Sublingual buprenorphine is used in the treatment of opioid use disorder (OUD) and neonatal opioid withdrawal syndrome (NOWS). The aim of this study was to develop a full physiologically-based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Linear regression modeling was explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for validation. The PBPK model’s predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O ratios) area under the curve (AUC), apparent clearance (CL/F), peak concentration (Cmax), and time to reach Cmax (Tmax) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2–32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC, CL/F, Cmax, and Tmax equaling 0.99 (0.86–1.12), 1.04 (0.92–1.18), 1.24 (1.09–1.40), and 1.07 (0.95–1.20), respectively. In conclusion, a fully validated PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. The model forms the foundation on which a fetomaternal PBPK model for buprenorphine can be built. Fetomaternal PBPK modeling will allow conceptualization of prenatal buprenorphine exposure and investigation of its influence on postnatal NOWS severity.

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.