J Crohns Colitis. 2024 Feb 26;18(2):212-222. doi: 10.1093/ecco-jcc/jjad140.

Emily K Wright ^1 2, Maria Chaparro ³, Paolo Gionchetti ⁴, Amy L Hamilton ^1 2, Julien Schulberg ^1 2 5, Javier P Gisbert ³, Maria Chiara Valerii ⁴, Fernando Rizzello ⁴, Peter De Cruz ^2 5, John C Panetta ⁶, Annelie Everts-van der Wind ⁷, Michael A Kamm ^1 2, Thierry Dervieux ⁷

Author information

¹Department of Gastroenterology, St Vincent's Hospital, Melbourne, VIC, Australia.

²Department of Gastroenterology, University of Melbourne, Melbourne, VIC, Australia.

³Department of Gastroenterology, Hospital Universitario de La Princesa, IIS-Princesa, UAM and CIBEREHD, Madrid, Spain.

⁴Department of Gastroenterology, IBD Unit IRCCS Azienda Ospedaliera Universitaria di Bologna and DIMEC University of Bologna, Bologna, Italy.

⁵Department of Gastroenterology, Austin Health, Melbourne, VIC, Australia.

⁶St Jude Children's Research Hospital, Department of Pharmaceutical Sciences,Memphis, TN, USA.

⁷Prometheus Laboratories, Research and Development, San Diego, CA, USA.

Abstract

Objective: We postulated that adalimumab [ADA] drug clearance [CL] may be a more critical determinant of therapeutic outcome than ADA concentration. This was tested in Crohn's disease [CD] patients undergoing ADA maintenance treatment.

Methods: CD patients from four cohorts received ADA induction and started maintenance therapy. Therapeutic outcomes consisted of endoscopic remission [ER], sustained C-reactive protein [CRP] based clinical remission [defined as CRP levels below 3 mg/L in the absence of symptoms], and faecal calprotectin [FC] level below 100 µg/g. Serum albumin, ADA concentration, and anti-drug antibody status were determined using immunochemistry and homogeneous mobility shift assay, respectively. CL was determined using a nonlinear mixed effect model with Bayesian priors. Statistical analysis consisted of Mann-Whitney test and logistic regression with calculation of odds ratio. Repeated event analysis was conducted using a nonlinear mixed effect model.

Results: In 237 enrolled patients [median age 40 years, 45% females], median CL was lower in patients achieving ER as compared with those with persistent active endoscopic disease [median 0.247 L/day vs 0.326 L/day, respectively] [p <0.01]. There was no significant difference in ADA concentration between patients in endoscopic remission compared with those with recurrence [median 9.3 µg/mL vs 11.7 µg/mL, respectively]. Sustained CRP-based clinical remission and FC levels below 100 µg/g were generally associated with lower CL and higher ADA concentration. Repeated event analysis confirmed those findings with better performances of CL than concentration in associating with ER and other outcomes.

Conclusion: Lower ADA clearance is associated with an improved clinical outcome for patients with Crohn's disease and may be a superior pharmacokinetic measure than concentration.