Quantitative clinical pharmacology practice for optimal use of antibiotics during the neonatal period

ABSTRACT

Introduction: For safe and effective neonatal antibiotic therapy, knowledge of the pharmacokinetic parameters of antibacterial agents in neonates is a prerequisite. Fast maturational changes during the neonatal period influence pharmacokinetic and pharmacodynamic parameters and their variability. Consequently, the need for applying quantitative clinical pharmacology and determining optimal drug dosing regimens in neonates has become increasingly recognized.

Areas covered: Modern quantitative approaches, such as pharmacometrics, are increasingly utilized to characterize, understand and predict the pharmacokinetics of a drug and its effect, and to quantify the variability in the neonatal population. Individual factors, called covariates in modeling, are integrated in such approaches to explain inter-individual pharmacokinetic variability. Pharmacometrics has been shown to be a relevant tool to evaluate, optimize and individualize drug dosing regimens.

Expert opinion: Challenges for optimal use of antibiotics in neonates can largely be overcome with quantitative clinical pharmacology practice. Clinicians should be aware that there is a next step to support the clinical decision-making based on clinical characteristics and therapeutic drug monitoring, through Bayesian-based modeling and simulation methods. Pharmacometric modeling and simulation approaches permit us to characterize population average, inter-subject and intra-subject variability of pharmacokinetic parameters such as clearance and volume of distribution, and to identify and quantify key factors that influence the pharmacokinetic behavior of antibiotics during the neonatal period.

KEYWORDS:

• Antibiotics
• clinical pharmacology
• modeling and simulation
• neonate
• pharmacometrics
• therapeutic drug monitoring

Article highlights

• Low plasma protein binding, changes in body compartments, and kidney function influence pharmacokinetic (PK) behavior of antibiotics in neonates.

• Quantitative PK approaches, including pharmacometric modeling and simulation, tailored to neonates are needed to further enhance understanding of PK behavior of antibiotics in neonates.

• Pharmacometric models can integrate the time course of dose–concentration relationships, identify sources of PK variability, and provide a scientific basis for optimizing dosing of antibiotic agents in neonates.

• In conjunction with quantitative pharmacology approaches and appropriate clinical interpretation, therapeutic drug monitoring (TDM) is a valuable tool in neonatal intensive care units.

• Advanced TDM practice leverages Bayesian modeling and simulation methods to ensure safe and effective antibiotic therapy in neonates based on four components: (i) measured drug concentrations, (ii) developed population PK models with quantified variability in key PK parameters, such as clearance and volume of distribution, (iii) identified time-dependent factors that influence key PK parameters during the first weeks of life, and (iv) characterized PD behavior and target levels of antibiotics in neonates.

This box summarizes key points contained in the article.

Declaration of Interest

J Samardzic is supported by ERAWEB II scholarship for postdoctoral program at the KU Leuven, Belgium (2014-2015) and Ministry of Education, Science and Technological Development of the Republic of Serbia (project No. 175076). K Allegaert is supported by the Fund for Scientific Research, Flanders (fundamental clinical investigatorship 1800214N) and the research activities are further facilitated by the agency for innovation by Science and Technology in Flanders (IWT) through the SAFEPEDRUG project (IWT8SBO 130033). JN van den Anker is supported by NIH (K24DA027992, R01HD048689, U54HF071601) and the European Commission (TINM [223614], TINN2 [260908], NEUROSIS [223060]). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.