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Defining drug disposition determinants: a pharmacogenetic–pharmacokinetic strategy

Nature Reviews Drug Discovery volume 7, pages 293–305 (2008)Cite this article

Abstract

In preclinical and early clinical drug development, information about the factors influencing drug disposition is used to predict drug interaction potential, estimate and understand population pharmacokinetic variability, and select doses for clinical trials. However, both in vitro drug metabolism studies and pharmacogenetic association studies on human pharmacokinetic parameters have focused on a limited subset of the proteins involved in drug disposition. Furthermore, there has been a one-way information flow, solely using results of in vitro studies to select candidate genes for pharmacogenetic studies. Here, we propose a two-way pharmacogenetic–pharmacokinetic strategy that exploits the dramatic recent expansion in knowledge of functional genetic variation in proteins that influence drug disposition, and discuss how it could improve drug development.

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Figure 1: Flow chart of the proposed pharmacogenetic–pharmacokinetic strategy.
Figure 2: Scenarios in which pharmacogenetic information related to pharmacokinetics in early drug development can support decision-making for later development.

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Acknowledgements

The authors would like thank B. Spear for his leadership and mentoring, as well as C. Locke and numerous colleagues in the Department of Clinical Pharmacokinetics at Abbott for helpful discussions and collaboration.

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Authors and Affiliations

  1. David A. Katz and Anahita Bhathena are at Abbott Global Pharmaceutical Research & Development, 100 Abbott Park Road, Abbott Park, Illinois 60064-3500, USA.,

    David A. Katz & Anahita Bhathena

  2. Bernard Murray is at Gilead Sciences, 333 Lakeside Drive, Foster City, California 94404, USA.,

    Bernard Murray

  3. Leonardo Sahelijo is at Takeda Global Research & Development, One Takeda Parkway, Deerfield, Illinois 60015, USA.,

    Leonardo Sahelijo

Authors
  1. David A. Katz
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  2. Bernard Murray
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Corresponding author

Correspondence to David A. Katz.

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All the authors are or were employees of Abbott Laboratories.

Supplementary information

Supplementary information S1 (table)

Common functional genetic variants in drug disposition genes (PDF 924 kb)

Supplementary information S2 (table)

Drug disposition genes for which functions of common genetic variants have not been demonstrated (PDF 301 kb)

Supplementary information S3 (table)

Uncommon functional genetic variants in drug disposition genes (PDF 299 kb)

Supplementary information S4 (table)

Drug disposition genes for which information on common genetic variants has not been published (PDF 242 kb)

Supplementary information S5 (table)

Probe substrates and inhibitors for in vitro study of drug disposition pathways (PDF 1393 kb)

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FURTHER INFORMATION

OMIM

The Pharmacogenetics and Pharmacogenomics Knowledge Base

Glossary

Alternating group design

An alternating group design is similar to an escalating-dose design, except that each group of subjects participates in several study periods. The same subjects in each group receive placebo in every period, but the dose of study drug escalates at each subsequent period.

Crossover design

In a crossover design, each group of subjects is randomized to receive all treatments (including placebo), usually separated by a washout period to eliminate carry-over effects between treatments. A crossover design is generally considered to provide increased sensitivity to treatment effects as it virtually eliminates inter-individual variability (each study subject functions as their own control), and hence requires fewer participants than a parallel arm design. However, the informativeness of pharmacogenetic analysis is minimized in this study design.

Drug disposition

Drug disposition is what happens to a chemical after it enters the body. After oral dosing, drug disposition includes absorption from the gastrointestinal tract into central circulation; distribution to and between various tissues; metabolism to different chemicals; and excretion (usually in urine or faeces).

Escalating-dose design

In an escalating-dose design, a first group of subjects is randomized to either the lowest dose of study drug or matching placebo, and subsequent groups (composed of different subjects) are each randomized to the next higher dose of study drug or matching placebo.

Extensive metabolizers/extensive transporters

These are individuals who are homozygous for a wild-type (normal activity) form of a drug metabolizing enzyme or drug transport protein. This classification applies to a specific enzyme or protein; a single individual can be an extensive metabolizer for one enzyme and not for another.

Fish-odour syndrome

This is an inborn error of metabolism accompanied by fish-like body odour. The offensive odour is due to the build-up of amino-trimethylamine (TMA) derived from foodstuffs such as egg yolk, liver, kidney, legumes, soy beans, peas and saltwater fishes. TMA is normally oxidized by the drug metabolizing enzyme flavin monooxygenase 3 (FMO3); genetic deficiency in this enzyme is the syndrome's cause.

Functional genetic variants

These are variant gene sequences that alter the expression, activity or substrate specificity of the corresponding protein.

Heterologous transcription activation assays

These are experimental tools used to measure the interaction of a compound with nuclear receptors. These can either be cell-based or cell-free systems engineered so that a readily detectable product (RNA or protein) is made in larger amounts when a ligand for the nuclear receptor is present.

Intermediate metabolizers/intermediate transporters

These are individuals who have reduced activity of a drug metabolizing enzyme or drug transport protein. Reduced activity may result from a structural change in the enzyme or a lower level of protein expression. An intermediate phenotype can result either from heterozygosity (for example, one extensive metabolizer allele + one poor metabolizer allele) or homozygosity (for example, for a reduced expression allele).

New chemical entity

(NCE). This is a common term in the pharmaceutical industry for a chemical that is being tested to learn whether it is useful as a drug. Generally (and in this paper) NCE refers only to small molecules and not to large molecules such as peptides, proteins and nucleic acids that also may be developed as drugs.

Pharmacogenetics

(PG). This is the study of how genetic variation influences drug response. In this paper, we focus on the subset of PG that relates genetic and pharmacokinetic variation.

Pharmacokinetics

(PK). Is the study of how the body affects drugs. In this paper, we frequently talk about PK variation (or variability), which refers to differences between individuals of the concentration–time profile of a drug.

Polymorphic

In the context of pharmacogenetics, polymorphic refers to when a DNA sequence exists in two or more forms in human populations. Polymorphism refers to the DNA sequence that is polymorphic.

Poor metabolizers/poor transporters

These are individuals who have very low or no activity of a drug metabolizing enzyme or drug transport protein, respectively. Poor-metabolizer alleles include those that lead to premature termination of the protein, and gene deletions.

Ultrarapid metabolizers

These are individuals who have unusually high activity of a drug metabolizing enzyme. Most commonly this is a result of gene duplication. We are not aware of an ultrarapid transporter phenotype.

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Katz, D., Murray, B., Bhathena, A. et al. Defining drug disposition determinants: a pharmacogenetic–pharmacokinetic strategy. Nat Rev Drug Discov 7, 293–305 (2008). https://doi.org/10.1038/nrd2486

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