Morphine is widely used for pediatric pain management; however, clinicians working in the neonatal intensive care unit (NICU) still struggle with finding the right dose due to a large variability in plasma morphine levels and response to morphine among neonates and small infants. Age-appropriate dosing in these youngest populations is especially challenging since neonatal and infant pain management research still faces two major challenges: a lack of clear biomarkers and very heterogeneous pharmacokinetics (PK) and pharmacodynamics (PD) of morphine. In addition, the large PK variability leads to treatment failures and toxicities due to inadequate and excessive plasma morphine levels, respectively. Therefore, there is an unmet clinical need for a tool supporting age-appropriate morphine dose estimation for neonates and infants. Our long-term goal is to develop a PK-PD model of morphine to maximize treatment efficacy and to minimize the incidence of associated adverse effects. As a first step, this proposal is to develop and evaluate a neonatal physiologically-based PK (PBPK) model of morphine to explain the PK-related variability, before moving to PK-PD analysis. The developed model will support our understanding of the mechanisms behind the large PK variability. As an exploratory research aim, PK-PD relationship will be characterized using pain score, which have been collected from the ongoing study (n=120 neonates), in addition to the plasma levels of morphine 6-glucuronide (M6G), which is an active metabolite of morphine. Our hypothesis is that the large variability in plasma morphine levels observed among neonates and infants is due to the following factors: genotype-dependent developmental changes in hepatic expression of Organic Cation Transporter 1 (OCT1); ontogeny of UDP-Glucuronosyltransferase 2B7 (UGT2B7); and age-dependent anatomical and other physiological changes. Since a PBPK model is designed with multiple drug- and population-specific parameters, the models are able to mechanistically account for complexed changes in disposition of morphine due to age- and genotype-dependent physiological changes. However, there is no information available on the genotype-dependent developmental expression profile of OCT1 protein. The contiguous age-dependent expression profile of UGT2B7 protein is also very limited. Therefore, we will identify developmental expression profiles of these two proteins in pediatric liver tissue samples, especially focusing on OCT1 genotype-dependent expression levels. The obtained protein expression profiles will be implemented into the morphine PBPK model in order to simulate morphine concentration-time profiles in neonates. Subsequently, the predictive performance of the developed morphine PBPK model will be evaluated by comparing to in-house morphine concentration-time profile data in neonates for each genotype. Once the PBPK model is evaluated, it will predict age- and genotype-appropriate doses for neonates according to their stage of development and genotype of OCT1 and UGT2B7. In addition, PK-PD relationship characterized in the exploratory aim will support our long-term goal that is to develop a PBPK-PD model of morphine and its metabolites for neonatal patients. In a follow-up grant proposal, we will create a combined PBPK model of morphine with M6G, and then will move to the development of a PBPK-PD model of morphine with M6G, using plasma M6G levels in neonates and potential PD marker data obtained from the exploratory research aim in this proposal. Our long-term goal is to develop model-informed dosing support platform to improve pediatric pain management using morphine.
Morphine has been widely used for pediatric pain management; however, clinicians working in the neonatal intensive care unit (NICU) still struggle with finding the right dose due to large variability in plasma morphine levels and response to morphine among neonates and small infants. To satisfy this unmet need, the purpose of this research project is to develop a mathematical in silico computer tool incorporating genotype-dependent developmental changes in drug transporters and metabolizing enzymes for supporting safe and effective age- appropriate morphine dosing.