Physiologically Based Pharmacokinetic Modeling of Vedolizumab in Healthy Adults and Patients with Inflammatory Bowel Disease

Background and Objective Vedolizumab is a gut-selective, humanized monoclonal antibody that binds to α4β7 integrin, preventing lymphocyte trafficking to the intestinal mucosa. While approved for adults with moderate-to-severe ulcerative colitis (UC) or Crohn’s disease (CD), drug exposure may vary significantly with disease activity. Physiologically based pharmacokinetic (PBPK) modeling provides a mechanistic framework to integrate drug properties with system physiology, enabling the prediction of pharmacokinetics (PK) under these various pathophysiological conditions. In this study, we developed a minimal mechanistic PBPK model incorporating target-mediated drug disposition (TMDD) to characterize the PK of healthy adults and patients with varying inflammatory bowel disease severity. Methods A minimal PBPK model incorporating TMDD was developed for vedolizumab using the Simcyp Simulator. The model was parameterized with literature values for healthy adults, verified against clinical PK data from healthy volunteers, and adapted for patients with varying disease severity by estimating target abundance (Rmax) to reflect α4β7 upregulation in active inflammation. Model performance was assessed by comparing simulated and observed concentration–time profiles and predicted-to-observed (P/O) ratios for peak concentration (Cmax), area under the curve from time 0 to time of the last concentration (AUC0–tlast), and trough concentration (Ctrough). Results The PBPK model demonstrated robust predictive performance across varying disease states and ethnicities, compared with reported PK parameters in clinical studies. In healthy adults, mean P/O ratios for Cmax and AUC0–tlast ranged from 0.81 to 1.11 and 0.80 to 1.02, respectively, across single doses of 0.2–10 mg/kg. For patients with mild-to-moderate UC, the estimated Rmax yielded mean P/O ratios for Cmax and AUC0–tlast of 0.88–1.02 and 0.78–0.99, respectively. Additionally, for moderate-to-severe UC and CD, mean P/O ratios for Ctrough fell within 0.67–1.49. Simulations indicated that higher Rmax values increased clearance and reduced systemic exposure, with mean predicted Ctrough in high target-expression groups frequently falling below the efficacy thresholds of 12 μg/mL and 14 μg/mL. Conclusions This study presents the first PBPK model for vedolizumab that quantitatively captures disease-related α4β7 upregulation and its impact on PK in adults. The model provides a mechanistic basis for simulating exposure across disease states and supports model-informed precision dosing strategies to optimize treatment outcomes in UC and CD.