Pavan Vajjah, Gerry Parker, Ruth Oliver
UCB Celltech, 208 Bath road, Slough, SL1 3WE, United Kingdom
Objectives: To describe the relationship between pharmacokinetics (PK) of certolizumab pegol (CZP) and the time course of ACR 20/50/70 in patients with psoriatic arthritis (PsA). The other objective was to compare the time course and magnitude of effect on ACR 20/50/70 response rates at week 24 given the two dosage regimens.
Methods: Data from a phase 3 study in subjects (n=409) with active and progressive PsA was used for the analysis [1]. Subjects were allocated to the following study treatments in a 1:1:1 ratio: 1. CZP administered subcutaneously (sc) at the dose of CZP 400 mg Q2W at Weeks 0, 2 and 4 followed by CZP 200 mg Q2W sc (starting at Week 6) or 2. CZP 400 mg Q2W at Weeks 0, 2 and 4 followed by CZP 400 mg Q4W sc (starting at Week 8) or 3. Placebo. The CZP plasma-concentration-time data was used to develop a PK model. Secondary PK parameters such as Cmax, Cmin and Cavg were determined using the PK model. A proportional odds model was used to simultaneously analyze the ACR 20/50/70 response rates observed in the study. The individual plasma concentrations, AUC, Cmax, Cmin and Cavg were used as exposure measures.
Simulations were performed to predict the time course and magnitude of the of ACR 20/50/70 response rate of CZP in this patient population, given the two dosage regimens used in the current study, to evaluate whether the difference between dosage regimens, if any, could be detected.
Results: A one compartment disposition, zero-order input into a depot compartment, with subsequent first order absorption to central compartment population PK model adequately characterized the plasma CZP concentration time course. The residual variability took the form of a proportional error model. Body weight and anti-drug antibodies (ADA’s) were the identified covariates on CL/F Body weight was also a covariate on V/F. An Emax model on the logit scale provided the best description of the time course of ACR 20/50/70. Cavg was determined to be the best predictor of ACR 20/50/70 response criteria.
The simulations performed using the final model indicated that the both the magnitude and the time course of the predicted ACR 20/50/70 response rates for the two dosage regimens (200 mg Q2W and 400 mg Q4W) were similar.
Conclusions: An exposure response model was developed to simultaneously describe the time course of ACR 20/50/70 response rates in psoriatic arthritis population following sc administration of CZP. The results of simulations indicate that the time course and magnitude of ACR 20/50/70 response rates at week 24 are similar for the two tested dosage regimens
References:
[1]. Mease, P.J., Fleischmann, R., et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann Rheum Dis 73(1), 48-55 (2014).
Reference: PAGE 23 (2014) Abstr 3239 [www.page-meeting.org/?abstract=3239]
Poster: Drug/Disease modeling - Other topics