Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Abstract

The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

Keywords: NONMEM; metabolism; morphine; pediatric; pharmacokinetics.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1

Schematic representation of the pharmacokinetic model for morphine and its metabolites. CL and CLD denote morphine total and inter-compartmental clearances, respectively; VC and VP denote morphine central and peripheral distribution volumes, respectively; Cint denotes morphine–metabolite intermediate concentrations; Kint is the rate constant for intermediate compartment; M denotes metabolite (M3G or M6G) concentrations; Mmax is the maximum metabolite concentration; and Cint,50 is intermediate concentration producing half-maximal metabolite concentration

Fig. 2

Morphine, M3G, and M6G plasma logarithmic concentration–time profiles obtained in 20 post-cardiac surgery pediatric patients. Lines connect observations obtained in the same individual

Fig. 3

Effect of glomerular filtration rate on individual (post hoc) predicted PK parameters of M3G and M6G. Linear regression lines are shown

Fig. 4

Goodness-of-fit plots for the final population pharmacokinetic model of morphine and its metabolites showing observed versus population (left column) and individual predicted concentrations (right column) for morphine (a and b), M3G (c and d), and M6G (e and f). Concentrations are shown on logarithmic scales

Fig. 5

Plot of M3G (left column) and M6G (right column) observed plasma concentrations against predicted concentrations at the intermediate compartment in four representative subjects showing Emax relationship. The solid lines are metabolite individual predictions

Fig. 6

The final population pharmacokinetic model normalized prediction distribution error (NPDE) results for morphine (upper row), M3G (middle row), and M6G (lower row). The histograms show the NPDE distribution, and the solid lines represent the normal distribution. The mean and variance of the NPDE are shown below each histogram. Asterisk indicates significant difference of the mean from 0 and the variance from 1 at the p < 0.05 level, using Student’s t test for mean and Fisher test for variance. The scatter plots show the distribution of NPDE versus time since last dose and population predicted concentrations (on logarithmic scale). The dotted lines represent the NPDE 5th and 95th percentiles. Zero line (dashed) and LOWESS smoother (solid) are shown

Fig. 7

Box plot of the simulation results following the administration of 0.1 mg/kg morphine every 3 h showing morphine AUC0–24 h in 1-month-, 6-month-, and 2-year-old children, M3G, and M6G AUC0–24 h in patients, with glomerular filtration rates of 20, 50, 70, and 100 mL/min/1.73 m2, respectively