Phase I pharmacological study of continuous chronomodulated capecitabine treatment

Autor: Alwin D. R. Huitema, Hilde Rosing, Niels de Vries, Jan H.M. Schellens, Dick Pluim, Bart A. W. Jacobs, Bastiaan Nuijen, Jeroen Roosendaal, Erik van Werkhoven, Serena Marchetti, Jos H. Beijnen
Přispěvatelé: Afd Pharmacoepi & Clinical Pharmacology, Pharmacoepidemiology and Clinical Pharmacology, Pharmacy, Graduate School, APH - Methodology, APH - Personalized Medicine
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Male
chronomodulation
Pharmaceutical Science
Uridine Triphosphate
Pharmacology
01 natural sciences
Thymidylate synthase
metronomic
0302 clinical medicine
Neoplasms
Fluorouracil/blood
Pharmacology (medical)
Thymidylate Synthase/metabolism
Morning
biology
capecitabine
Drug Chronotherapy
Uridine Triphosphate/analogs & derivatives
Middle Aged
Antineoplastic Agents/administration & dosage
Circadian Rhythm
Tolerability
Capecitabine/administration & dosage
030220 oncology & carcinogenesis
Molecular Medicine
Female
Fluorouracil
Biotechnology
medicine.drug
Research Paper
Adult
Antineoplastic Agents
Capecitabine
03 medical and health sciences
Pharmacokinetics
medicine
Dihydropyrimidine dehydrogenase
Humans
Dihydrouracil Dehydrogenase (NADP)
Aged
business.industry
010401 analytical chemistry
Organic Chemistry
Thymidylate Synthase
phase I
0104 chemical sciences
Neoplasms/drug therapy
Regimen
Pharmacodynamics
biology.protein
Dihydrouracil Dehydrogenase (NADP)/metabolism
business
Zdroj: Pharmaceutical Research
Pharmaceutical Research, 37(5). Springer New York LLC
Pharmaceutical research, 37(5):89. Springer New York
ISSN: 0724-8741
Popis: Purpose Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). Methods Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. Results A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. Conclusion The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1–14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.
Databáze: OpenAIRE
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