Brigitte D. Lacroix(1), Gerald Parker(2) and Maria-Laura Sargentini-Maier(3)
(1)UCB Pharma, Braine-l’Alleud, Belgium, (2)UCB Pharma, Slough, UK, (3)Ablynx NV, Zwijnaarde, Belgium
Objectives: To characterize the rate and extent of the antibody response at the recommended dose schedules in rheumatoid arthritis subjects treated with certolizumab pegol (CZP), related to the drug exposure.
Methods: Subjects were flagged antibody-positive from the first incidence of anti-CZP antibody level >2.4 U/mL onwards. Antibody incidence was analyzed using a right-censored time-to-event model, based on data from 1752 subjects from phase II and phase III studies (population PK database [1-4]). Follow-up visits were included for subjects who did not enter the open-label follow-up studies. The analysis was performed in SAS using a parametric model with Weibull distribution. Potential covariate effects on the hazard rate were tested, including various CZP exposure measurements and concomitant use of methotrexate (MTX). Model selection was based on the Akaike information criterion and goodness of fit plots. Simulations to predict the rate and extent of antibody response at the recommended dose schedules were performed in TS2, based on the antibody model in addition to the population PK model and the dropout model [5] previously developed.
Results: Patients with lower trough concentrations were more likely to develop antibodies earlier. The analysis confirmed that the concomitant use of MTX (immunosuppressant) delayed the appearance of anti-CZP antibodies. The fraction of simulated antibody-positive patients obtained from the model was consistent with observed data, e.g. 10.7%(observed) vs 4 to 21% (simulated, weekly MTX dose from 5 to 20 mg) after 12 months of treatment every 2 weeks; 22.5% (observed) vs 25% (simulated) at 6 months for the worst case scenario, i.e. monotherapy and every 4 week dosing. The model over-predicted the rate of antibody formation when extrapolated beyond the observation period.
Conclusions: Higher trough concentration, which can be achieved with the use of higher doses and/or increased dosing frequency (e.g. loading doses) is a predictor of lower formation of antibody. The time to event model accurately predicted the incidence of anti-CZP response during the 6- to 12- month observation period of the studies from which it was derivated, however cannot be used to extrapolate the anti-CZP antibody response with long term treatment over 1 year.
References:
[1] E Keystone, D Mason, RM Fleischmann. Certolizumab pegol 400 mg every 4 weeks as monotherapy rapidly reduces disease activity in active rheumatoid arthritis. Arthritis Rheum 2007 56(Suppl9):S156 (2007).
[2] Fleishmann, R. et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann.Rheum.Dis. 68, 805-811 (2009)
[3] Keystone, E et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two weeks, phase III, multicenter, randomized, double blind, placebo controlled, parallel-group study. Arthritis Rheum. 58, 3319-3329 (2008)
[4] Smolen, J.S. et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann. Rheum. Dis. 68, 797-804 (2009)
[5] Lacroix, B.D., Lovern, M.R., Stockis A., Sargentini-Maier M.L., Karlsson M.O. & Friberg L.E. A pharmacodynamic markov mixed-effects model for determining the effect of exposure to certolizumab pegol on the ACR20 score in patients with rheumatoid arthritis. Clin Pharm Ther. 86, 387-395 (2009)
Reference: PAGE 23 () Abstr 3158 [www.page-meeting.org/?abstract=3158]
Poster: Drug/Disease modeling - Other topics