Abstract
Background: Certolizumab pegol (CZP) is effective for moderately to severely active Crohn’s disease (CD). Higher plasma concentrations are associated with better outcomes and increased drug clearance is the driver of subtherapeutic CZP concentrations. Objective: We aimed to develop a prediction model incorporating predicted CZP clearance and patient variables to allow estimation of the probability for remission prior to initiating therapy. Methods: A population pharmacokinetic model estimated baseline CZP clearance in patients with CD from nine phase II and III trials. Multivariable prediction models were developed and validated using the PRECiSE 1 and PRECiSE 2 datasets to identify candidate predictors for a composite remission outcome (Crohn’s Disease Activity Index ≤ 150 and fecal calprotectin concentration ≤ 250 μg/g) at Weeks 6 or 26. An online clinical decision support tool (CDST) was developed. Results: Baseline predicted CZP clearance ≥ 0.5 L/day was associated with subtherapeutic Week 6 CZP plasma concentrations. Baseline weight (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02–1.07), calculated CZP clearance (OR 0.92; 95% CI 0.87–0.96), hematocrit (OR 2.55; 95% CI 1.43–4.54), and fecal calprotectin (OR 0.66; 95% CI 0.54–0.80) were associated with Week 6 remission (p ≤ 0.0015 for all predictors). Baseline weight (OR 1.04; 95% CI 1.02–1.07), calculated CZP clearance (OR 0.93; 95% CI 0.88–0.97), and Patient-Reported Outcome-2 (PRO2) (OR 0.93; 95% CI 0.87–0.99) were associated with Week 26 remission (p ≤ 0.033 for all predictors). Conclusions: Patients who are predicted to have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Patient-level probabilities for a composite remission outcome can be predicted for patients with CD by entering commonly available patient- and disease-related factors into an online CDST (https://premedibd.com) incorporating predicted CZP clearance.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 85-93 |
| Number of pages | 9 |
| Journal | BioDrugs |
| Volume | 36 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2022 |
Funding
NVC and PSD are recipients of a Research Scholar Award from the American Gastroenterological Association. PD, NVC, and WJS are supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases-funded San Diego Digestive Diseases Research Center (P30 DK120515). PLCL, LG, and ZW are employees of Alimentiv, Inc. (formerly Robarts Clinical Trials, Inc.). BGF has received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, and UCB; consulting fees from Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestle, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., and Zyngenia; speakers bureau fees from Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, and UCB Pharma; is a scientific advisory board member for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestle, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, and UCB Pharma; and is the Senior Scientific Officer of Alimentiv, Inc. (formerly Robarts Clinical Trials Inc.). AP is a former employee of UCB Pharma and is currently employed by Sanofi Genzyme. None of the work related to this publication was performed in her capacity as an employee of the latter. MY is a former employee of UCB Pharma and is currently employed by Aimmune Therapeutics. None of the work related to this publication was performed in his capacity as an employee of the latter. LMS has received consulting fees from Alimentiv, Inc (formerly Robarts Clinical Trials, Inc.). WJS has received research grants from Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma; consulting fees from Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (previously Robarts Clinical Trials, owned by Alimentiv Health Trust), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma (acquired by Ventyx Biosciences), Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivreon Biosciences; and employee at Shoreline Biosciences. Spouse: Iveric Bio - consultant, stock options; Progenity - stock; Oppilan Pharma (acquired by Ventyx Biosciences) - consultant, stock options; Prometheus Biosciences - employee, stock, stock options; Prometheus Laboratories – stock, stock options, consultant; Ventyx Biosciences – stock, stock options; Vimalan Biosciences – stock, stock options. PD has received research support from Pfizer, Takeda, Janssen, Abbvie; and consulting fees from Takeda, Janssen, Abbvie. VJ has received consulting fees from AbbVie, Eli Lilly, GlaxoSmithKline, Arena Pharmaceuticals, Genentech, Pendopharm, Sandoz, Merck, Takeda, Janssen, Alimentiv, Inc. (formerly Robarts Clinical Trials Inc.), Topivert, and Celltrion; and speaker’s fees from Takeda, Janssen, Shire, Ferring, Abbvie, and Pfizer. NVC received research grants from R-Biopharm; grants and personal fees from Takeda and UCB; and personal fees from Alimentiv, Inc. (formerly Robarts Clinical Trials, Inc.), Celltrion and Prometheus. These activities were all outside of the submitted work.
ASJC Scopus subject areas
- Biotechnology
- Pharmacology
- Pharmacology (medical)