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Pharmacogenetics-based therapeutic recommendations — ready for clinical practice?

Nature Reviews Drug Discovery volume 4, pages 639–647 (2005)Cite this article

Abstract

Although considerable progress has been made in basic pharmacogenetic research, less has been demonstrated in the application of pharmacogenetics (PGx)-based diagnostics to drug development and in clinical practice. There are drugs that are currently used in the clinic for which individualized therapy could be beneficial based on PGx data. However, specific, actionable recommendations on how to implement individualized therapy — particularly with respect to dosage — still have to be developed. Moreover, to apply PGx efficiently in clinical drug development, and later in drug therapy, study designs and the generation and handling of PGx data need to become more standardized. Here, we argue for the development of concise guidelines for implementation of PGx analyses in drug development and therapy.

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Figure 1: Schematic showing the potential benefit of adjusting dose to genotype.
Figure 2: Examples of dose adjustments based on PGDx.
Figure 3: The development of a valid PGDx test.
Figure 4: Optimal study designs for pharmacogenetic studies using cytochrome P450 2D6 polymorphisms as an example.

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Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Cologne, Gleueler Strasse 24, Köln, 50931, Germany

    Julia Kirchheiner & Uwe Fuhr

  2. Department of Clinical Pharmacology, University of Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany

    Jürgen Brockmöller

Authors
  1. Julia Kirchheiner
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  2. Uwe Fuhr
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  3. Jürgen Brockmöller
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Corresponding author

Correspondence to Julia Kirchheiner.

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The authors declare no competing financial interests.

Related links

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DATABASES

Entrez Gene

CYP2D6

NAT2

SERT

Swiss-Prot

TPMT

Glossary

ACTIONABLE RECOMMENDATION

An actionable recommendation in the present context is a recommendation or rule by which all physicians would make the same decision based on a given pharmacogenetic test result.

AUC

Area under the concentration–time curve of a drug, usually measured in human plasma or serum.

BIOAVAILABILITY

Availability of a drug at its site of action measured by AUC.

BIOEQUIVALENCE

Two formulations of a given drug are considered bioequivalent if AUC, maximum blood concentrations and times of maximum blood concentrations differ by no more than 80–125%.

CASE-CONTROL STUDY

A retrospective study design in which a study group suffering from a disease or particular drug response are compared by genotype with a control group. The control group is selected after the cases have been identified.

COHORT STUDY

A study design in which all subjects exposed to a certain condition are studied prospectively and then compared by genotype.

NESTED CASE-CONTROL STUDY

A cohort study in which not all participants are analysed but only a subgroup of cases are compared with controls drawn from the same cohort.

PANEL STUDY

A study in groups (panels) pre-selected for a certain property, for example, genotype.

PHARMACOGENETICS-BASED DIAGNOSTICS

Diagnosis of genetic variants that facilitates the optimization of drug therapy. Also encompasses genetic analysis of disease, for example, the genomes of tumours or of infectious agents in an individual patient.

PHARMACOKINETIC–PHARMACODYNAMIC RELATIONSHIP

Quantitative relationship between blood and tissue concentrations of the drug (pharmacokinetics) and the effects (pharmacodynamics) of a drug.

STEADY-STATE CONCENTRATION

Drug concentrations during long-term therapy.

STRATIFICATION

Separate and joint analysis of subgroups (the strata) of a study concerning the parameters of interest, for example, a specific genotype.

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Kirchheiner, J., Fuhr, U. & Brockmöller, J. Pharmacogenetics-based therapeutic recommendations — ready for clinical practice?. Nat Rev Drug Discov 4, 639–647 (2005). https://doi.org/10.1038/nrd1801

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