Tofacitinib exposure-response modeling of partial Mayo score in ulcerative colitis patients in phase 3 induction studies
Chenhui Deng (1); Rujia Xie (1); Camille Vong (2); Steven W Martin (2); Chinyu Su (3); Arnab Mukherjee (4)
(1) Pfizer (China) Research & Development Center, Shanghai, China; (2) Pfizer Inc, Cambridge, MA, United States; (3) Pfizer Inc, Collegeville, PA, United States; (4) Pfizer Inc, Groton, CT, United States.
Objectives: Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for ulcerative colitis (UC). This analysis aimed to characterize the relationship between tofacitinib exposures and partial Mayo score (PMS) over time and identify covariates that may impact exposure-response of tofacitinib as induction therapy.
Methods: Two phase 3 induction studies were analyzed. Categorical PMS (range 0-9) from 1161 patients (pts) receiving either placebo (234pts), 10 (905pts) or 15 mg (22pts) tofacitinib twice daily were analyzed using FOCE with Interaction in NONMEM. A proportional odds model was used to describe the probability of each PMS. The following characteristics were tested as covariates on tofacitinib efficacy using a stepwise covariate modeling approach: race, age, sex, baseline albumin, baseline body mass index, concomitant medication (oral steroid, immunosuppressant or 5-ASA), Mayo score at baseline, prior tumor necrosis factor inhibitor (TNFi) failure and non-failure. Likelihood ratio test and simulation approach such as visual predictive checks (VPC) were applied for model selection and evaluation.
Results: A longitudinal proportional odds model was built to fit the data and steady-state average concentration was used as an exposure metric describing linear drug effect. The time courses of placebo and drug effect were characterized by exponential equations. The final model included baseline albumin on baseline logit value and TNFi failure on placebo effect. The half-life of onset of drug effect, after accounting for onset of placebo response, was estimated to be 1.24 weeks, indicating hysteresis between plasma tofacitinib concentration (half-life = 3h) and drug effect. VPC results indicated the final model described data adequately except for the 15mg group due to the small sample size. Simulations were conducted to illustrate the model-predicted drug efficacy and the influence of covariates. For a reference pt, >95% of maximum effect was achieved at Week 8 (end of the induction treatment period), and 68% of the Week 8 effect was achieved by Week 2. In pts who did not fail TNFi, PMS decrease from baseline was 3.35, compared to a decrease of 2.62 in pts with prior TNFi failure.
Conclusion: The proposed longitudinal proportional odds model adequately describes exposure-response of PMS for the induction studies. Onset of efficacy was achieved within 2 weeks of start of induction therapy, with near-maximal effect by Week 8.
References:
[1] Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010; 105:501-23.
[2] Meyer DM, et al., Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010. 11; 7:41.
