title: The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor.
abstract: Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with GI147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. GI147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. administration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median Tmax at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of GI147211. The terminal half-life after administration of oral GI147211 was 6.85 +/- 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor GI147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: Gerrits
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: G J
authors.initials: GJ
authors.lastname: Creemers
authors.forename: P
authors.initials: P
authors.lastname: Wissel
authors.forename: A S
authors.initials: AS
authors.lastname: Planting
authors.forename: J F
authors.initials: JF
authors.lastname: Pritchard
authors.forename: S
authors.initials: S
authors.lastname: DePee
authors.forename: M
authors.initials: M
authors.lastname: de Boer-Dennert
authors.forename: M
authors.initials: M
authors.lastname: Harteveld
authors.forename: J
authors.initials: J
authors.lastname: Verweij
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000628:therapy; D009503:Neutropenia / Q000139:chemically induced; D013280:Stomatitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C091719:lurtotecan; D002166:Camptothecin