Current and future physiologically based pharmacokinetic (PBPK) modeling approaches to optimize pharmacotherapy in preterm neonates

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 (pharmacokinetic-dynamic 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.

KEYWORDS:

• Preterm
• physiologically based pharmacology
• precision medicine
• computer simulation
• pharmacotherapy

Article highlights

• PBPK modeling is an established tool for drug development with a track record, including regulatory acceptance. This is because PBPK methodology is instrumental on data integration, hypothesis testing (‘what if’), or knowledge generation.

• Its use to inform pharmacotherapy in preterm neonates is still limited. Knowledge gaps exist, giving rise to various levels of uncertainty.

• Using a systematic search strategy, we retained 25 records (20 papers, 2 letters, 3 abstracts) on PBPK modeling in preterm neonates. Based on this search, we collated the published information on PBPK software packages (PK-Sim®, Simcyp®) in preterm neonates.

• Applications cover a broad range of scenarios (pharmacokinetic/dynamics, drug–drug interactions, developmental pharmacogenetics, or lactation related exposure). Furthermore, different types of compounds (small molecules, monoclonals, and proteins), specific compartments (cerebrospinal fluid compartment and tissue), or (patho)physiologic (cardiac output, biliary excretion ontogeny, and first-pass metabolism) processes are explored.

• A limitation in the PBPK software development reports is the lack of longitudinal system parameters or data on physiological processes and - related to this - the high variability in cross-sectional studies in preterm neonates. Furthermore, good-quality PK studies are needed for PBPK model improvement.

• Once physiological processes are captured and uncertainty is improved, integration of pathophysiology processes can be considered, while criteria for evaluating model performance can be fine-tuned.

Acknowledgments

The authors wish to thank Medical Library for developing and updating the search strategies.

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.

Supplementary material

Supplemental data for this article can be accessed here

Additional information

Funding

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).