Katarina Vučićević 1, Valentina Topić Vučenović 2, Marija Jovanović 1, Srđan Marković 3,4, Đorđe Kralj 3, Petar Svorcan 3,4
1 Faculty of Pharmacy – University of Belgrade, Department of Pharmacokinetics and Clinical Pharmacy (, Republic of Serbia), 2 Faculty of Medicine – University of Banja Luka, Department of Pharmacokinetics and Clinical Pharmacy (Banja Luka, Bosnia and Herzegovina), 3 University Hospital Medical Center “Zvezdara”, Department of Gastroenterology and Hepatology (Belgrade, Republic of Serbia), 4 Faculty of Medicine – University of Belgrade (Belgrade, Republic of Serbia)
Introduction: Therapeutic drug monitoring (TDM) of adalimumab is used in Crohn’s disease management due to high interindividual variability in drug exposure [1]. However, translating measured concentrations into individualized dosing decisions requires robust population pharmacokinetic (PopPK) models applicable to real-world settings.
Objective: The objective of this study was to develop a population pharmacokinetic (PopPK) model using routine TDM data, supporting model-informed therapy in order to support model-informed precision dosing based on TDM in clinical settings.
Methods: This study included data retrospectively collected from medical charts of inflammatory bowel disease patients treated with adalimumab at the Department of Gastroenterology and Hepatology, University Hospital Medical Center “Zvezdara”. We analysed data from adult Crohn’s patients receiving s.c. 40 mg weekly or biweekly. Adalimumab concentrations were routinely collected. Serum concentrations and clinical/laboratory data were modelled using NONMEM® version 7.6 (Icon Development Solutions Inc, Dublin, Ireland). A one-compartment model with first-order absorption and elimination was used, with absorption rate constant and volume of distribution fixed to literature values (0.15 day-1 and 13.5 L). Concentrations above the upper limit of quantification (ULOQ = 12 µg/mL) were handled via the M3 method, and anti-drug antibody (ADA) status was included on clearance using a prior based approach. Covariate selection was guided by plausibility and statistics, and goodness-of-fit diagnostics and visual predictive checks (VPC) were used for model performance assessment.
Results: The analysis included 942 adalimumab concentrations (7.4% exceeded ULOQ) from 195 patients. Average age was 30.1 (ranging from 18 to 67) years, with almost equal number of male and females (50.8 % males). Observed troughs showed wide variability, with a mean (±SD) of 9.9 ± 5.8 µg/mL. ADA measurements were available for 31% of samples, of which 3.1% were ADA-positive. Typical clearance was estimated at 0.38 L/day (95% confidence interval, CI, 0.354 – 0.404), with moderate interindividual variability of 12.4% (estimated variance was 0.117 and relative standard error, %RSE was 18.9%). Ln-transformed C-reactive protein values was identified as a significant covariate on oral clearance, indicating increased oral clearance with higher inflammatory burden. Estimated coefficient (%RSE) for ln-CRP influence was 0.162 (19.8%). Residual variability was modelled as combined error with proportional part of 0.267 (%RSE = 27.8%) and additive 3.51 mg/L (%RSE = 13.8%). The final model adequately described the observed concentration–time data, as confirmed by VPC.
Conclusion: We developed a PopPK model of adalimumab from real-world TDM data in Crohn’s disease, providing a framework for future indirect response models to link PK, biomarkers, and outcomes for personalized therapy.
Acknowledgement: This research was supported by the Science Fund of the Republic of Serbia, through grant agreement No. 6777, Improving Clinical Outcomes with Precision Dosing in Patients with Inflammatory Bowel Disease Through Investigating Variability of Monoclonal Antibodies Based on Population Pharmacokinetic-Pharmacodynamic Modelling —optYmAb.
References:
[1] Cheifetz AS, Abreu MT, Afif W, Cross RK, Dubinsky MC, Loftus EV Jr, Osterman MT, Saroufim A, Siegel CA, Yarur AJ, Melmed GY, Papamichael K. A Comprehensive Literature Review and Expert Consensus Statement on Therapeutic Drug Monitoring of Biologics in Inflammatory Bowel Disease. Am J Gastroenterol. 2021; 116(10): 2014-2025.
Reference: PAGE 34 (2026) Abstr 11977 [www.page-meeting.org/?abstract=11977]
Poster: Drug/Disease Modelling - Other Topics