Intranasal diamorphine population pharmacokinetics modeling and simulation in pediatric breakthrough pain

Intranasal diamorphine (IND), approved for managing breakthrough pain in the UK, has been identified as an acceptable alternative offering effective, expedient, and less traumatic analgesia for children. However, the current dose regimen in pediatric populations relies on clinical expertise while the pharmacokinetics properties are poorly understood. This study aimed to develop diamorphine population pharmacokinetics (pop-PK) models and simulate the IND dosing in virtual pediatric subjects. An integrated four-compartment pop-PK model with first-order absorption and elimination provided an appropriate fit and characterized publicly available 385 concentration measurements of diamorphine, 6-monoacetylmorphine, and morphine collected from adults. Body weight allometry and renal function maturation (age) were incorporated into the final model, serving as two covariates. The estimated IND relative bioavailability was around 52% compared with intramuscularly injected diamorphine. Using this final model, the morphine plasma concentrations, as the active metabolite for pain relief, were simulated in virtual subjects. The utility of model extrapolation was supported by external verification with acceptable average fold errors of 1.06 ± 0.30 and 0.83 ± 0.07 for morphine maximum concentration and exposures. Meanwhile, the simulated morphine concentration-time profiles could recover the PK profiles observed in children after a single dose of IND. The model-based dosing simulations were therefore assessed in four children age groups to match the therapeutic window of morphine concentrations in steady state (10-20 μg/L). Our study demonstrates that the dose regimen of 0.3 mg/kg loading dose plus 0.1 mg/kg hourly maintenance dose is generally appropriate for multiple pediatric populations with breakthrough pain, in the view of PK.