Abstract
Introduction: There is a need for structured approaches to inform on pharmacotherapy in preterm
neonates. With their proven track record up to regulatory acceptance, physiologically based pharmacokinetic (PBPK) modeling and simulation provide a structured approach, and hold the promise to
support drug development in preterm neonates.
Areas covered: Compared to general and pediatric use of PBPK modeling, its use to inform pharmacotherapy in preterms is limited. Using a systematic search (PBPK + preterm), we retained 25 records (20
research papers, 2 letters, 3 abstracts). We subsequently collated the published information on PBPK
software packages (PK-Sim®, Simcyp®), and their applications and optimization efforts in preterm
neonates. It is encouraging that applications cover a broad range of scenarios (pharmacokineticdynamic analyses, drug-drug interactions, developmental pharmacogenetics, lactation related exposure) and compounds (small molecules, proteins). Furthermore, specific compartments (cerebrospinal
fluid, tissue) or (patho)physiologic processes (cardiac output, biliary excretion, first pass metabolism) are
considered.
Expert opinion: Knowledge gaps exist, giving rise to various levels of uncertainty in PBPK applications
in preterm neonates. To improve this, we need cross talk between clinicians and modelers to generate
and integrate knowledge (PK datasets, system knowledge, maturational physiology and pathophysiology) to further refine PBPK models.
neonates. With their proven track record up to regulatory acceptance, physiologically based pharmacokinetic (PBPK) modeling and simulation provide a structured approach, and hold the promise to
support drug development in preterm neonates.
Areas covered: Compared to general and pediatric use of PBPK modeling, its use to inform pharmacotherapy in preterms is limited. Using a systematic search (PBPK + preterm), we retained 25 records (20
research papers, 2 letters, 3 abstracts). We subsequently collated the published information on PBPK
software packages (PK-Sim®, Simcyp®), and their applications and optimization efforts in preterm
neonates. It is encouraging that applications cover a broad range of scenarios (pharmacokineticdynamic analyses, drug-drug interactions, developmental pharmacogenetics, lactation related exposure) and compounds (small molecules, proteins). Furthermore, specific compartments (cerebrospinal
fluid, tissue) or (patho)physiologic processes (cardiac output, biliary excretion, first pass metabolism) are
considered.
Expert opinion: Knowledge gaps exist, giving rise to various levels of uncertainty in PBPK applications
in preterm neonates. To improve this, we need cross talk between clinicians and modelers to generate
and integrate knowledge (PK datasets, system knowledge, maturational physiology and pathophysiology) to further refine PBPK models.
| Original language | English |
|---|---|
| Pages (from-to) | 301-312 |
| Number of pages | 12 |
| Journal | Expert Opinion on Drug Metabolism & Toxicology |
| Volume | 18 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 15 Jul 2022 |
Bibliographical note
Funding Information:The activities related to the research line on the clinical pharmacology and PBPK model development during whole body hypothermia are supported by FWO Flanders (iPREDICT project: G0D0520N). The authors wish to thank Medical Library for developing and updating the search strategies.
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