A Physiological-Based Pharmacokinetic (PBPK) Model embedded with Pulmonary Compartmental Absorption and Transit (PCAT™) Module to Predict Intranasal Ketamine Pharmacokinetics in Pediatric Population

Objectives: Intravenous ketamine (IVK) is commonly utilized for emergency pediatric procedural sedation but is resource-consuming and associated with significant child distress. Conversely, intranasal ketamine (INK) is noninvasive and provides rapid absorption and onset of action, which could improve patient outcomes. The objective of the present study is to model the pharmacokinetics of INK in pediatric patients using GastroPlus® to aid in the design of a clinical trial. Methods: Compartmental and physiological-based pharmacokinetic (PBPK) models of IVK 3 mg/kg and INK 3 mg/kg in pediatric patients were constructed using existing literature data1 and a Pulmonary Compartmental and Absorption and Transit (PCAT™️) module was used to model nasal deposition. The model was calibrated through optimization of nasal systemic absorption rate constant and inclusion of lysosomal trapping in the model. The population simulator was used to simulate INK at three dose levels (4, 6, and 9 mg/kg) in 200 pediatric patients ages 3 months-17 years and weighing 10-65 kg. Results: Using preexisting data, a compartmental and PBPK models were built for IVK. The PBPK INK model was able to predict Cmax, tmax, and AUC values that closely matched observed values of INK 3 mg/kg (R2=0.923). Using population pharmacokinetics incorporating the demographics of the intended clinical trial population, the PBPK INK model predicted the Cp-time profiles, and estimated the Cmax, tmax and AUC0-inf to be 623ng/mL, 0.43h, and 1694ng.h/mL, respectively for the 4 mg/kg dose; 899ng/mL, 0.43h, and 2395ng.h/mL, respectively for the 6 mg/kg dose; and 1378ng/mL, 0.43h, and 3723ng.h/mL, respectively for the 9 mg/kg dose. Conclusion: A PBPK model was successfully developed and used to predict the pharmacokinetics of INK in the pediatric population at three different doses. This data represents a valuable strategic tool to aid in the careful planning of pediatric clinical trials.Citations: Citations: [1] Malinovsky JM, Servin F, Cozian A, Lepage JY, Pinaud M. Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth. 1996 Aug;77(2):203-7. doi: 10.1093/bja/77.2.203. PMID: 8881626