title: Phase I dose-finding and pharmacokinetic trial of orally administered indibulin (D-24851) to patients with solid tumors.
abstract: Indibulin is a synthetic small molecule which antitumor activity is based upon destabilization of microtubules. The primary study objectives were to determine the impact of fasted and fed condition on pharmacokinetic parameters, as well as the maximum tolerated dose of the oral drinking solution of indibulin administered once daily for 14 days every 3 weeks in patients with solid tumors. In the pilot food effect part, patients received a single dose of 20 mg indibulin on day-8 and -4, fasted or fed, in a randomized crossover design. In the dose-escalation part, patients received a single dose of indibulin on day-4. Three dose levels were evaluated: 20, 40 and 80 mg. After a washout period, patients received indibulin once daily for 14 days every 3 weeks (multiple dose part). Blood samples were collected in the pilot food effect- and in the dose escalation study. A total of 14 patients entered, of which 6 completed the food effect study. The ratio of indibulin (fed/fasted) in the food effect study for AUC(0-72) was estimated as 1.24 (P=0.082, 95%CI 0.96-1.41) and C(max) ratio was 0.89 (P=0.54, 95%CI 0.55-1.44). Interpatient variability was high. Higher peak plasma concentrations were reached under fasting conditions which was undesired regarding tolerability. Therefore the dose escalation study was continued under fed conditions. Dose limiting toxicities, nausea and vomiting, appeared to be related to the increased volume of the solvent lactic acid. This study is continued, evaluating indibulin administered as capsules on the recommended dose level of 60 mg daily for 14 days.
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands. isa_kuppens@hotmail.com
authors.forename: I E L M
authors.initials: IE
authors.lastname: Kuppens
authors.forename: P O
authors.initials: PO
authors.lastname: Witteveen
authors.forename: M
authors.initials: M
authors.lastname: Schot
authors.forename: V M
authors.initials: VM
authors.lastname: Schuessler
authors.forename: A
authors.initials: A
authors.lastname: Daehling
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: E E
authors.initials: EE
authors.lastname: Voest
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005215:Fasting / Q000097:blood; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009426:Netherlands; D010865:Pilot Projects; D019518:Postprandial Period; D016896:Treatment Outcome; D050257:Tubulin Modulators / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D007211:Indoles; D050257:Tubulin Modulators; C419187:indibulin