Background/Objectives: Intravenous ketamine, though effective for pediatric sedation, poses logistical challenges and patient distress. Intranasal administration offers a noninvasive alternative with rapid onset, yet dosing variability in children remains poorly characterized. The objective of the study reported here is to develop a computational model predicting nasal ketamine pharmacokinetics in the pediatric population, enabling precision dosing to enhance safety and efficacy.
Methods: A mechanistic pharmacokinetic model was developed using published pediatric data [1]. A quantitative systems pharmacology approach integrated nasal absorption dynamics, incorporating intracellular distribution mechanisms and population variability. Simulations were performed for 200 children (3 months–17 years; 10–65 kg) across escalating doses (4–9 mg/kg). Model calibration leveraged clinical observations of plasma concentrations. Key steps included:
- Model Calibration: Initial intravenous ketamine (3 mg/kg) pharmacokinetic profiles were derived from literature to develop the model.
- Intranasal Optimization: Nasal absorption kinetics and intracellular sequestration mechanisms were integrated to refine predictions of intranasal ketamine (3 mg/kg).
- Population Variability: Simulations incorporated age (3 months–17 years) and weight (10–65 kg) distributions across three intranasal ketamine doses (4, 6, 9 mg/kg) in 200 virtual patients.
Results: Compartmental and PBPK models successfully characterized intravenous ketamine pharmacokinetics (compartmental model: R²=0.989; PBPK: R²=0.976). For intranasal ketamine, a prior underestimation of Cmax and tmax was resolved with the optimized PBPK model which demonstrated robust predictive performance, with simulated Cmax, Tmax, and AUC0-t closely aligning with observed clinical data for the 3 mg/kg dose (R² = 0.923). By integrating population pharmacokinetic analysis, accounting for demographic variability within the pediatric trial cohort, the model further simulated plasma concentration-time profiles across escalating doses:
- 4 mg/kg: Cmax = 623 ng/mL, tmax = 0.43 h, AUC0-t = 1354 ng·h/mL
- 6 mg/kg: Cmax= 899 ng/mL, tmax = 0.43 h, AUC0-t = 1937 ng·h/mL
- 9 mg/kg: Cmax= 1378 ng/mL, tmax = 0.43 h, AUC0-t = 2994 ng·h/mL
Conclusion: The developed PBPK model successfully predicted intranasal ketamine pharmacokinetics across three clinically relevant pediatric doses (4, 6, and 9 mg/kg), with robust agreement to observed data. By integrating nasal absorption dynamics, lysosomal trapping mechanisms, and population variability, the model provided a mechanistic framework to optimize dosing strategies while minimizing reliance on invasive clinical sampling. This PBPK model aligns with regulatory priorities (e.g., FDA/EMA guidelines) advocating for model-informed drug development (MIDD) in pediatrics. It provides actionable evidence to support dosing recommendations in drug labeling. The methodology can be extrapolated to other intranasal drugs or pediatric populations with limited clinical data, bridging critical gaps in pediatric pharmacotherapy.
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.