The AAPS Journal

, Volume 18, Issue 4, pp 933–947 | Cite as

Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations

  • Angela Villiger
  • Cordula Stillhart
  • Neil Parrott
  • Martin Kuentz
Research Article

Abstract

Paediatric pharmaceutics has become an important topic, but currently, there is an incomplete knowledge of paediatric gastrointestinal physiology and adequate biopharmaceutical tools still have to be developed. The present study aimed to increase the understanding of oral drug absorption in paediatric populations by using physiologically based pharmacokinetic (PBPK) modelling and in vitro dissolution testing. The oral absorption of two model compounds, sotalol and paracetamol, was studied by collection of reported pharmacokinetic profiles from adult and paediatric subjects. A PBPK model based on input parameters collected from the literature was first developed and validated in adults before being extrapolated to paediatric age groups. The accuracy of the model simulations was assessed by comparison to the observed pharmacokinetic profiles, and in the case of discrepancy, further investigations were made via parameter sensitivity analysis and in vitro dissolution testing. The PBPK models accurately predicted sotalol and paracetamol exposure in adult populations. An accurate simulation was also obtained after model extrapolation to children older than 2 years of age. However, the simulation in infants and newborns resulted in a discrepancy, which was further analysed. Dissolution testing suggested no significant difference in the drug release rate between paediatric and adult age groups. In contrast, mean gastric emptying time seemed to be underestimated in infants and newborns, and optimisation of this input parameter improved the prediction of the model. Considering age-specific differences in gastrointestinal tract physiology should improve prediction of drug absorption in paediatric patients.

KEY WORDS

in vitro dissolution mean gastric transit time oral drug absorption paediatric gastrointestinal physiology paediatric PBPK modelling 

Abbreviations

API

Active pharmaceutical ingredient

AUC

Area under the curve

B/P

Blood to plasma concentration ratio

BSA

Body surface area

LCDC

Centers for Disease Control and Prevention

Cmax

Maximal concentration of the plasma concentration-time curve

CL

Clearance

FaSSIF

Fasted state simulated intestinal fluid

FeSSIF

Fed state simulated intestinal fluid

fu

Fraction unbound

EMA

European Medicines Agency

MGTT

Mean gastric transit time

GI

Gastrointestinal

HCl

Hydrochloric acid

HPLC

High-performance liquid chromatography

ICH

International Conference on Harmonisation

IV

Intravenous

KH2PO4

Potassium dihydrogen phosphate

Kp

Partition coefficient

MW

Molecular weight

NaCl

Sodium chloride

NaH2PO4·H2O

Sodium dihydrogen phosphate monohydrate

NaOH

Sodium hydroxide

PBPK

Physiologically based pharmacokinetic

PD

Pharmacodynamics

pKa

Acid dissociation constant

PK

Pharmacokinetic

PO

Peroral

PSA

Parameter sensitivity analysis

ratio(Obs/Pred)

Observed to predicted ratio

SD

Standard deviation

SGFsp

Simulated gastric fluid without pepsin

SI

Small intestine

SITT

Small intestinal transit time

TFA

Trifluoroacetic acid

tmax

Time to reach the maximal concentration

Vss

Volume of distribution at steady state

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Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Angela Villiger
    • 1
    • 3
  • Cordula Stillhart
    • 1
  • Neil Parrott
    • 2
  • Martin Kuentz
    • 3
  1. 1.Formulation Research & DevelopmentF. Hoffmann - La Roche Ltd.BaselSwitzerland
  2. 2.Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center BaselF. Hoffmann - La Roche Ltd.BaselSwitzerland
  3. 3.Institute of Pharmaceutical TechnologyUniversity of Applied Sciences and Arts Northwestern SwitzerlandMuttenzSwitzerland

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