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Pharmacokinetic variability of anticancer agents

Nature Reviews Cancer volume 5, pages 447–458 (2005)Cite this article

Key Points

  • The field of pharmacokinetics attempts to describe the bodily disposition of drugs in terms of numerical parameters that are calculated from plasma concentrations obtained at time points after drug administration. These parameters can be correlated with treatment outcomes such as toxicity and efficacy.

  • Anticancer drugs can have considerable interindividual pharmacokinetic variability, which, given the narrow therapeutic index of these drugs, results in unpredictable clinical effects.

  • There are many potential sources of pharmacokinetic variation, including interindividual differences in absorption, distribution, metabolism and excretion of anticancer drugs.

  • A considerable amount of research is currently directed towards defining genetic polymorphisms in drug-disposition pathways that explain observed interindividual pharmacokinetic variability.

  • Tailoring doses of anticancer drug to the individual patient will decrease interpatient pharmacokinetic variability and reduce the risks of severe toxicity and subtherapeutic treatment.

  • Individualized dosing strategies currently being examined in the research setting are promising, although few are used in routine clinical practice.

Abstract

The translation of advances in cancer biology to drug discovery can be complicated by pharmacokinetic variation between individuals and within individuals, and this can result in unpredictable toxicity and variable antineoplastic effects. Previously unrecognized variables (such as genetic polymorphisms) are now known to have a significant impact on drug disposition. How can the pharmacokinetic variability of anticancer agents be reduced? This will require the understanding of correlations between pharmacokinetics and treatment outcomes, the identification of relevant patient parameters, mathematical modelling of individual and population pharmacokinetics, and the development of algorithms that will tailor doses to the individual patient.

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Figure 1: The process of drug disposition.

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Authors and Affiliations

  1. Cancer Research Center, The University of Chicago, 5841 South Maryland Avenue, MC 2115, Chicago, 60637, Illinois, USA

    Samir D. Undevia, Gonzalo Gomez-Abuin & Mark J. Ratain

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  1. Samir D. Undevia
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  2. Gonzalo Gomez-Abuin
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  3. Mark J. Ratain
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Correspondence to Mark J. Ratain.

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DATABASES

Entrez Gene

ABCB1

ABCC2

ABCG2

CYP2C19

CYP2D6

CYP3A4

CYP3A5

PXR

SLCO1B1

UGT1A1

FURTHER INFORMATION

Pharmacogenetics of Anticancer Agents Research Group

The Pharmacogenetics and Pharmacogenomics Knowledge Base

Glossary

ABSORPTION

The process by which a drug leaves its site of administration and enters systemic circulation. Not relevant to intravenously administered agents.

DISTRIBUTION

The process by which a drug distributes into interstitial and intracellular fluids.

METABOLISM

The process by which a drug undergoes biotransformation to a usually inactive (but sometimes active) metabolite.

EXCRETION

The process by which a drug and/or its metabolites are removed from the body.

THERAPEUTIC INDEX

Conceptual description of the ratio of the toxic dose to the therapeutic dose of a drug, describing the dose range over which a drug is therapeutic but not unacceptably toxic.

COEFFICIENT OF VARIATION

The ratio of the standard deviation to the mean, multiplied by 100%. A high coefficient of variation means high interindividual variability.

BIOAVAILABILITY

The fraction of an administered dose that reaches systemic circulation.

FIRST-PASS EFFECT

The decrease in bioavailability of an oral drug owing to enteric metabolism, hepatic metabolism and excretion before the drug reaches the systemic circulation.

AREA UNDER THE CURVE (AUC).

The area under the curve in a graph of plasma concentration against time — a measure of drug exposure.

POLYMORPHISM

The presence of two or more alleles with a frequency of at least 1% in the general population at the same gene locus.

CYTOCHROME P450 ENZYMES

A family of haeme-containing intracellular oxidizing enzymes that are responsible for the first phase of metabolism of many drugs.

PRODRUGS

Pharmacologically inactive derivatives of active drugs that must undergo metabolic conversion to the active agent.

PHARMACOGENETICS

The study of genetically determined variations in drug response.

PLEURAL EFFUSION

An abnormal collection of fluid between the thin layers of tissue (pleura) lining the lung and wall of the chest cavity.

AMPHIPATHIC

Containing both hydrophilic and hydrophobic domains.

GLOMERULAR FILTRATION RATE

A measure of renal function that equals the quantity of glomerular filtrate formed per unit of time in all nephrons of both kidneys.

VENO-OCCLUSIVE DISEASE

A complication of bone-marrow transplantation in which there is obstruction of the terminal venules and/or sinusoids in the liver. Clinical features include hyperbilirubinaemia, painful hepatomegaly and fluid retention.

BILIRUBIN

A breakdown product of haeme that circulates in the plasma, is taken up by the liver and conjugated so that it is water soluble, and is then excreted in the bile. It is routinely measured as a blood test to assess liver function.

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Undevia, S., Gomez-Abuin, G. & Ratain, M. Pharmacokinetic variability of anticancer agents. Nat Rev Cancer 5, 447–458 (2005). https://doi.org/10.1038/nrc1629

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