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

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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.

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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

C max :

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

K p :

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

t max :

Time to reach the maximal concentration

V ss :

Volume of distribution at steady state

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Authors and Affiliations

  1. Formulation Research & Development, F. Hoffmann - La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland

    Angela Villiger & Cordula Stillhart

  2. Pharmaceutical Research & Early Development, Pre-Clinical CMC, Roche Innovation Center Basel, F. Hoffmann - La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland

    Neil Parrott

  3. Institute of Pharmaceutical Technology, University of Applied Sciences and Arts Northwestern Switzerland, Gründenstrasse 40, 4132, Muttenz, Switzerland

    Angela Villiger & Martin Kuentz

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  1. Angela Villiger
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Villiger, A., Stillhart, C., Parrott, N. et al. Using Physiologically Based Pharmacokinetic (PBPK) Modelling to Gain Insights into the Effect of Physiological Factors on Oral Absorption in Paediatric Populations. AAPS J 18, 933–947 (2016). https://doi.org/10.1208/s12248-016-9896-z

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