title: Single ascending dose tolerability, pharmacokinetic-pharmacodynamic study of dihydropyrimidine dehydrogenase inhibitor Ro 09-4889.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey, USA.
authors.forename: S Eralp
authors.initials: SE
authors.lastname: Bellibas
authors.forename: Indra
authors.initials: I
authors.lastname: Patel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Chamorey
authors.forename: Bettyna
authors.initials: B
authors.lastname: Brivet
authors.forename: Ernest D
authors.initials: ED
authors.lastname: Bush
authors.forename: Catherine
authors.initials: C
authors.lastname: Kircher
authors.forename: Stephane
authors.initials: S
authors.lastname: Nave
authors.forename: Ludger
authors.initials: L
authors.lastname: Banken
authors.forename: Nicole
authors.initials: N
authors.lastname: Renée
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
mesh_terms: D000284:Administration, Oral; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D019540:Area Under Curve; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008956:Models, Chemical; D010919:Placebos; D013997:Time Factors; D014498:Uracil / Q000097:blood / Q000652:urine
chemical_list: C477084:2',3'-O-diacetyl-5'-deoxy-5-vinylcytidine; D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D010919:Placebos; D003841:Deoxycytidine; C011381:5-vinyl-2'-deoxyuridine; D014498:Uracil; D000069287:Capecitabine; C035868:5-vinyl-2'-deoxycytidine; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil; D003857:Deoxyuridine