Pharmacokinetic models of morphine and its metabolites in neonates:

Abstract

Morphine is commonly used for pain management in preterm neonates. The aims of this study were to compare published models of neonatal pharmacokinetics of morphine and its metabolites with a new dataset, and to combine the characteristics of the best predictive models to design a meta-model for morphine and its metabolites in preterm neonates. Moreover, the concentration-analgesia relationship for morphine in this clinical setting was also investigated. A population of 30 preterm neonates (gestational age: 23–32 weeks) received a loading dose of morphine (50–100 μg/kg), followed by a continuous infusion (5–10 μg/kg/h) until analgesia was no longer required. Pain was assessed using the Premature Infant Pain Profile. Five published population models were compared using numerical and graphical tests of goodness-of-fit and predictive performance. Population modelling was conducted using NONMEM® and the $PRIOR subroutine to describe the time-course of plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide, and the concentration-analgesia relationship for morphine. No published model adequately described morphine concentrations in this new dataset. Previously published population pharmacokinetic models of morphine, morphine-3-glucuronide, and morphine-6-glucuronide were combined into a meta-model. The meta-model provided an adequate description of the time-course of morphine and the concentrations of its metabolites in preterm neonates. Allometric weight scaling was applied to all clearance and volume terms. Maturation of morphine clearance was described as a function of postmenstrual age, while maturation of metabolite elimination was described as a function of postnatal age. A clear relationship between morphine concentrations and pain score was not established.

Prior information for population pharmacokinetic and pharmacokinetic/pharmacodynamic analysis: overview and guidance with a focus on the NONMEM PRIOR subroutine

“…In four studies, the use of priors allowed a better fit of the new data than fixing the parameters [7,9,30,31]. In another study, fixing some parameters led to unrealistic estimates of other parameters, while the use of informative and non-informative (vague) priors on all parameters allowed a correct estimation [12].…”

“…Combined model If needed, the reference model can combine models from two (or more) studies having different focus and providing complementary information. Knosgaard et al analyzed both parent drug and metabolite: they combined the parent drug model and the metabolite model that performed the best in the systematic model comparison stage for each molecule [9]. Brill et al built a model to quantify the interaction effect of antiretrovirals on tuberculosis treatment in patients with both HIV and tuberculosis [7].…”

“…Covariates of the reference model can be included a priori in the model built with prior, especially if there is a strong belief that they are the same in the previous and the new population. For example, besides allometric scaling, scaling factors for preterm neonates are supposed to remain the same: one can prefer to fix the scaling factor values to their previous estimates, and to estimate the standardized parameter with or without prior [9]. However, the risk of over-parameterizing the model by introducing covariates based on assumptions should be taken into account.…”

“…After implementation a priori, the impact of covariates can be assessed in terms of effect on the parameter, for example graphically plotting parameter versus covariate [7,9,12]. The physiological plausibility has to be taken into account.…”

“…Two articles used MCMC Bayesian analysis with $PRIOR NWPRI statement, which allowed the specification of prior parameters distributions [ 6 , 26 ]. The PRIOR subroutine was mostly used for empirical popPK models in special populations, for example to analyze sparse data from children [ 9 , 10 , 12 , 13 , 18 , 20 , 25 – 27 ] or pregnant women [ 19 , 20 , 28 ]. In one pediatric model, the PRIOR subroutine was used to stabilize the parameters of the maturation function ( i.e.…”