Intranasal Diamorphine Population Pharmacokinetics Modeling and Simulation in Pediatric Breakthrough Pain
Authors: Cai Lianjin 
Published: February 2025

Objectives: 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.[1] This study aimed to develop a pop-PK model for diamorphine, 6-monoacetylmorphine, and morphine, using data from adult subjects to extrapolate for pediatric dosing to assess the feasibility of current IND dosing for children.Methods: We collected and analyzed the publicly available PK data in subjects receiving low-dosage diamorphine across two routes of administration over a twofold range of doses using Monolix Suite. Integrated compartment pop-PK model was developed to describe the concentration-time (C-T) profiles of diamorphine, 6-monoacetylmorphine, and morphine simultaneously. Besides conducting model diagnosis using internal dataset, two additional clinical datasets, including the only one diamorphine PK data from children, were used for evaluation of model extrapolation. Finally, the model-based dosing simulations were assessed in four children age groups to match the therapeutic window of morphine concentrations in steady-state (10-20 µg/L).[2] Results: The C-T profiles of diamorphine and 6-monoacetylmorphine were best described with the one-compartment model while the morphine data fitted better with the two-compartment model. All population estimates of PK parameters of the final model are standardized by weight 70 kg whilst a model capturing the maturation of renal function was used to characterize the total clearance of the morphine. The estimated IND relative bioavailability was ~ 52% compared to 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 an acceptable average fold error of 1.06 (95% CI: 0.77–1.36) for morphine maximum concentration and 0.83 for exposures (95% CI: 0.76–0.90). Meanwhile, the simulated morphine concentration-time profiles could recover the PK data observed in children after a single dose of IND. To better understand the model generalizability performance across age and weight changes in children, the model was simulated in four representative pediatric populations . It suggest that the dose regimen of 0.3 mg/kg loading dose plus 0.1 mg/kg maintenance dose hourly is generally appropriate for multiple pediatric populations.Conclusions: This study analyzed, developed and evaluated pop-PK models for IND and its metabolites in adults and children, for the first time. Moreover, model-based simulations was used to derive an optimal weight-based dosage regimen to promote the appropriate use of intranasal diamorphine in children with breakthrough pain.Citations: [1] Gastine S, et al. Diamorphine pharmacokinetics and conversion factor estimates for intranasal diamorphine in paediatric breakthrough pain:systematic review. BMJ Supportive & Palliative Care bmjspcare-2021-003461. (2022)[2] Holford NHG, Ma SC, Anderson BJ. Prediction of morphine dose in humans. Pediatric Anesthesia 22 209-222. (2012)