Model-based determination of abatacept exposure in support of the recommended dose for Japanese rheumatoid arthritis patients.
Author(s): Hasegawa M, Imai Y, Hiraoka M, Ito K, Roy A
Affiliation(s): Pharmacometrics, Research and Development, Bristol-Myers K.K., Shinjuku i-Land Tower, 6-5-1 Nishi-Shinjuku, Shinjuku-ku, Tokyo, 163-1328, Japan, firstname.lastname@example.org.
Publication date & source: 2011-12, J Pharmacokinet Pharmacodyn., 38(6):803-32. Epub 2011 Oct 15.
The objective of this study was to provide support for a body weight-tiered dosing regimen by characterizing abatacept pharmacokinetics (PK) and the relationship between exposure and the ACR20 (American College of Rheumatology criteria for 20% improvement) response in Japanese patients with rheumatoid arthritis (RA). A population PK model was developed using NONMEM with 2,535 samples from 344 Japanese RA patients in two clinical trials. The exposure-response relationship was characterized using a Generalized Estimating Equation (GEE) logistic regression model, with time-varying actual trough concentrations and ACR20 responder rates over 6 months in a randomized, placebo-controlled phase 2 trial for stable methotrexate. Abatacept exposure was well characterized using a linear, two-compartment model, in which body weight and the empirically calculated glomerular filtration rate were significant covariates for clearance. The ACR20 response model was developed by examining the quasi-likelihood information criterion, and the cumulative logit in the final model was specified by the log-transformed trough concentration. The predicted ACR20 responder rate was consistent with the actual values in the clinical trial and this model revealed trough concentrations higher than the recommended body weight-tiered dose are unlikely to result in substantial increases in clinical efficacy. Considering that ACR20 is a longitudinal binary variable and the response to RA treatment is delayed, the GEE model was useful for predicting the probability of an ACR20 response. In conclusion, the same dosing regimen as non-Japanese patients is recommended because a body weight-tiered dosing regimen achieves similar exposures across the wide range of body weight.