Phase I Pharmacokinetic and Pharmacodynamic Study of Carboplatin and Topotecan Administered Intravenously Every 28 Days to Patients with Malignant Solid Tumors

Abstract

Purpose: Preclinical studies have shown that the combination of topotecan and carboplatin is synergistic. To evaluate the schedule dependency of this interaction, the following phase I trial was designed to determine the safety and maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carboplatin and topotecan in patients with malignant solid tumors. Experimental Design: In part 1, patients received carboplatin on day 1and topotecan on days 1, 2, and 3 (C!Tschedule). In part 2, topotecan was administered on days 1, 2, and 3, followed by carboplatin on day 3 (T!C schedule). Pharmacokinetics were determined in plasma and DNA topoisomerase I catalytic activity and Pt-DNA adducts in WBC and tumor tissue. Results: Forty-one patients were included. Dose-limiting toxicities during the C!T schedule were grade 4 thrombocytopenia and febrile neutropenia (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 4 min mg/mL; topotecan, 0.5 mg/m 2 /d). Dose-limiting toxicities during the T!C schedule included grade 4 neutropenia, thrombocytopenia, neutropenic fever, and grade 4 nausea and vomiting (MTD: carboplatin target area under the free carboplatin plasma concentration versus time curve, 6 min mg/mL; topotecan, 0.9 mg/m 2 /d). One complete response and five partial responses were observed. The clearance of and exposure to carboplatin and topotecan did not depend on the sequence of drug administration. No schedule-dependent effects were seen in Pt-DNA levels and DNA topoisomerase I catalytic activity in WBC and tumor tissue. However, myelotoxicity was clearly more evident in the C!Tschedule. Conclusion: TheT!C schedule was better tolerated because both hematologic and nonhematologic toxicities were milder. Other pharmacodynamic factors than the ones investigated must explain the schedule-dependent differences in toxicities.Topotecan and carboplatin are both active anticancer drugs with an established use in the clinic. Topotecan, a water-soluble semisynthetic analogue of camptothecin, is licensed for the treatment of small-cell lung cancer, cervical cancer, and metastatic ovarian carcinoma (1 -4). Carboplatin is an analogue of cisplatin, but with a milder nonhematologic toxicity profile and a broad spectrum of antitumor activity (5, 6). Topotecan undergoes pH-dependent reversible hydrolysis from the active lactone form into the carboxylate form and vice versa (7,8). Topotecan inhibits DNA topoisomerase I (TopI) by binding to the cleavable complex (consisting of TopI covalently bound to DNA). The stabilized cleavable complex results in irreversible DNA double-strand breaks leading to cell death (9 -11). The antineoplastic effect of carboplatin involves the formation of a covalent interaction with DNA, after which several Pt-DNA adducts are formed, ultimately leading to cell death. Approximately 90% of an administered dose of carboplatin is eliminated by glomerular filtration (12). This makes it possible to individualize the dose of carboplatin based on rena...

Sequenciamento de infusão de antineoplásicos: contribuições para a prática de enfermagem oncológica baseada em evidência

“…Trombocitopenia grau 4 foi maior no braço que recebeu a sequência C-T. A combinação tem importantes implicações para enfermagem: náuseas e vômitos grau 4, neutropenia febril e trombocitopenia são efeitos esperados. Se constituem em toxicidades dose limitante do protocolo (56) . III * Considerado o estudo com maior nível de evidência (57) .…”

“…Os eventos adversos mais encontrados nos estudos in vivo dependentes do sequenciamento de infusão nesta revisão foram a neutropenia (18,25,28,30,33,45,51,56) e a trombocitopenia (51,56) , os quais estão intimamente relacionados aos diagnósticos de enfermagem 'risco para infecção' e 'risco para sangramento'. Outros efeitos tóxicos implicados na ordem de administração foram a diarreia (49) , a hepatotoxicidade (50) , náuseas (49) , vômitos (56) , mucosite (33) e cardiotoxicidade (34) , os quais também estão associados a diagnósticos de enfermagem previstos no sistema de classificação da NANDA Internacional (81) .…”