Unit:
Department of PharmacyLibrary of the School of Science
Dissertation committee:
Maria Vertzoni, Assistant Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece | Member of the Advisory committee, Academic Supervisor
Christos Reppas, Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece | Member of the Advisory committee
Mira Symillides, Associate Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece | Member of the Advisory committee
Sophia Antimisiaris, Professor, Department of Pharmacy, University of Patras, Greece
Aristeidis Dokoumetzidis, Assistant Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Vangelis Karalis, Assistant Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Georgia Valsami, Professor, Department of Pharmacy, National and Kapodistrian University of Athens, Greece
Original Title:
Developing new in vivo and in silico methodologies to predict performance of paediatric formulations
Translated title:
Developing new in vivo and in silico methodologies to predict performance of paediatric formulations
Summary:
Background
Extending licensed drug use to paediatric population has become an essential part of the drug development process. Ethical concerns limit clinical testing in paediatric populations and data collected from oral bioavailability and food effect studies in adults are often extrapolated to the paediatric (sub)populations. Preclinical animal models could offer an alternative approach for paediatric products evaluation. Recently, a draft guidance by regulatory authorities suggested the consideration of age-appropriate meal types and quantities for the target paediatric populations, e.g., infant formula for age groups receiving mainly milk-based feeds, without specifying exact feeding volumes and dosing conditions.
Aims
To design an exploratory clinical study to understand whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. To describe and evaluate a PBPK modeling approach for extrapolation of drug exposure from adults to infants and children with a view to the different dosing conditions that can be used to inform the modeling process.
To explore the usefulness of the Beagle model in the evaluation of drug exposure after oral administration to paediatric populations and compare the usefulness of the Beagle data in evaluating drug exposure in paediatrics with the usefulness of human adult data.
Methods
An exploratory single-dose bioavailability study was performed in eight healthy adult male volunteers following a randomized, three-phase, crossover design. After confirming lack of pharmaceutical and pharmacokinetic interactions, a paracetamol suspension and an ibuprofen suspension were co-administered to healthy adults on three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, reference-meal fed conditions) and under conditions simulating the fed state in infants (infant-formula fed conditions). Similar oral dosing conditions were applied to an exploratory single-dose bioavailability study in six Beagle dogs following a blocked, crossover design.
Physiologically based pharmacokinetic (PBPK) approaches for modeling paracetamol and ibuprofen suspension data collected in adults and in Beagles were developed in order to investigate whether extrapolation to infants and children is affected by the dosing conditions applied in each study. Extrapolation of these dosing conditions was performed by using the mechanical understanding gained from the collected data and after scaling to infants and children considering physiological, anatomical, and drug clearance changes. The development of the PBPK models was performed using GastroPlus™ V9.7.
The usefulness of the developed models in adults and in Beagles to predict drug exposure in infants and in children was evaluated using literature clinical data sets in infants and in children following oral administration of paracetamol and ibuprofen.
Results
In adults, under infant-formula fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen, unlike under reference-meal fed conditions. Also, for ibuprofen, Cmax values under infant-formula fed conditions were significantly higher than under reference-meal fed conditions. For paracetamol, successful simulations of previously observed plasma concentration levels in infants were achieved when extrapolating from fasted and infant formula–fed conditions data in healthy adults, whereas data collected following the reference meal appeared less useful for simulating paracetamol suspension performance in infants. For ibuprofen, successful predictions were achieved when employing the adult-based model for fasted conditions or by applying appropriate fed conditions for different age groups, i.e., infant formula for infants and reference meal for children.
For paracetamol, fasted dosing conditions and reference-meal fed conditions in Beagle dogs appeared useful to inform modeling for infant formulations. Extrapolation of paracetamol performance during infant formula administration in Beagles appeared less successful to predict plasma levels in infants. Fasted conditions in Beagles appeared useful for predicting ibuprofen performance in a mixed paediatric population while reference-meal fed conditions appeared to lead to adequate predictions for the children dataset.
Despite the differences observed between the Beagle-based model and human adult-based model predictions, the Beagle-based model appears suitable for investigating paediatric products at early development stages, when applying fasted and/or reference-meal fed conditions.
Concluding remarks
Clinical data from this study suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied in adults. Preclinical data coupled with PBPK modeling could be a useful tool for paediatric product evaluation at the early stage pharmaceutical development. Better understanding of luminal conditions’ changes in paediatrics and age-dependent post-absorptive processes could improve modeling confidence. The two proposed methodologies to predict performance of paediatric formulations deserve further evaluation using high-quality preclinical data and clinical data both in adults and in infants.
Main subject category:
Science
Keywords:
clinical study, canine study, oral drug absorption, paediatrics, food effect, PBPK modeling
Number of references:
236
