Model-Based Comparison of Dose-Response Profiles of Tofacitinib in Japanese Versus Western Rheumatoid Arthritis Patients

Abstract

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this analysis was to characterize the relationship between tofacitinib dose and efficacy, as measured by American College of Rheumatology (ACR) response rates, and to compare this between Japanese and Western patients with RA. Efficacy data were pooled from 2 double-blind, dose-ranging phase 2 studies of tofacitinib monotherapy 1-15 mg twice daily in patients with RA with an inadequate response to disease-modifying antirheumatic drugs (DMARDs). NCT00550446 was carried out in mostly Western patients and NCT00687193 in Japanese patients. ACR20, ACR50, and ACR70 response rates in week 12 were analyzed using maximum drug effect (Emax ) models on the logit domain. Both studies showed a dose-response for each end point, supporting the efficacy of tofacitinib in patients with inadequate response to DMARDs. Study-specific differences in Emax were noted, whereas potency (dose providing half the maximum effect [ED50 ]) was similar across studies. After adjustment for study differences in Emax by calculating the fractions of the maximum placebo-adjusted proportion of ACR responses, the estimated locations for the 5- and 10-mg twice-daily doses on the dose-response curves were similar for the 2 patient populations: ACR20, ACR50, andACR70 mean fractional responses for 5 and 10 mg twice daily were 0.78, 0.43, 0.32 and 0.90, 0.69, and 0.56, respectively, for the Japanese study and 0.54, 0.41, and 0.22 and 0.73, 0.61, and 0.40, respectively, for the Western study. This analysis therefore supports the rationale for the same dosing regimen in Japanese patients as in Western patients from an efficacy perspective.

Keywords: Japanese; dose-response; efficacy; rheumatoid arthritis; tofacitinib.

Conflict of interest statement

M. Suzuki, S. Shoji, S. Miyoshi, and S. Krishnaswami are employees of and hold stocks and shares in Pfizer Inc.

© 2019 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1

Mean (90%CI) model‐predicted ACR20, ACR50, and ACR70 responses in week 12 for the base model. Shaded range shows 90% prediction interval (from 5.0 to 95.0 percentile points) of simulation based on binomial distribution. To calculate 90% predictive intervals, data for 1000 trials, based on study design and population from the Japanese and Western studies, were generated using NONMEM‐derived maximum likelihood parameter estimates. Parameter estimates to depict the predictive intervals were derived from pooled data. ACR, American College of Rheumatology response criteria.

Figure 2

Mean (90%CI) model‐predicted ACR20, ACR50, and ACR70 responses in week 12 for the final model with study effect on Emax. Shaded range shows 90% prediction interval (from 5.0 to 95.0 percentile points) of simulation based on binomial distribution. To calculate 90% prediction, data for 1000 trials, based on study design and population from the Japanese and Western studies, were generated using NONMEM‐derived maximum likelihood parameter estimates. Parameter estimates to depict the predictive intervals were derived from pooled data. ACR, American College of Rheumatology response criteria; CI, confidence interval; Emax, maximum drug effect.

Figure 3

Mean fraction of the maximum, placebo‐adjusted proportion of ACR20, ACR50, and ACR70 responders in week 12. Lines show median and 90% prediction interval (from 5 to 95 percentile points) of simulation based on binomial distribution. To calculate 90% prediction intervals, data for 1000 trials, based on study design and population from the Japanese and Western studies, were generated using NONMEM‐derived maximum likelihood parameter estimates. ACR, American College of Rheumatology response criteria.