Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Abstract

The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children

“…21 However, depth of anesthesia monitoring is of little value in neonates and infants where the target concentration is seldom known and EEG monitoring is inadequate. 23 Quantitative EEG is the most commonly used biomarker for anesthetic drug activity in both preclinical and clinical PKPD modeling. 4,[24][25][26][27] voltage fluctuations within neurons in the brain and can be analyzed using different indices such as Bispectral index (BIS) and entropy, depending on the algorithm used.…”

“…Common indices include spectral edge frequency (SEF), density spectral array, burst suppression ratio, Patient State Index and Narcotrend Index 21 . However, depth of anesthesia monitoring is of little value in neonates and infants where the target concentration is seldom known and EEG monitoring is inadequate 23 …”

“… 21 However, depth of anesthesia monitoring is of little value in neonates and infants where the target concentration is seldom known and EEG monitoring is inadequate. 23 …”

Pharmacokinetic/Pharmacodynamic anesthesia model incorporating psi-Caputo fractional derivatives

“…Pharmacokinetic/Pharmacodynamic (PK/PD) modeling is a mathematical approach used in pharmacology to study the relationship between drug concentrations (Pharmacokinetics) and their effects on the body (Pharmacodynamics) [31,37]. The PK/PD models help researchers and clinicians to understand how drugs are absorbed, distributed, metabolized, and eliminated from the body [7].…”

“…The field of Pharmacokinetics and Pharmacodynamics plays a crucial role in understanding the behavior of drugs in biological systems [37]. Traditional PK/PD models have predominantly relied on integer-order derivatives to describe various processes involved in drug absorption, distribution, metabolism, and elimination [13,31,43]. However, these models often fall short in accurately capturing the complexity of Pharmacokinetic behaviors [8,19].…”