Abstract | PURPOSE: EXPERIMENTAL DESIGN: This was a single-center, double-blind, placebo-controlled, single-dose escalation study in 64 healthy male volunteers at 1-, 5-, 20-, 50-, 75-, 100-, and 200-mg oral dose of Ro 09-4889. Also, food effect was assessed separately in a group dosed with 20 mg of the compound. RESULTS: No serious adverse effects or significant laboratory and electrocardiogram abnormalities were observed during the study. Ro 09-4889 has a short elimination half-life (t(1/2)) of 0.5 h, followed by metabolites 5'-deoxy-5-vinyluridine (5'-DVUR), 5'-deoxy-5-vinylcytidine (5'-DVCR), and 5-VU with t(1/2) of 1.3, 1.2, and 2 h, respectively. The major metabolite excreted in urine was 5-DVCR (45% of dose). The inhibition of PBMC DPD activity and the increase in plasma uracil were related to Ro 09-4889 dose. DPD inhibition versus dose and uracil AUC (area under the curve) versus dose were modeled using the E(max) model with a baseline effect. The model-predicted ED(50) value was 100 mg. CONCLUSION: Single oral doses of Ro 09-4889 ranging from 1 to 200 mg were well tolerated. On the basis of these findings, a 10-to-30-mg dose range of Ro 09-4889 combined with capecitabine could be appropriate for further evaluation in cancer patients.
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Authors | S Eralp Bellibas, Indra Patel, Emmanuel Chamorey, Bettyna Brivet, Ernest D Bush, Catherine Kircher, Stephane Nave, Ludger Banken, Nicole Renée, Gérard Milano |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 10
Issue 7
Pg. 2327-35
(Apr 01 2004)
ISSN: 1078-0432 [Print] United States |
PMID | 15073108
(Publication Type: Clinical Trial, Clinical Trial, Phase I, Controlled Clinical Trial, Journal Article)
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Chemical References |
- 2',3'-O-diacetyl-5'-deoxy-5-vinylcytidine
- Antimetabolites, Antineoplastic
- Enzyme Inhibitors
- Placebos
- Deoxycytidine
- 5-vinyl-2'-deoxyuridine
- Uracil
- Capecitabine
- 5-vinyl-2'-deoxycytidine
- Dihydrouracil Dehydrogenase (NADP)
- Fluorouracil
- Deoxyuridine
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Topics |
- Administration, Oral
- Antimetabolites, Antineoplastic
(administration & dosage)
- Antineoplastic Combined Chemotherapy Protocols
(administration & dosage)
- Area Under Curve
- Capecitabine
- Deoxycytidine
(administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
- Deoxyuridine
(analogs & derivatives, pharmacology)
- Dihydrouracil Dehydrogenase (NADP)
(antagonists & inhibitors)
- Dose-Response Relationship, Drug
- Double-Blind Method
- Drug Synergism
- Enzyme Inhibitors
(pharmacokinetics, pharmacology)
- Fluorouracil
(analogs & derivatives)
- Humans
- Leukocytes, Mononuclear
(metabolism)
- Male
- Models, Chemical
- Placebos
- Time Factors
- Uracil
(blood, urine)
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