Phase I pharmacological study of continuous chronomodulated capecitabine treatment.
Adult
Aged
Antineoplastic Agents
/ administration & dosage
Capecitabine
/ administration & dosage
Circadian Rhythm
Dihydrouracil Dehydrogenase (NADP)
/ metabolism
Drug Chronotherapy
Female
Fluorouracil
/ blood
Humans
Male
Middle Aged
Neoplasms
/ drug therapy
Thymidylate Synthase
/ metabolism
Uridine Triphosphate
/ analogs & derivatives
capecitabine
chronomodulation
metronomic
phase I
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
07 May 2020
07 May 2020
Historique:
received:
05
01
2020
accepted:
21
04
2020
entrez:
9
5
2020
pubmed:
10
5
2020
medline:
22
9
2020
Statut:
epublish
Résumé
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). 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. A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m
Identifiants
pubmed: 32382808
doi: 10.1007/s11095-020-02828-6
pii: 10.1007/s11095-020-02828-6
pmc: PMC7205843
doi:
Substances chimiques
Antineoplastic Agents
0
5-fluorouridine 5'-triphosphate
3828-96-4
Capecitabine
6804DJ8Z9U
Dihydrouracil Dehydrogenase (NADP)
EC 1.3.1.2
Thymidylate Synthase
EC 2.1.1.45
Fluorouracil
U3P01618RT
Uridine Triphosphate
UT0S826Z60
Types de publication
Clinical Trial, Phase I
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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