THE BIOAVAILABILITY OF ORAL GI147211 (GG211), A NEW TOPOISOMERASE-I INHIBITOR

Topoisomerase I inhibitors are new compounds of interest for cancer ch emotherapy. We performed a study with GI147211, a new semisynthetic ca mptothecin 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 eligibl e for the study. GI147211 was given orally on day 1 and as a 30-min in fusion daily on days 2-5. The treatment course was repeated every 3 we eks. In subsequent patient cohorts, the dose of the oral formulation w as escalated from 1.5 mg m(-2) to 6.0 mg m(-2); the dose for i.v. admi nistration was fixed at 1.2 mg m(-2). Plasma pharmacokinetics was perf ormed on day 1 and 2 of the first course and on day 1 of the second co urse using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not eva luable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioava ilability of GI147211 averaged 1.3 +/- 5.2%. Drug appeared quickly in plasma with a median T-max at 0.5 h. Fasting or fed state had no signi ficant influence on the bioavailability of GI147211. The terminal half -life after administration of oral GI147211 was 6.85 +/- 3.13 h, simil ar to the half-life after intravenous administration. The major toxici ties were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other tox icities predominantly consisted of mild and infrequent nausea and vomi ting, and fatigue. The oral administration of the drug is well tolerat ed. 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 develop ment of this promising topoisomerase I inhibitor.