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Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect

Key Points

  • Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities

  • Despite the important information they provide, preclinical and clinical pharmacokinetic studies have had a secondary role during the conceptual development of metronomic chemotherapy

  • Different metronomic drug concentrations and schedules might affect different prevalent mechanisms of antitumour action, which suggests that therapy protocols could be selected on the basis of different prevalent effects

  • To develop better computational models for future metronomic chemotherapy studies, pharmacokinetic parameters of metronomic chemotherapy should be investigated more extensively in relation to pharmacodynamics (with a PK/PD approach) in future clinical trials

  • Therapeutic drug monitoring of metronomic chemotherapy is essential to maintain drug concentrations in the 'activity range', while maintaining a low toxicity profile

  • Randomized, prospective, clinical studies on metronomic chemotherapy should include pharmacokinetic/pharmacodynamic substudies with the aim of achieving personalized metronomic chemotherapy protocols in the future

Abstract

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

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Acknowledgements

G.B. and R.S.K. would like to thank C. Cheng for excellent secretarial assistance, and the whole editorial team of Nature Reviews Clinical Oncology for the important editing process. G.B.'s research is currently supported by grants from the Italian Association of Cancer Research (AIRC, IG 17672) and the Istituto Toscano Tumori (ITT). R.S.K's research on metronomic chemotherapy is currently supported by grants from the Canadian Institute of Health Research, the Israel Cancer Research Fund, and the Canadian Breast Cancer Foundation.

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G.B. and R.S.K. researched data for article, contributed to discussion of the content, wrote the manuscript, and reviewed/edited the article before submission.

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Correspondence to Guido Bocci.

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Competing interests

R.S.K. is a Scientific Advisory Board member of Angiocrine Biosciences, Eli Lilly, and MolMed; is a consultant to Cerulean Pharma, Merrimack Pharmaceuticals, and Triphase Accelerator; and holds stock from Angiocrine Biosciences. Over the past 2 years, R.S.K. has received honoraria from Boehringer-Ingelheim, Eli Lilly, Oncology Education, NED Biosciences and Regeneron. G.B. declares no competing interests.

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Glossary

Clearance

(Cl). Is the volume of blood cleared of the drug over the time unit. In other words, the loss of drug across an organ of elimination (for example, the liver or kidney). The systemic clearance is the sum of the clearances by each of the eliminating organs26.

Volume of distribution

(Vd). Is the theoretical volume in which the drug is distributed to achieve a mean concentration equal to that measured in plasma26.

Steady state concentrations

(CSS). Also referred to as concentrations of the drug achieved at the steady state. Is the equilibrium reached such that the amount of drug eliminated during each dosing interval is equivalent to the amount of drug administered during that same interval. The time to achieve the steady state, regardless of the drug or dose, corresponds to five drug elimination half-lives26.

Area under the curve

(AUC). Refers to the area under the plasma drug-concentration time curve and represents the total drug exposure within the body over time26.

Mean residence time

(MRT). Is the average time the number of molecules introduced (injected or taken orally) reside in the body26.

Bioavailability

(F). Is the percentage of a drug dose that reaches the systemic circulation, whatever the route of administration. In other words, a term commonly applied to both the rate and extent of drug input into the systemic circulation26.

Elimination half-life

(elimination t1/2). Is the time taken for the plasma concentration, as well as the total amount of the drug in the body, to decline by one-half26.

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Bocci, G., Kerbel, R. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol 13, 659–673 (2016). https://doi.org/10.1038/nrclinonc.2016.64

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