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

Martyn Howard, Jill Barber, Naved Alizai, Amin Rostami-Hodjegan

Research output: Contribution to journalReview articlepeer-review


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.

Original languageEnglish
Pages (from-to)1315-1330
Number of pages16
JournalExpert Opinion on Drug Metabolism & Toxicology
Issue number12
Early online date22 Nov 2018
Publication statusPublished - 1 Dec 2018


  • Aged
  • Child
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Labeling
  • Female
  • Humans
  • Models, Biological
  • Pharmaceutical Preparations/administration & dosage
  • Precision Medicine/methods
  • Pregnancy
  • Rare Diseases/drug therapy


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