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

ABSTRACT: 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) ? 5 mg/L, faecal calprotectin (FC) ? 250 ?g/g, and a composite endpoint of CDAI ? 150 and FC ? 250 ?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 ? 5 mg/L or FC ? 250 ?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 ?g/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 ?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.

SUBMITTER: Vande Casteele N

PROVIDER: S-EPMC5765392 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Vande Casteele N N Feagan B G BG Vermeire S S Yassine M M Coarse J J Kosutic G G Sandborn W J WJ

Alimentary pharmacology & therapeutics 20171121 2

<h4>Background</h4>Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD).<h4>Aim</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 29159893

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Project description:BackgroundCrohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response.ObjectivesThe primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD.Search methodsWe searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP.Selection criteriaWe included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients.Data collection and analysisWe used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI).Main resultsFour studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy.Authors' conclusionsModerate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.

Dataset Information

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

Publications

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

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