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Pharmacokinetics in Cancer Treatment

Clinical Implications of Interindividual Variability and Drug Interactions

  • Review Article
  • Published:
American Journal of Cancer

Abstract

The design of chemotherapy schedules for treatment of malignancies is based on the selection of optimal drug doses with tolerable adverse effects. Interindividual variation in absorption, distribution, metabolism and excretion may exist for a given dose, which depend on both physiological and pathological factors. These factors will be of importance for the outcome of treatment in terms of efficacy as well as toxicity. As chemotherapy usually consists of a combination of drugs, pharmacological interactions may be expected. This also holds for other drug classes, such as analgesics, antidepressants, antibiotics, that are frequently coadministered to patients receiving chemotherapy. The study of pharmacokinetics can give insight in to the extent of interindividual variability based on genetic and patient factors, as well as in the occurrence of drug interactions.

Many anticancer agents need specific enzymes for their metabolism. Polymorphisms in gene expression resulting in differences in enzyme activity have been described, such as thiopurine methyltransferase for metabolism of 6-mere ap top urine, dihydropyrimidine dehydrogenase for fluorouracil and uridine diphosphate (UDP) glucuronosyl transferase 1A1 for SN-38 (the active metabolite of irinotecan). Cytochrome P450 isoenzymes form a very important drug-metabolizing family and CYP3A4 is responsible for the metabolism of several classes of drugs. This isoenzyme system can easily be induced or inhibited by other drugs. Interactions combining drugs requiring both CYP3A4 for metabolism and P1 70-glycoprotein (Pgp) for transport may result in enhanced adverse effects in patients. A well-known example is the interference of taxanes with the pharmacokinetics of anthracyclines.

Patient factors, other than variable expression of drug-metabolizing enzymes, that may account for altered pharmacokinetic properties are: age, obesity, hypoalbuminemia, impaired renal or liver function. A combination of these factors may occur, especially in patients with advanced cancer.

The presence of a drug interaction may be advantageous in some instances. For example, the limited oral bioavailability of paclitaxel may be improved by inhibition of Pgp-mediated drug efflux from the intestine. The same holds true for blocking the breast cancer resistance protein transporter in the intestine to enhance oral absorption of topotecan.

It is only through prospective, preclinical and early clinical evaluation of both pharmacokinetics and pharmacodynamics, i.e. the effects of the drug on the body, that the pharmacological behavior of a particular drug can be identified. Changes in drug dose, sequence, or infusion duration, increase of the time-interval between drugs, etc., can be measures required to provide an optimal therapeutic index of combination chemotherapy for the patient with cancer.

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Boven, E. Pharmacokinetics in Cancer Treatment. Am J Cancer 1, 33–53 (2002). https://doi.org/10.2165/00024669-200201010-00005

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