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Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889.

AbstractPURPOSE:
Ro 09-4889 was designed to enhance the anticancer efficacy of capecitabine (Xeloda) by generating a dihydropyrimidine dehydrogenase inhibitor (DPDi) 5-vinyluracil (5-VU) preferentially in tumor tissues. This study assessed the tolerance to Ro 09-4889 treatment, and related pharmacokinetic and pharmacodynamic data such as inhibition of DPD activity in peripheral blood mononuclear cells (PBMCs) and plasma uracil levels.
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.
AuthorsS Eralp Bellibas, Indra Patel, Emmanuel Chamorey, Bettyna Brivet, Ernest D Bush, Catherine Kircher, Stephane Nave, Ludger Banken, Nicole Renée, Gérard Milano
JournalClinical 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
PMID15073108 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Controlled Clinical Trial, Journal Article)
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
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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