Mechanistic Population Pharmacokinetics of Morphine in Neonates With Abstinence Syndrome After Oral Administration of Diluted Tincture of Opium

Abstract

Conducting and analyzing clinical trials in vulnerable neonates are extremely challenging. The aim of this analysis is to develop a morphine population pharmacokinetics (PK) model using data collected during a randomized control trial in neonates with abstinence syndrome (NAS). A 3-compartment morphine structural PK model after intravenous (IV) administration from previously published work was utilized as prior, whereas an allometric scaling method with physiological consideration was used to extrapolate a PK profile from adults to pediatrics. The absorption rate constant and bioavailability were estimated in NAS after oral administration of diluted tincture of opium (DTO). Goodness-of-fit plots along with normalized prediction distribution error and bootstrap method were performed for model evaluation. We successfully extrapolated the PK profile from adults to pediatrics after IV administration. The estimated first-order absorption rate constant and bioavailability were 0.751 hour(-1) and 48.5%, respectively. Model evaluations showed that the model can accurately and precisely describe the observed data. The population pharmacokinetic model we derived for morphine after oral administration of DTO is reasonable and acceptable; therefore, it can be used to describe the PK and guide future studies. The integration of the previous population PK knowledge as prior information successfully overcomes the logistic and practical issue in vulnerable neonate population.

Keywords: bioavailability; diluted tincture of opium; morphine; neonatal abstinence syndrome; neonate; population pharmacokinetic model.

Figure 1

Maturation of extracellular body water as a percentage of body weight. The red solid dots represent digitized data from previous work. The solid blue line represents model fit

Figure 2

External evaluation of morphine structural models a) after IV bolus administration of morphine 0.14 mg/kg plus infusion of 0.05mg/kg/hour for 4hours in 20 healthy adults with mean age 24.6 years and mean body weight 74.2kg. b) after IV bolus administration 10mg/70kg in 6 healthy volunteers with mean body weight 71.4kg and mean age 25.8 years.

Figure 3

External evaluation of morphine structural model after intravenous bolus administration a) in infants undergoing elective surgery (mean age 21 months). b) in children with leukemia undergoing therapeutic lumbar puncture (median age 5.5 years and median weight 20.0 kg) c) in neonates (N=10, mean age 1.1 days and mean weight 3.5kg) d) in neonates (N=10, mean age 29 days and mean weight 3.9kg) e) in infants (N=7, mean age 112 days and 6.2kg) f) in infants (N=5, mean age 0.3 years and mean weight 5.3kg) g) in children (N=5, mean age 3.7 years and mean weight 16.3kg) h) in children (N=4, mean age 6.4 years and mean weight 22.3kg)

Figure 4

a) Population predicted plasma concentration versus observed plasma concentration. b) Individual predicted plasma concentration versus observed plasma concentration

Figure 5. Comparison of post hoc PK profiles with observed concentration in representative neonate

Figure 6

a) Histogram of normalized prediction distribution error. The blue curve is the normal distribution with corresponding mean (-0.169) and standard deviation (1.03). b) Normalized prediction distribution error versus time after dose. c) Normalized prediction distribution error versus population prediction. The three dash lines represent NPDE (CWRES) = -2, 0 and 2 separately