Lacroix BD (1,2), Kirby H(3), Oliver R(3), Parker G(3), Friberg LE(1), Karlsson MO(1)
(1)Uppsala University, dept of pharmaceutical Sciences, Uppsala, Sweden (2)UCB, Braine, Belgium (3)UCB, Slough, UK
Objectives: The advent of biologic therapies improved greatly the treatment of chronic inflammatory diseases. However, these drugs may induce an unwanted specific immune response directed against them. The immunogenicity of biologic drugs is of concern for all healthcare stakeholders and methods for better characterization are needed, as well as means to minimize the occurrence of anti-drug antibodies (ADA). The objective of this analysis was to develop a time-to-event model for characterizing the immunogenicity of certolizumab pegol in subjects suffering from rheumatoid arthritis included in phase II and phase III clinical trials.
Methods: The time to event model was analyzed based on previously estimated individual certolizumab pegol concentration-time profiles. A model describing the time to appearance of ADA was developed. The probability of an individual not to develop ADA to time t was described by a parametric survival function. Various functions for describing the shape if the hazard function were tested during the model building. In the addition to the drug exposure other covariates were tested, such as the dose of concomitant methotrexate, the frequency of dosing, the formulation and the concomitant use of other medications.
Results: The hazard of developing ADAs was predicted to depend on time since start of treatment, trough drug concentration in the preceding dosing interval and the concomitant use of methotrexate. Specific study effects were added into the model in order to capture the trends in two studies that remained non-explained after the covariates had been tested.
Conclusions: The proposed model characterized the time to initiation of ADA formation. The immunogenicity was predicted to appear mainly during the first three months following the start of the treatment and to be reduced at higher trough concentrations of CZP, as well as with concomitant administration of methotrexate. The model may be used to test strategies for minimizing the immunogenicity, such as the use of a loading dose or the reduction of the intervals between dosing.
Reference: PAGE 24 (2015) Abstr 3554 [www.page-meeting.org/?abstract=3554]
Poster: Drug/Disease modeling - Other topics