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Intranasal Diamorphine Population Pharmacokinetics and Dose Regimen Optimization in Pediatric Breakthrough Pain

Cai, Lianjin (2023) Intranasal Diamorphine Population Pharmacokinetics and Dose Regimen Optimization in Pediatric Breakthrough Pain. Master's Thesis, University of Pittsburgh. (Unpublished)

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Diamorphine hydrochloride (Pharmaceutical heroin) is licensed in the United Kingdom in Accident and Emergency department for breakthrough pain management. Intranasal diamorphine (IND) might represent an acceptable alternative for the pediatric population offering a less traumatic, effective, and expedient treatment. However, the current weight-based dose regimen of pediatrics IND is historical and empirical, relying on clinical expertise and the developmental Pharmacokinetics (PK) properties are poorly understood in children. This study aimed to (i). develop a population PK (pop-PK) model in adults following a single small dose of IND and (ii). extrapolate the model to the pediatric population with allometry (size) and maturation function (age), with the goal (iii). to devise a pediatric dosing regimen that yields a comparable morphine exposure to adults.

The pop-PK analysis of plasma concentrations of diamorphine, 6-monoacetylmorphine, and morphine was conducted utilizing the software package Monolix (v2021R1). The development PK data was collected from two open-access reports of “snorted heroin” published by the National Institute on Drug Abuse (Baltimore). Using nonlinear mixed-effect modeling, an integrated four-compartment pop-PK model with linear absorption and elimination provided an appropriate fit. The estimated IND relative bioavailability was ~ 52% with an indistinguishable first-order absorption rate constant compared to intramuscularly injected diamorphine. The external evaluations confirmed that the model is useful to extrapolate outside the development dataset scope incorporating the covariates of weight and age, which attains an acceptable average fold error for morphine Cmax (0.95) as well as for AUC0-t (0.80). More importantly, the predicted morphine concentration-time profiles were basically in agreement with the observed PK data in children after a single dose of IND (0.1 mg/kg). The model-based simulation showed that children cannot achieve a similar morphine exposure compared to adults using the current dosing regimen. Thus, we proposed a dosing scheme that uses optimal doses for different age groups based on PK examination, which recommended that infants less than 6 months should start with a low dosage of IND (0.085 mg/kg) while others require a higher initial dose (0.12-0.125 mg/kg). This PK-guided dosing equivalence using similar exposure at different ages could become a reasonable starting point for the clinical usage of nasal diamorphine spray, before individualized adjustments with the varying pain experience.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Cai, Lianjinlic154@pitt.edulic1540000-0001-5354-4050
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairJunmei,
Committee MemberRaman,
Committee MemberWang,
Date: 14 April 2023
Date Type: Publication
Defense Date: 5 April 2023
Approval Date: 14 April 2023
Submission Date: 7 April 2023
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 58
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: diamorphine, population pharmacokinetics, pediatric breakthrough pain, pharmacometrics analysis, modeling and simulation, pediatric analgesia, dosage optimization, non-linear mixed effects modeling, pharmaceutical heroin
Date Deposited: 14 Apr 2023 18:56
Last Modified: 14 Apr 2023 18:56


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