Population Pharmacokinetics of Tofacitinib in Patients With Moderate to Severe Ulcerative Colitis

Abstract

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We characterized tofacitinib pharmacokinetics in patients with moderate to severe UC, and the effects of covariates on variability in pharmacokinetic parameter estimates. Data were pooled from 1 8-week phase 2 and 2 8-week phase 3 induction studies, and a 52-week phase 3 maintenance study (N = 1096). Population pharmacokinetic analysis was conducted using nonlinear mixed-effects modeling. Potential predictors of apparent oral clearance (CL/F) and volume of distribution (V/F) were evaluated. The PK was described by a 1-compartment model parameterized in terms of CL/F (26.3 L/hour [h]) and V/F (115.8 L), with first-order absorption (Ka ; 9.85 h-1 ) and lag time (0.236 h). The derived elimination half-life was approximately 3.05 h. In the final model, baseline creatinine clearance, sex, and race (Asian vs non-Asian) were significant covariates for CL/F; significant covariates for V/F were age, sex, and body weight; baseline albumin and baseline Mayo score were not significant covariates. CL/F between-patient variability was estimated at 22%. Tofacitinib exposure did not change significantly over the duration of induction/maintenance treatment in patients with UC. Although statistically significant covariate effects on CL/F and V/F were observed, the magnitude of the effects are not clinically significant. Therefore, dose adjustment/restrictions for age, body weight, sex, race, or baseline disease severity are not required during tofacitinib treatment. ClinicalTrials.gov numbers: NCT00787202, NCT01465763, NCT01458951, NCT01458574.

Keywords: CP-690,550 (tofacitinib); Janus kinase (JAK) inhibitors; inflammatory bowel disease; pharmacokinetics; ulcerative colitis.

Conflict of interest statement

S.W.M., R.X., C.S., and A.M. are employees and stockholders of Pfizer Inc. C.V., C.D., and K.I. were employees of Pfizer Inc at the time the study was conducted. W.J.S. reports consulting fees from AbbVie, Akros Pharma, Allergan, Ambrx Inc., Amgen, Ardelyx, Arena Pharmaceuticals, Atlantic Pharmaceuticals, Avaxia, Biogen, Boehringer Ingelheim, Bristol‐Myers Squibb, Celgene, Conatus, Cosmo Technologies, Escalier Biosciences, Ferring, Ferring Research Institute, Forward Pharma, Galapagos, Genentech, Gilead Sciences, Gossamer Biosciences, Immune Pharmaceuticals, Index Pharmaceuticals, Janssen, Kyowa Hakko Kirin Pharma, Lilly, MedImmune, Mesoblast, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka, Palatin, Paul Hastings, Pfizer Inc, Precision IBD, Progenity, Prometheus Laboratories, Qu Biologics, Regeneron, Ritter Pharmaceuticals, Robarts Clinical Trials (owned by University of Western Ontario), Salix, Seattle Genetics, Seres Therapeutics, Shire, Sigmoid Biotechnologies, Takeda, Theradiag, Theravance, TiGenix, Tillotts Pharma, UCB Pharma, Vascular Biogenics, and Vivelix; research grants from AbbVie, Amgen, Atlantic Healthcare Limited, Celgene/Receptos, Genentech, Gilead Sciences, Janssen, Lilly, and Takeda; payments for lectures/speakers bureau from AbbVie, Janssen, and Takeda; and he holds stock/stock options in Escalier Biosciences, Gossamer Biosciences, Oppilan Pharma, Precision IBD, Progenity, and Ritter Pharmaceuticals.

© 2021 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Impact of covariates on the PK of tofacitinib 10 mg twice daily in patients with UC. The dashed lines represent the limits of a range from 80% to 125%. Data are presented as ratios (with 90%CI) for AUC and Cmax for each covariate of interest, relative to a reference patient (non‐Asian male; BWT, 72.0 kg; 40.0 years of age; baseline creatinine clearance, 108.7 mL/min). Weights of 53 kg and 95 kg are the 10th and 90th percentiles of BWT in this analysis data set. The current recommendation in US tofacitinib prescribing information is to reduce dose by half in patients with moderate and severe renal impairment. AUC, area under the concentration‐time curve over a dosing interval; BCCL, baseline creatinine clearance; BWT, body weight; CI, confidence interval; Cmax, maximum concentration at steady state; PK, pharmacokinetics; UC, ulcerative colitis.

Figure 2

Prediction‐corrected VPCs for the final model stratified by (A) study and (B) dose. The green dashed lines represent the 90%CI of observed data. The green solid line is the median of observed data. The blue dashed lines represent the 90% predictive interval based on simulations. The blue solid line represents the median based on simulations. The blue or gray shaded area is the predicted 95%CI of upper limit, lower limit, or median (50%), based on simulations. CI, confidence interval; h, hours; VPC, visual predictive check.