Exposure-response relationship of certolizumab pegol induction and maintenance therapy in patients with Crohn's disease

Background: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). Aim: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. Methods: Adults (N=2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline >= 100 points), remission (CDAI <= 150), C-reactive protein (CRP)5mg/L, faecal calprotectin (FC) <= 250 mu g/g, and a composite endpoint of CDAI <= 150 and FC <= 250 mu g/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. Results: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP <= 5mg/L or FC <= 250 mu g/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P<.001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 mu g/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 mu g/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. Conclusions: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.