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Keywords:

  • pharmacokinetics/pharmacodynamic models;
  • cancer chemotherapy;
  • individualized drug therapy;
  • drug metabolizing enzymes;
  • simulations;
  • biomarker;
  • dihydropyrimidine dehydrogenase;
  • anticancer agent

Abstract

We developed a pharmacokinetic/pharmacodynamic (PK/PD) model with the value of the plasma ratio of dihydrouracil (UH2)/uracil (Ura), which is a possible surrogate biomarker of hepatic dihydropyrimidine dehydrogenase activity, determined before 5-fluorouracil (5-FU) treatment to simulate the growth of tumors after 5-FU treatment in rats with colorectal cancer (CRC). In the PK/PD model, the value of the elimination rate constant of 5-FU—ke—was estimated using the plasma UH2/Ura ratio observed before 5-FU treatment for simulating PKs of 5-FU and tumor growth. The PK/PD model with plasma UH2/Ura ratio effectively captured the features of tumor growth and the anticancer effect of 5-FU treatment, which provided reliable parameter estimates. In addition to an appropriate dosing regimen, pretherapeutic assessment of the UH2/Ura ratio in the plasma of CRC patients and PK/PD analysis with the plasma UH2/Ura ratio could enable the development of an optimal therapeutic scheme for each patient. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:2056–2067, 2013