Elsevier

Advanced Drug Delivery Reviews

Volume 73, 30 June 2014, Pages 102-126
Advanced Drug Delivery Reviews

Paediatric oral biopharmaceutics: Key considerations and current challenges☆

https://doi.org/10.1016/j.addr.2013.10.006Get rights and content

Abstract

The complex process of oral drug absorption is influenced by a host of drug and formulation properties as well as their interaction with the gastrointestinal environment in terms of drug solubility, dissolution, permeability and pre-systemic metabolism. For adult dosage forms the use of biopharmaceutical tools to aid in the design and development of medicinal products is well documented. This review considers current literature evidence to guide development of bespoke paediatric biopharmaceutics tools and reviews current understanding surrounding extrapolation of adult methodology into a paediatric population. Clinical testing and the use of in silico models were also reviewed. The results demonstrate that further work is required to adequately characterise the paediatric gastrointestinal tract to ensure that biopharmaceutics tools are appropriate to predict performance within this population. The most vulnerable group was found to be neonates and infants up to 6 months where differences from adults were greatest.

Section snippets

General introduction

Biopharmaceutical science is used widely within drug development to predict in vivo performance of a medicine. The use of biopharmaceutical science within paediatric formulation development is limited and has previously been highlighted as an area where additional research is required [1], [2].

Prediction of in vivo performance of medicines requires knowledge regarding the physiology and anatomy of the site of drug absorption. Although many differences will be highlighted within this review the

Paediatric biopharmaceutics — Current regulatory guidance status

There has been global emphasis on improving paediatric accessibility to medicines which has increased the number of drugs tested in and labelled for use in children. For example, the United States (US) Food and Drug Administration's (FDA) paediatric labelling database has 467 reports on paediatric clinical studies listed in response to paediatric legislative changes [6]. There are existing reviews detailing overarching paediatric medicines regulations in the USA and Europe (e.g. [7], [8]).

Solubility

Intestinal absorption of drugs following oral administration is a function of drug dissolution and subsequent permeation and/or transport of the dissolved compound through the mucosa at the absorptive sites in the gastrointestinal (GI) tract. Since only dissolved drugs can be absorbed to a relevant extent, the solubility of the compound in the intraluminal fluids/contents is an essential prerequisite for its oral bioavailability.

In general, the solubility of a drug depends on the physical and

Permeability

Intestinal absorption of macronutrients (carbohydrates, fat and proteins) as well as ions and trace elements is essential for the growth of children. Maturation of the gastrointestinal tract is reported to occur within the first 6 months; therefore drugs absorbed by transport processes used for nutrients that are essential for growth may show different absorption profiles during the first 6 months of life. Permeability of drugs within in paediatric populations is an under-researched area; this

Dissolution testing and in vitro in vivo correlation (IVIVC)

Drug dissolution in the physiological environment of the GI tract is often a rate limiting step in the oral drug absorption process. Only dissolved drug can permeate the mucosa at the absorptive sites in the GI tract [83]. Hence, both solubility of the drug and its dissolution rate are crucial for the in vivo behaviour. To some extent these properties are determined by the physicochemical characteristics of the drug itself and in addition, they can be strongly affected by the physiological

Metabolism

First pass metabolic inactivation of drugs can affect the bioavailability of orally administered medicines; the intestine and liver are the most significant sites involved in first pass drug metabolism. There are many drugs whose oral bioavailability is reduced to half the administered dose as a result of first pass metabolism in the intestine and liver [120].

It is generally stated that the activity of drug metabolising enzymes is low at birth and reaches adult values by early childhood.

Paediatric clinical testing

In paediatric drug development several factors need to be considered to justify the decision to proceed with a paediatric clinical programme for a medicinal product. These include: the presence of a serious or life-threatening disease for which the medicinal product represents a potentially important advance in therapy; the novelty of the medicinal product; the existence of unique paediatric indication and the need for paediatric formulation.

In drug development, bioavailability clinical studies

In silico modelling of clinical data

Regulatory requirements make the application of model-based approaches an essential step in paediatric drug development and can be used as decision tools, as study optimisation tools and as data analysis tools [205]. Modelling and simulation techniques can be used to optimize trial designs, to characterize and predict pharmacokinetic–pharmacodynamic (PK–PD), to select dose level and dosing regimens, to develop sampling schemes, and to select outcome measures. These applications are usually

Paediatric formulations

Lack of age-appropriate medicines for children is a global problem, which significantly affects developing countries. Furthermore, off-label use of drugs (prescribing outside the terms indicated in the product licence) in the paediatric population ranges from 60 to 90% with the highest percentage being in infants (< 1 year of age), indicating that drug treatment in children is still driven by empiricism [205], [217].

In response to these challenges, the WHO launched its ‘Make Medicines Child Size’

Conclusions

Paediatric biopharmaceutics is crucial in optimisation of the design and development of age-appropriate oral medicines.

Successful biopharmaceutic tools for paediatric populations require reliable clinical experimental data coupled with mechanistic understanding of all ADME processes. With specific research required on: ontogeny of various biological components; maturation of biliary excretion of drugs; metabolic capacity of gastrointestinal tract; carrier mechanisms; drug transporters in the

References (270)

  • T.G.H.A. Tucker et al.

    Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 2 in human liver and duodenum

    Biochem. Pharmacol.

    (2012)
  • P. Annaert et al.

    Ex vivo permeability experiments in excised rat intestinal tissue and in vitro solubility measurements in aspirated human intestinal fluids support age-dependent oral drug absorption

    Eur. J. Pharm. Sci.

