Multigenic control of drug response and regulatory decision-making in pharmacogenomics

The need for an upper-bound estimate of genetic contributions

Vural Ozdemir, W. Kalow, L. Tóthfalusi, L. Bertilsson, L. Endrenyi, J. E. Graham

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Nature or nurture? To what extent genetics play a role in drug efficacy and safety? These questions are not new. They are however gaining increasing prominence with the implementation of pharmacogenomics in various facets of medicine ranging from therapeutics, drug development and regulatory science to research funding decisions. For predisposition to common complex diseases, twin and family studies have been the mainstay for estimating genetic components of the attendant risk. On the other hand, the rapid pace of drug development in the pharmaceutical industry and the need for faster regulatory decisions call for an approach of higher throughput to identify the compounds for which heritability is likely to play a significant role in their pharmacokinetics and/or pharmacodynamics. A second predicament related to multifactorial nature of drug effects is that one typically observes a considerable overlap in the distribution of drug response phenotypes among subpopulations identified by each pharmacogenomic biomarker. This is in sharp contrast to monogenic pharmacological traits wherein it is feasible to partition the patient populations into discrete subgroups by analysis of a single gene. Hence, as pharmacogenomic investigations progress from monogenic to increasingly multigenic or multifactorial drug response phenotypes, the regulatory decision-makers are faced with a dilemma: How can a reviewer or a clinician determine if a given separation of a drug response profile by a pharmacogenomic biomarker is worthwhile for clinical implementation? The present manuscript makes an attempt to address these broad and emerging issues in pharmacogenomics and regulatory science. We propose that a comparison of inter- versus intra-subject variability in drug response under minimal environmental exposure may provide an upper-bound estimate of heritability of drug efficacy and safety. It is also argued that seemingly modest changes in population averages may underestimate the dramatic impact of a genetic biomarker at the tails of a population. To this end, a conceptual framework for graded risk assessment among subpopulations with overlapping quantitative phenotypes is presented. We conclude with a broader discussion of the evolution of genetic biomarkers from monogenic to multigenic traits in pharmacology, the associated ethical, social and therapeutic policy corollaries and the challenges lying ahead.

Original languageEnglish
Pages (from-to)53-71
Number of pages19
JournalCurrent Pharmacogenomics
Volume3
Issue number1
DOIs
Publication statusPublished - Mar 2005

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Drug and Narcotic Control
Pharmacogenetics
Decision Making
Pharmaceutical Preparations
Biomarkers
Phenotype
Pharmacology
Population
Safety
Twin Studies
Molecular Evolution
Manuscripts
Environmental Exposure
Drug Industry
Public Policy
Pharmacokinetics
Medicine
Therapeutics

Keywords

  • Bioethics
  • Biomarkers
  • Drug regulation
  • Genetic components
  • Pharmacogenomics
  • RDA
  • Repeated drug administration study
  • Risk assessment
  • Therapeutic policy
  • Twin study

ASJC Scopus subject areas

  • Pharmacology
  • Genetics

Cite this

Multigenic control of drug response and regulatory decision-making in pharmacogenomics : The need for an upper-bound estimate of genetic contributions. / Ozdemir, Vural; Kalow, W.; Tóthfalusi, L.; Bertilsson, L.; Endrenyi, L.; Graham, J. E.

In: Current Pharmacogenomics, Vol. 3, No. 1, 03.2005, p. 53-71.

Research output: Contribution to journalArticle

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