Drug metabolism in early infancy: opioids as an illustration

Abstract

Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed. Pre- and post-model selection criteria were applied to assess and evaluate the validity of these models. It was observed that maturational changes have been rather well investigated, be it with variability in the maturational function estimates. The same holds true for Pop-PK models, where non-maturational covariates have also been reported (pharmacogenetics, disease state or external influences), although less incorporated in the PK models and with limited knowledge on mechanisms involved. Expert opinion: PK models for fentanyl and morphine are currently available. Consequently, we suggest that researchers should not continue to develop new models, but should investigate whether collected data fit in already existing models and provide additional value concerning the impact of (non)-maturational factors like drug-drug interactions or pharmacogenetics.

Recently Registered Midazolam Doses for Preterm Neonates Do Not Lead to Equal Exposure: A Population Pharmacokinetic Model

“…7 CYP3A activity is known to be very low directly after birth and to increase rapidly during the first weeks of life, reaching values comparable to those in adults around the age of 1 year. 8,9 In accordance with this, the lowest clearance values have been reported in preterm neonates, 10,11 and these increase with age. [12][13][14][15] In addition to the influence of maturational status, severity of disease and inflammation may affect midazolam elimination in critically ill neonates and children.…”

“…Concerning the pharmacokinetics of midazolam, an influence of maturation in preterm neonates is likely, as midazolam is mainly metabolized by CYP3A . CYP3A activity is known to be very low directly after birth and to increase rapidly during the first weeks of life, reaching values comparable to those in adults around the age of 1 year . In accordance with this, the lowest clearance values have been reported in preterm neonates, and these increase with age .…”

Paracetamol in Older People: Towards Evidence-Based Dosing?

“…In this way, we should use these already available datasets and published Pop pharmacokinetics models to put new datasets into these perspectives. This is a very effective approach to explore additional covariates or specific subpopulations, but should be preceded by a critical assessment of the published models [ 39 , 58 ].…”

Key Components for Antibiotic Dose Optimization of Sepsis in Neonates and Infants

“…An example of these software tools is the model-supported TDM tool for precision dosing TDMx ( http://www.tdmx.eu/ ). Since there are several population PK models published for antimicrobial agents, researchers should assess new data or use existing data to extend and improve existing population PK models ( 56 , 58 ). Pharmacometric PK/PD models can help identify the optimal (effective and safe) therapeutic window necessary to successfully treat an infection ( 59 ).…”