RESUMEN
GI147211 is a novel, totally synthetic camptothecin with promising preclinical and early clinical activity. This study was designed to determine the maximum tolerated dose of Gl147211 as a 72-h infusion and to describe its pharmacokinetics and pharmacodynamics on this schedule. In a single-arm, rising-dose study in patients with advanced cancer, eight cohorts of three or more patients received 72-h infusions of Gl147211 at doses ranging from 0.25 to 2.5 mg m(-2) day(-1). Forty-four patients received a total of 124 cycles. All patients had refractory tumours and 40 had received prior chemotherapy and/or radiotherapy. Whole-blood Gl147211 lactone, total blood and total concentrations were measured during and over the 12 h following the infusion. Myelosuppression was observed at all dose levels. Neutropenia was dose limiting at 2.0 mg m(-2) day(-1) in minimally pretreated patients, while both neutropenia and thrombocytopenia were limiting at 1.5 mg m(-2) day(-1) in those more heavily pretreated. Phlebitis occurred with infusions through peripheral veins early in this study, necessitating the use of central venous access. Other toxicities included mild nausea and vomiting, fatigue, headache, central venous catheter infections and alopecia. Three partial and two minor responses lasting 8-34+ weeks were noted in patients with ovarian, colon and breast carcinomas and hepatoma. Mean steady-state concentrations of Gl147211 increased with dose over a range of 0.25-1.24 ng ml(-1). The mean terminal elimination half-life was 7.5 h, and the clearance averaged 1074 ml min(-1) m(-2) over the doses studied. The mean fractional excretion of unchanged drug in urine was 0.114. Gl147211 lactone exposure correlated with haematological toxicity. The recommended phase II doses for this regimen are 1.75 mg m(-2) day(-1) and 1.2 mg m(-2) day(-1) for minimally pretreated and heavily pretreated patients respectively. At these doses, steady-state Gl147211 concentrations within the range of those effective in vitro were achieved. Extensive phase II evaluation of this compound and further phase I trials evaluating more prolonged infusions are ongoing.
Asunto(s)
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Inhibidores de Topoisomerasa I , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Factores de TiempoRESUMEN
GI1147211 is a 7-substituted 10,11-ethylenedioxy-20(S)-camptothecin analogue that inhibits the nuclear enzyme topoisomerase I. In this Phase I and pharmacological study, 24 patients with advanced solid malignancies received a total of 72 courses of GI147211 as a 30-min infusion daily for 5 consecutive days, at doses ranging from 0.3 to 1.75 mg/m2/day. Severe neutropenia precluded dose escalation above 1.5 mg/m2/day in minimally pretreated patients, and both severe neutropenia and thrombocytopenia were dose limiting in heavily pretreated patients at doses above 1.0 mg/m2/day. These doses are, therefore, recommended for subsequent Phase II evaluations of GI147211 in patients with comparable prior therapy. Nonhematological toxicities, including nausea, vomiting, fatigue, and anorexia, were mild to moderate. The disposition of GI147211 in blood was described by a linear three-compartment model, with renal elimination accounting for only 11% of drug distribution. No relationship was observed between the pharmacological exposure to GI147211 and effects on neutrophils; however, patients who developed dose-limiting myelosuppression did experience greater exposure to both the lactone and total forms of the drug. The hydrolysis kinetics of GI147211 revealed not only a shift of the drug to the inactive carboxylate form in human serum albumin but also stabilization of the lactone in erythrocytes, perhaps accounting for the observed lactone:total area under the concentration-time curve ratio of 0.27. These results indicate that GI147211 exhibits predictable toxicities and that further studies are warranted to determine the distinct role of this compound among currently available camptothecin analogues.
Asunto(s)
Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Esquema de Medicación , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neutropenia/inducido químicamente , Trombocitopenia/inducido químicamenteRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Inhibidores de Topoisomerasa I , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Fatiga/inducido químicamente , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/terapia , Neutropenia/inducido químicamente , Estomatitis/inducido químicamente , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
GI147211 (GG211) is a camptothecin analogue, which exhibits antileukemic and antitumor activity by blocking DNA synthesis. The drug stability considerations and specimen handling were important aspects in method development and validation. This method involves collection of blood at the clinical site, immediate freezing, and storage at -70 degrees C. The lactone form is extracted from blood at physiological pH with a mixture of n-butyl chloride and acetonitrile (4:1); the carboxylate is not extracted under these conditions. After evaporation the extract is injected into an HPLC system with a fluorescence detector set at 378/420 nm. The internal standard used is 6,7-dimethoxy-4-methylcoumarin. The main advantages of the procedure are the separation of lactone and carboxylate by means of extraction, simplified specimen collection at clinical sites and the ability to inject almost all of the extracted material (extraction recovery, 60%) into an HPLC system. The method has been validated over the range 0.15-100 ng ml-1 with sufficient precision and accuracy (coefficient of variation below 10%) to support pharmacokinetic studies. Under the conditions of this procedure, the drug is stable in human blood at -70 degrees C for at least 93 days, as well as through two additional freeze-thaw cycles.