Real-World Pharmacokinetics-Pharmacodynamics and Pharmacogenomic Analysis of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients with Active Ulcerative Colitis

Tofacitinib is an oral small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). We conducted a multicenter prospective observational study to investigate the pharmacokinetics (PK) and pharmacogenomics of tofacitinib and its exposure-response relationship in real-world practice. Thirty-nine patients with moderate to severe UC receiving tofacitinib were enrolled (induction [n=7] and maintenance [n=32] therapies). Serum and urine samples, as well as biopsy specimens at endoscopic examination if possible, were collected for PK analysis using HILIC-MS/MS method. Serum concentrations of tofacitinib and its major metabolite M9 showed large interindividual variability. The UGT1A4*3 polymorphism significantly influenced the urinary excretion ratio of the glucuronide metabolite M20 (p = 0.041). No effects of the genetic polymorphisms examined were observed on the serum PK of tofacitinib. Interestingly, dose-normalized tissue concentration of tofacitinib appeared to be lower in patients with the CYP3A5*1 allele (p for trend = 0.033), which might be potentially related to decreased efficacy. By ROC analysis, the optimal threshold of post-dose serum tofacitinib concentration to achieve/maintain remission was estimated to be 48.6 ng/mL (AUCROC = 0.860). In conclusion, therapeutic drug monitoring of tofacitinib including CYP3A5 genotyping may improve the efficacy of tofacitinib for UC, warranting further investigation in a larger study.