2008 - Marseille - France

PAGE 2008: Applications- Biologicals/vaccines
Brigitte Lacroix

Exposure-Response Modeling of the ACR20 Score in Rheumatoid Arthritis Patients Treated with Certolizumab Pegol.

Brigitte Lacroix(1,2), Mark Lovern(1), Armel Stockis(1), Maria Laura Sargentini-Maier(1), Mats O. Karlsson(2) and Lena E. Friberg(2)

(1) Pharmacometrics, Global Exploratory Development, UCB Pharma SA, Belgium; (2)Division of Pharmacokinetics & Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Sweden

Objectives: This analysis aimed to describe the exposure-response relationship of certolizumab pegol (CZP) in patients with rheumatoid arthritis, using the changes in the ACR20 clinical score (American College of Rheumatology 20% improvement criteria) as a response variable.

Methods: The ACR20 data from 1747 patients treated with CZP and 633 patients treated with placebo (from one Phase II and four phase III clinical trials) were used for non-linear mixed effects modeling using NONMEM VI. Placebo or CZP at doses ranging from 50 to 800 mg was administered subcutaneously every 2 or 4 weeks, with or without concomitant administration of methotrexate, for 8 to 48 weeks. At each visit, the ACR20 scores (responder/non-responder) and drop out events were coded in 3 categories. The probabilities of the transitions between these 3 different states were modeled using logit functions. The drug effect was introduced as various functions of the plasma concentration. The model was used to predict the clinical outcome following various treatment regimens in a variety of patient sub-populations.

Results: The best model combined Emax functions on the logit scale to describe the increase of the probability of becoming a responder and the decrease of the probability of becoming a non-responder as a function of the average plasma concentration between successive doses (Cavg). The population value of EC50, i.e. the Cavg leading to half the maximum probability of becoming a responder and half the minimum probability of becoming a non-responder was estimated at 16.8 mg/mL (95%CI: 10.2-23.4). Simulations from the final exposure-response model, in fully compliant patients, predicted similar response probabilities for 200 mg every 2 weeks and 400 mg every 4 weeks dosing schedules (response rate of 0.71 versus 0.69). Loading doses of 400 mg at weeks 0, 2 and 4 were predicted to increase the response rate at week 12 (0.64 versus 0.55) but not at week 22 (0.71 versus 0.68).

Conclusions: A significant exposure-response relationship was demonstrated for CZP in rheumatoid arthritis.  The simulations support dosing regimens of 200 every other week or 400 every 4 weeks. Loading doses of 400 mg on weeks 0, 2 and 4 were predicted to result in a faster onset of action that is still perceivable on week 12 whereas no difference persisted on week 22.

Reference: PAGE 17 (2008) Abstr 1318 [www.page-meeting.org/?abstract=1318]
Poster: Applications- Biologicals/vaccines