Background and aim: Morphine is a routinely used drug in neonates undergoing therapeutic hypothermia (TH) as treatment for hypoxic-ischemic encephalopathy (HIE). The aim of this study was to examine the effect of hypothermia on the PK of morphine in neonates with HIE.

Methods: Data was collected in two prospective cohort studies in the Netherlands. (Near) term neonates who received morphine while treated with TH for HIE were eligible for inclusion. A maximum of four plasma samples per neonate were obtained of four consecutive days during and after TH. Plasma concentrations for morphine and metabolites M3G and M6G were analysed using LC-MS/MS. PK analyses were performed using NONMEM (version 7.3). A dynamic model of temperature over time was included, which took the timing and the rate of cooling and rewarming into account. The predicted body temperature was subsequently included in the PK model. A model for serum creatinine (SCr) was developed and parameters related to renal function from this model were included in the PK model.

Results: 244 patients were assessed; characteristics are presented in Table 1. Morphine was administered as continuous infusion; dose varied between 5 and 20 μg/kg/h. 830 plasma samples were analysed; 66% were drawn during TH. Morphine levels varied between 10 and 371 ng/ml (Figure 1). In one patient (0.4%) plasma levels exceeded the potentially toxic upper limit of 300 μg/l. 
PK parameters were best described with a one-compartment model for morphine and subsequent one-compartment models for both metabolites using birth weight based allometric scaling for body size and postnatal age for maturation. Rewarming increased morphine clearance by 5.3% (95% confidence interval (CI) 3.62 – 7.01%, p<0.001) per one °C and metabolite clearance by 7.2% (95% CI 5.95 – 8.22%, p<0.001) per one °C. SCr derived renal function parameters were not related to metabolite clearance. A starting dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h leads to acceptable plasma concentrations between 10 and 40 μg/l2 (Figure 2).

Conclusion: clearance of morphine, M3G and M6G is reduced in neonates undergoing TH compared to normothermia. The present study suggests that morphine dosing according to current practice rarely leads to undesirable high plasma levels in this population. Although morphine dosing is based on clinical need and a therapeutic window for morphine plasma concentrations has not been firmly established, a starting dose of 50 μg/kg followed by continuous infusion of 5 μg/kg/h is recommended to prevent excessive morphine exposure.

0402 - PHARMACOKINETICS OF MORPHINE AND ITS METABOLITES IN NEONATES WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY DURING AND AFTER THERAPEUTIC HYPOTHERMIA