LB-021 - MORPHINE-METABOLITE POPULATION PHARMACOKINETIC MODELING IN NEONATES WITH NEONATAL OPIOID WITHDRAWAL SYNDROME FOLLOWING ORAL ADMINISTRATION OF MORPHINE.

F. Tang¹, C. Ng², H. Bada³, J. Horn⁴, M. Leggas⁴; ¹Genentech, , , ²NewGround Pharmaceutical Consulting LLC, , , ³University of Kentucky, , , ⁴St. Jude Children's Research Hospital, , .

Background: Opioids, including morphine, are commonly used for treating neonatal opioid withdrawal syndrome (NOWS). Despite the availability of published population pharmacokinetic (PK) models in neonates, most models were developed based on intravenous (IV) morphine, while published models of oral morphine did not describe the PK of morphine’s major metabolites, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). This work was the first to develop a morphine-metabolite population PK model in neonates following oral administration of morphine by leveraging prospective data and published models for IV morphine.

Methods: We used data from a randomized control trial comparing oral morphine vs clonidine as the primary therapy for NOWS (NCT03396588) with sparse PK sampling (up to 6 samples per neonate). The best-performing parent drug model1 and metabolite model2 concluded in a systematic comparison3 were first combined to form the base meta-model. Known covariate relationships between weight, age, and PK parameters were incorporated (Table). Apparent metabolite volumes were fixed to adult values2 divided by bioavailability estimated from the initial fitting of morphine data. Apparent morphine clearance, apparent morphine volume, M3G formation fraction (FM3G), apparent metabolite clearance, and absorption rate constant (Ka) were estimated by the simultaneous fitting of morphine and metabolite data.

Results: 915 observations (305 from each analyte) from 69 neonates were analyzed. The proposed meta-model converged successfully with good parameter precision (Table). The estimated standardized morphine volume was at the low end of adult values, likely due to the sparsity of quantifiable observations in the elimination phase. The estimated Ka was 0.7 hr−1. Estimated bioavailability and FM3G were 43% and 75%, respectively, and higher than adult values. The estimated standardized apparent metabolite clearance was 30 and 42 L/h for M3G and M6G, respectively, close to adult values after adjusting for bioavailability.

Conclusion: A morphine-metabolite meta-model leveraging prior information well captured the available data and added to the current understanding of the disposition of morphine and its major metabolites in neonates following oral morphine administration.