    (2010)
  • J.D. Irvine et al.

    MDCK (Madin-Darby canine kidney) cells: a tool for membrane permeability screening

    J. Pharm. Sci.

    (1999)
  • J. McIntyre et al.

    Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial

    Lancet

    (2005)
  • D. Horter et al.

    Influence of physicochemical properties on dissolution of drugs in the gastrointestinal tract

    Adv. Drug Deliv. Rev.

    (1997)
  • Y. Shono et al.

    Prediction of food effects on the absorption of celecoxib based on biorelevant dissolution testing coupled with physiologically based pharmacokinetic modeling

    Eur. J. Pharm. Biopharm.

    (2009)
  • Y. Shono et al.

    Forecasting in vivo oral absorption and food effect of micronized and nanosized aprepitant formulations in humans

    Eur. J. Pharm. Biopharm.

    (2010)
  • N. Fotaki et al.

    A comparative study of different release apparatus in generating in vitro–in vivo correlations for extended release formulations

    Eur. J. Pharm. Biopharm.

    (2009)
  • E. Jantratid et al.

    Application of biorelevant dissolution tests to the prediction of in vivo performance of diclofenac sodium from an oral modified-release pellet dosage form

    Eur. J. Pharm. Sci.

    (2009)
  • Y. Shono et al.

    Precipitation in the small intestine may play a more important role in the in vivo performance of poorly soluble weak bases in the fasted state: case example nelfinavir

    Eur. J. Pharm. Biopharm.

    (2011)
  • T. Taupitz et al.

    Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: itraconazole

    Eur. J. Pharm. Biopharm.

    (2013)
  • G. Garbacz et al.

    Irregular absorption profiles observed from diclofenac extended release tablets can be predicted using a dissolution test apparatus that mimics in vivo physical stresses

    Eur. J. Pharm. Biopharm.

    (2008)
  • H. Batchelor et al.

    Application of in-vitro biopharmaceutic methods in development of immediate release oral dosage forms intended for paediatric patients

    Eur. J. Pharm. Biopharm.

    (2013)
  • J.L. Kaye

    Review of paediatric gastrointestinal physiology data relevant to oral drug delivery

    Int. J. Clin. Pharm.

    (2011)
  • M.G. Mooij et al.

    Ontogeny of oral drug absorption processes in children

    Expert Opin. Drug Metabol. Toxicol.

    (2012)
  • FDA. New Pediatric Labeling Information Database. [cited 2013 1/5/2013]; Available from:...
  • J. Zisowsky et al.

    Drug development for pediatric populations: regulatory aspects

    Pharmaceutics

    (2010)
  • R. Steinbrook

    Testing medications in children

    N. Engl. J. Med.

    (2002)
  • FDA

    Draft Guidance for Industry and Review Staff: Pediatric Information Incorporated Into Human Prescription Drug and Biological Products Labeling

  • FDA

    Guidance for Industry. Exposure–response relationships — study design, data analysis and regulatory applications

  • EMA

    ICH Topic E11

    Clinical Investigation of Medicinal Products in the Paediatric Population, CPMP/ICH/2711/99

    (2001)
  • EMA

    Concept paper on extrapolation of efficacy and safety in medicine development

  • G.L. Kearns

    Pharmacogenetics and development: are infants and children at increased risk for adverse outcomes?

    Curr. Opin. Pediatr.

    (1995)
  • C.F. Weiss et al.

    Chloramphenicol in the newborn infant

    N. Engl. J. Med.

    (1960)
  • FDA

    Guidance for Industry. Dissolution Testing of Immediate Release Solid Oral Dosage Forms

  • FDA

    Guidance for Industry. Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations

  • FDA

    Guidance for Industry: Waiver of in vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System

  • FDA

    Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies

  • FDA

    Guidance for Industry. Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations

  • EMA

    Guideline on the Investigation of Bioequivalence

  • EMA

    Guideline on the Role of Pharmacokinetics in the Development of Medicinal Products in the Paediatric Population, Corrigendum

    EMEA/CHMP/EWP/147013/2004

    (2006)
  • EMA

    Guideline on Pharmaceutical Development of Medicines for Paediatric Use, Rev.1

  • EMA

    Guideline on the investigation of medicinal products in the term and preterm neonate EMEA/536810/2008

    Committee for Medicinal Products for Human Use (CHMP) and Paedaitric Committee (PDCO)

    (2009)
  • EMA

    Guideline on the Investigation of Drug Interactions

    CPMP/EWP/560/95/Rev. 1

    (2012)
  • P.J. Sinko

    Solubility and distribution phenomena

  • S.S. Ozturk et al.

    Dissolution of ionizable drugs in buffered and unbuffered solutions

    Pharm. Res.

    (1988)
  • PhEur

    European Pharmacopoeia

    (2011)
  • USP, USP 35/NF 30, USP 35 ed., United States Pharmacopoeia Convention, Inc., Rockville MD,...
  • G.L. Amidon et al.

    A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability

    Pharm. Res.

    (1995)
  • EMA

    Note for Guidance on the Investigation of Bioavailability and Bioequivalence

    • Cited by (0)

    ☆

    This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug delivery and the paediatric population: where are we at?”.

    1

    Tel.: + 44 1225 386728.

    2

    Tel.: + 49 3834 86 4897.

    View full text
    Crown copyright © 2013 Published by Elsevier B.V. All rights reserved.