studies, particularly in terms of reducing the radioactive dose administered to humans and integrating various assessments into a single clinical study.