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Background and Objective: Predicting adalimumab pharmacokinetics (PK) for patients impacted by anti-drug antibodies (ADA) has been challenging. The present study assessed the performance of the adalimumab immunogenicity assays in predicting which patients with Crohn's disease (CD) and ulcerative colitis (UC) have low adalimumab trough concentrations; and aimed to improve predictive performance of adalimumab population PK (popPK) model in CD and UC patients whose PK was impacted by ADA., Methods: Adalimumab PK and immunogenicity data obtained from 1459 patients in SERENE CD (NCT02065570) and SERENE UC (NCT02065622) were analyzed. Adalimumab immunogenicity was assessed using electrochemiluminescence (ECL) and enzyme-linked immunosorbent (ELISA) assays. From these assays, three analytical approaches (ELISA concentrations, titer, and signal-to-noise [S/N] measurements) were tested as predictors for classifying patients with/without low concentrations potentially affected by immunogenicity. The performance of different thresholds for these analytical procedures was assessed using receiver operating characteristic curves and precision-recall curves. Based on the results from the most sensitive immunogenicity analytical procedure, patients were classified into PK-not-ADA-impacted and PK-ADA-impacted subpopulations. Stepwise popPK modeling was implemented to fit the PK data to an empirical adalimumab two-compartment model with linear elimination and ADA delay compartments to account for the time delay to generate ADA. Model performance was assessed by visual predictive checks and goodness-of-fit plots., Results: The classical ELISA-based classification (with 20 ng/mL ADA as lower threshold) showed a good balance of precision and recall, to determine which patients had at least 30% adalimumab concentrations below 1 µg/mL. Titer-based classification with the lower limit of quantitation (LLOQ) as threshold showed higher sensitivity to classify these patients compared to the ELISA-based approach. Therefore, patients were classified as PK-ADA-impacted or PK-not-ADA impacted using the LLOQ titer threshold. In the stepwise modeling approach ADA-independent parameters were first fit using PK data from titer-PK-not-ADA-impacted population. The identified ADA-independent covariates included the effect of indication, weight, baseline fecal calprotectin, baseline C-reactive protein, baseline albumin on clearance; and sex and weight on volume of distribution of the central compartment. Pharmacokinetic-ADA-driven dynamics were characterized using PK data for the PK-ADA-impacted population. The categorical covariate based on the ELISA classification was the best at describing the additional effect of immunogenicity analytical approaches on ADA synthesis rate. The model was able to adequately describe the central tendency and variability for PK-ADA-impacted CD/UC patients., Conclusions: The ELISA assay was found to be optimal for capturing impact of ADA on PK. The developed adalimumab popPK model is robust in predicting PK profiles for CD and UC patients whose PK was impacted by ADA., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objective: Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints., Methods: Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn's disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5-45 mg once daily (QD) for induction and 15-30 mg QD for maintenance., Results: Upadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods., Conclusion: These analyses supported selection of upadacitinib UC induction and maintenance doses., Trial Registration: Data from studies NCT02819635 and NCT03653026 were included in these analyses., (© 2022. The Author(s).)