RESUMO
The entry of new anticancer treatments into phase I clinical trials is ordinarily based on relatively modest preclinical data. This report defines the battery of preclinical tests important for assessing safety under an Investigational New Drug application (IND) and outlines a basis for extrapolating starting doses of investigational anticancer drugs in phase I clinical trials from animal toxicity studies. Types of preclinical studies for the support of marketing of a new anticancer drug are also discussed. This report addresses differences and similarities in the preclinical development of cytotoxic drugs (including photosensitizers and targeted delivery products), drugs used chronically (chemopreventive drugs, hormonal drugs, immunomodulators), and drugs intended to enhance the efficacy (MDR-reversing agents and radiation/chemotherapy sensitizers) or diminish the toxicity of currently used anticancer therapies. Factors to consider in the design of preclinical studies of combination therapies, alternative therapies, and adjuvant therapies in the treatment of cancer, and to support changes in clinical formulations or route of administration, are also discussed.
Assuntos
Antineoplásicos , Avaliação Pré-Clínica de Medicamentos/métodos , Drogas em Investigação , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Ensaios Clínicos Fase I como Assunto , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos/normas , Drogas em Investigação/farmacocinética , Drogas em Investigação/uso terapêutico , Drogas em Investigação/toxicidade , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
The pharmacokinetics of 5-fluorouracil (5-FU) injected into a surgically isolated pelvic circuit during hyperthermic perfusion was studied in five patients with local recurrence of anorectal cancer. 5-FU doses ranged from 11 to 23 mg/kg. The geometric mean ratio of peak plasma 5-FU in the isolated to systemic circuits was 10, the ratio at the end of the 45-minute perfusion was 12.5. The mean half-life of 5-FU in the isolated circuit was 18.5 minutes. Total drug exposure for the isolated circuit was 7.8-fold greater than for the systemic compartment. These results demonstrate a large pharmacologic advantage for the use of the isolation-perfusion technique.
Assuntos
Adenocarcinoma/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Quimioterapia do Câncer por Perfusão Regional/métodos , Fluoruracila/metabolismo , Neoplasias Pélvicas/tratamento farmacológico , Cromatografia Líquida de Alta Pressão/métodos , Fluoruracila/administração & dosagem , Fluoruracila/sangue , Humanos , Hipertermia Induzida , Cinética , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
Nephrotoxicity frequently limits the dose of cisplatin to less than 120 mg/m2 per injection. Sodium thiosulfate is a neutralizing agent for cisplatin that protects against renal damage. To determine whether injection of thiosulfate would permit larger doses of cisplatin to be administered, a fixed 9.9-g/m2 dose of thiosulfate was given intravenously over three hours concurrently with escalating doses of cisplatin. Cisplatin was administered over the last two hours of the thiosulfate infusion. Using this technique, it was possible to escalate the cisplatin dose to 225 mg/m2 before dose-limiting toxicities were encountered. Comparison of cisplatin pharmacokinetics in patients treated with 202.5 mg/m2 plus thiosulfate to those in patients treated with 100 mg/m2 without thiosulfate indicated that there were no changes in the elimination rate constant, volume of distribution, or total body clearance of cisplatin. The total drug exposure for the plasma was approximately twofold at the higher cisplatin dose. This study demonstrates that concurrent administration of thiosulfate permits at least a twofold increase in dose and total exposure to cisplatin.