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Journal of Pharmacokinetics and Pharmacodynamics

, Volume 45, Issue 6, pp 765–785 | Cite as

The use of PBPK modeling across the pediatric age range using propofol as a case

  • Robin Michelet
  • Jan Van Bocxlaer
  • Karel Allegaert
  • An Vermeulen
Original Paper
  • 298 Downloads

Abstract

The project SAFEPEDRUG aims to provide guidelines for drug research in children, based on bottom-up and top-down approaches. Propofol, one of the studied model compounds, was selected because it is extensively metabolized in liver and kidney, with an important role for the glucuronidation pathway. Besides, being a lipophilic molecule, it is distributed into fat tissues, from where it redistributes into the systemic circulation. In the past, both bottom-up (Physiologically based pharmacokinetic, PBPK) and top-down approaches (population pharmacokinetic, popPK) were applied to describe its pharmacokinetics (PK). In this work, a combination of the two was used to check their performance to describe PK in children and neonates (both term and preterm) using propofol as a case compound. First, in vitro data was generated in human liver microsomes and recombinant enzymes and used to develop an adult PBPK model in Simcyp®. Activity adjustment factors (AAFs) were calculated to account for differences between in vitro and in vivo enzyme activity. Clinical data were analyzed using a 3-compartment model in NONMEM. These data were used to construct a retrograde PBPK model and for qualification of the PBPK models. Once an accurate in vivo clearance was obtained accounting for the contribution of the different metabolic pathways, the resulting PBPK models were challenged with new data for qualification. After that, the constructed adult PPBK model for propofol was extrapolated to the pediatric population. Both the default built-in and in vivo derived ontogeny functions were used to do so. The models were qualified by comparing their predicted PK parameters to published values, and by comparison of predicted concentration–time profiles to available clinical data. Clearance values were predicted well, especially when compared with values obtained from trials where long-term sampling was applied, whereas volume of distribution was lower compared to the most common popPK model predictions. Concentration–time profiles were predicted well up until and including the preterm neonatal population. In this work, it was thus shown that PBPK can be used to predict the PK up to and including the preterm neonatal population without the use of pediatric in vivo data. This work adds weight to the need for further development of PBPK models, especially regarding distribution modeling and the use of in vivo derived ontogeny functions.

Keywords

PBPK Propofol Pediatrics In vivo ontogeny Activity adjustment factor Retrograde modeling IVIVE Neonates 

Abbreviations

4HP

4-Hydroxy propofol

AAF

Activity adjustment factor

CLint

Intrinsic clearance

CLint,u

Unbound intrinsic clearance

CYP

Cytochrome P450

HLM

Human liver microsomes

HKM

Human kidney microsomes

IVIVE

In vitro in vivo extrapolation

MPPGK

Microsomal protein per gram kidney

MPPGL

Microsomal protein per gram liver

PBPK

Physiologically based pharmacokinetics

PG

Propofol glucuronide

PopPK

Population pharmacokinetics

rhCYP

Recombinant human CYP

rhUGT

Recombinant human UGT

UGT

Uridine 5′-diphospho-glucuronosyltransferase

SPE

Solid phase extraction

Notes

Acknowledgements

Funding was provided by Agentschap voor Innovatie door Wetenschap en Technologie (Grant No. IWT/SBO 130033).

Supplementary material

10928_2018_9607_MOESM1_ESM.docx (230 kb)
Supplementary material 1 (DOCX 229 kb)

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Laboratory of Medical Biochemistry and Clinical Analysis, Department of Bioanalysis, Faculty of Pharmaceutical SciencesGhent UniversityGhentBelgium
  2. 2.Department of Development & RegenerationKU LeuvenLeuvenBelgium
  3. 3.Division of Neonatology, Department of PediatricsErasmus MC-Sophia Children’s HospitalRotterdamThe Netherlands

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