Pharmacokinetic and pharmacodynamic considerations of general anesthesia in pediatric subjects

ABSTRACT

Introduction: The target concentration strategy uses PKPD information for dose determination. Models have also quantified exposure-response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development.

Areas covered: The prime PKPD consideration is parameter estimation and quantification of variability. The main sources of variability in children are age (maturation) and weight (size). Model use is mostly confined to pharmacokinetics, partly because anesthesia effect models in the young are imprecise. Exploration of PK and PD covariates and their variability hold potential to better individualize treatment.

Expert opinion: The ability to model drugs using computer-based technology is hindered because covariate data required to individualize treatment using these programs remain lacking. Target concentration intervention strategies remain incomplete because covariate information that might better predict individualization of dose is absent. Pharmacogenomics appear a valuable area for investigation for pharmacodynamics and pharmacodynamics. Effect measures in the very young are imprecise. Assessment of the analgesic component of anesthesia is crude. While neuromuscular monitoring is satisfactory, depth of anaesthesia EEG interpretation is inadequate. Closed loop anesthesia is possible with better understanding of EEG changes.

KEYWORDS:

• Anesthesia
• children
• disease progression
• modeling
• pharmacodynamics
• pharmacokinetics
• pharmacogenomics
• placebo

Article highlights

• The target concentration intervention strategy is the basis for drug dosing in anesthesia. Pharmacokinetics (PK) and pharmacodynamic (PD) models form a basis for this strategy. Inhalational drugs are commonly administered using this methodology. It is now common for infusion regimens to have programmed population PKPD information within pumps and these drive dose.

• Variability of PK and PD parameter estimates remains noteworthy. Characterization of this variability is required to personalize dose. Important sources of variability include age, size, pharmacogenomics, organ function, and drug interaction.

• Modeling limitations include poor quantification of unknown variability sources and inadequacy of current effect measures, particularly pain and sedation, in neonates and infants.

• PKPD modeling has quantified exposure–response relationships, improved understanding of developmental pharmacokinetics, rationalized dose prescription, provided insight into the importance of covariate information, explained drug interactions and driven decision-making and learning during drug development. However, unknown variability, inability to rapidly determine serum concentration and poor effect measures limit dose prediction in individuals.

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Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.