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

Abstract

SummaryBackgroundTherapeutic drug monitoring may optimize therapy for Crohn's disease (CD).AimTo 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.MethodsAdults (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) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 μg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 μg/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 ≤ 5 mg/L or FC ≤ 250 μg/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 μg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 μg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes.ConclusionsAn 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.

Editorial: early post‐induction anti‐TNF drug monitoring can predict long‐term therapeutic outcomes in inflammatory bowel disease

“…Vande Casteele et al also demonstrated, based on multivariable analyses, that higher CZP concentrations at week 6 were associated with composite remission at week 6 and most importantly week 26, suggesting that early post‐induction anti‐TNF drug monitoring can predict long‐term therapeutic outcomes in IBD . These findings are consistent with previous data reporting that higher post‐induction infliximab concentrations at week 14 are associated with higher rates of clinical response or remission at week 54 and less treatment failure or colectomy .…”

“…Vande Casteele et al have performed the largest combined exposure‐response analysis of any anti‐TNF agent to date and evaluated the association of CZP exposure with clinical and biomarker outcomes in patients with Crohn's disease (CD). They used pooled data from nine clinical trials and a refined population pharmacokinetic model that accounts for the time‐varying nature of covariates to simulate CZP concentrations at exact time points in individual patients .…”

“…They used pooled data from nine clinical trials and a refined population pharmacokinetic model that accounts for the time‐varying nature of covariates to simulate CZP concentrations at exact time points in individual patients . The authors demonstrated that CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical remission (Crohn's disease activity index [CDAI] score of ≤150), biomarker remission (C‐reactive protein ≤5 mg/L or fecal calprotectin [FC] ≤250 μg/g) or composite remission (CDAI ≤150 and FC ≤250 μg/g) at week 6 than without . Moreover, they showed a positive correlation between CZP concentrations and clinical, biomarker or composite remission based on quartile analysis, with the strongest exposure‐response relationship observed for the more objective outcomes of biomarker remission .…”

“…The authors demonstrated that CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical remission (Crohn's disease activity index [CDAI] score of ≤150), biomarker remission (C‐reactive protein ≤5 mg/L or fecal calprotectin [FC] ≤250 μg/g) or composite remission (CDAI ≤150 and FC ≤250 μg/g) at week 6 than without . Moreover, they showed a positive correlation between CZP concentrations and clinical, biomarker or composite remission based on quartile analysis, with the strongest exposure‐response relationship observed for the more objective outcomes of biomarker remission . Although CZP concentration thresholds varied depending on the therapeutic outcome of interest, a CZP concentration range of 33.4 to 40.9 μg/mL at week 6 was adequate to achieve the highest rate of the most stringent endpoint, composite remission; after that the dose‐response curve plateaued.…”

Vedolizumab exposure levels and clinical outcomes in ulcerative colitis: determining the potential for dose optimisation

“…Exposure‐response metrics have increasingly been used to optimise IBD treatment with anti‐TNFα agents, but the vast majority of the reported analyses were based on studies not prospectively designed from exposure‐response inferences or adjusted for potential confounding factors . In fact, only recently was the first study with patient‐level covariate adjustment of the exposure‐response relationship for anti‐TNFα therapy published, by Vande Casteele et al, in patients with CD treated with certolizumab pegol. Very limited data on the vedolizumab exposure‐response relationship are currently available to guide clinicians.…”