Dose adjustment in orphan disease populations: the quest to fulfill the requirements of physiologically based pharmacokinetics

ABSTRACT

Introduction: While the media is engaged and fascinated by the idea of ‘Precision Medicine’, the nuances related to ‘Precision Dosing’ seem to be largely ignored. Assuming the ‘right drug’ is selected, clinicians still need to decide on the ‘right dose’ for individuals. Ideally, optimal dosing should be studied in clinical trials; however, many drugs on the market lack evidence-based dosing recommendations, and small groups of patients (orphan disease populations) are dependent on local guidance and clinician experience to determine drug dosage adjustments.

Areas Covered: This report explores the current understanding of dosing adjustment in special populations and examines the requirements for developing ‘in silico’ models for pediatric, elderly and pregnant patients. The report also highlights current use of modeling to provide evidence-based recommendations for drug labeling in the absence of complete clinical trials in orphan disease populations.

Expert Opinion: Physiologically based pharmacokinetics (PBPK) is an attractive prospect for determining the best drug dosage adjustments in special populations. However, it is not sufficient for individualized, or even stratified dosing, unless the systems (drug-independent) data required to build robust PBPK models are obtained. Such models are not a substitute for clinical trials, but they are an alternative to undocumented and inconsistent guesswork.

KEYWORDS:

• Childhood liver disease
• drug metabolizing enzymes
• drug transporters
• ontogeny
• pediatric
• Physiologically-Based Pharmacokinetics (PBPK)
• special populations

Article Highlights

• Many at-risk special patient populations are excluded from clinical trials and therefore drugs new to market often lack appropriate drug dosing recommendations.

• The lack of labeling information results in clinicians using personal experience and/or, at its best, local guidance if such guidance exists, resulting in an inconsistency of treatment in various settings that might be associated with increased risk of under-treatment or adverse drug reactions.

• Regulators have recently supported the use of modeling and simulation to inform labeling decisions and aid in the design of future clinical trials.

• Physiologically based pharmacokinetics (PBPK) is a mechanistic approach to help with integration of prior knowledge of drug-independent parameters within a population which can help to determine likely changes required in the dose.

• The childhood liver disease, as a case example, highlights the framework that is needed for building decision support tools to help with dosage adjustment in special populations and the typical gaps in knowledge that can be filled by extrapolation of data from other sources, such as in vitro studies, to feed into PBPK models.

• The fate of PBPK modeling as a useful tool for drug dosage adjustment in special populations is at the mercy of the quality and breadth of data that informs it and the successful implementation of recommendations from experts and regulatory bodies.

Acknowledgments

The support of the Children's Liver Disease Foundation (CLDF) is gratefully acknowledged.

Declaration of interest

A Rostami-Hodjegan is an employee of the University of Manchester for 50% of his working hours and Certara for 50% of his working hours. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Notes

1. The Human Genome Organisation (HUGO) Gene Nomenclature Committee website contains an up-to-date list of transporter nomenclature http://www.genenames.org.

Additional information

Funding

M Howard is a recipient of a Children's Liver Disease (CLDF) PhD Student Fellowship (NL 1758) through which this paper was funded.