Modeling and simulation of abatacept exposure and interleukin-6 response in support of recommended doses for rheumatoid arthritis.
Abatacept is a recombinant soluble fusion protein that inhibits the CD80/CD86:CD28 costimulatory signal required for T cell activation and has demonstrated efficacy in the treatment of rheumatoid arthritis. The objectives of this analysis were to provide support for a body weight-tiered dosing regimen approximating 10 mg/kg by (1) quantifying the effect of body weight on exposure and (2) characterizing the relationship between exposure and serum interleukin (IL)-6 concentration. The abatacept exposure and exposure-response models were developed with 2148 abatacept serum concentrations (from 388 subjects) and 1894 IL-6 serum concentrations (from 799 subjects), respectively, followed by simulation with these models to address the above objectives. Abatacept exposure was characterized by a linear 2-compartmental model, in which clearance was linearly related to body weight. The IL-6 response was characterized by an indirect-response model, in which the IL-6 production rate increased with baseline C-reactive protein levels. Model-based simulations demonstrated that body weight-tiered dosing was desirable to ensure consistent steady-state abatacept trough concentrations across a range of body weights; doses approximating 10 mg/kg (500, 750, 1000 mg for subjects weighing <60, 60-100, and >100 kg, respectively) provided consistent exposure across the body weight groups. In addition, doses >10 mg/kg did not result in further increases in IL-6 suppression. These modeling and simulation results indicate that the body weight-tiered abatacept therapeutic doses approximating 10 mg/kg will ensure consistent abatacept exposure and optimal IL-6 suppression.
Roy
Amit
A
Clinical Discovery, Research and Development, Bristol-Myers Squibb, Princeton, NJ 08543-4000, USA. amit.roy@bms.com
Mould
Diane R
DR
Wang
Xiao-Feng
XF
Tay
Lee
L
Raymond
Ralph
R
Pfister
Marc
M
D000069594:Abatacept; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D002097:C-Reactive Protein / Q000032:analysis; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological
D018501:Antirheumatic Agents; C508600:IL6 protein, human; D018796:Immunoconjugates; D015850:Interleukin-6; D000069594:Abatacept; D002097:C-Reactive Protein