A phase I clinical and pharmacokinetic study of the dolastatin analogue cemadotin administered as a 5-day continuous intravenous infusion

Abstract

The cardiotoxic effects of cemadotin were completely avoided by administering it as a 120-h CIV infusion. Thus. cardiovascular toxicity appears to be associated with the magnitude of the peak blood levels of the parent drug or its metabolites, whereas myelotoxicity is related to the duration of time that blood levels exceed a threshold concentration. Nevertheless, the data acquired during the extensive clinical experience with cemadotin requires careful examination to assess whether advancing this compound into disease-oriented efficacy studies is merited.

Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

“…However, cemadotin is a weak agonist for the angiotensin II type 1 receptor and produced a dose-dependent increase in diastolic blood pressure preclinically (33). Unfortunately, this translated into dose-limiting cardiovascular toxicities in the clinic, including myocardial infarction, peripheral edema, and hypertension (9 -12), all of which were associated with the magnitude of peak blood levels of the parent drug or its metabolites (34). Further modification of dolastatin-15 led to the synthesis of tasidotin, which has now been evaluated on three different administration schedules in the phase I setting.…”

“…Of note, the pharmacokinetics of tasidotin were analyzed by a Good Laboratory Practices -validated mass spectral assay, whereas cemadotin was analyzed by RIA and had severe crossreactivity problems with metabolites in the sample (34). Thus, any measurement of pharmacokinetic variables of cemadotin actually reflects a conglomerate of parent and metabolite concentrations.…”

Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications

“…TZT-1027, which acts by binding with microtubules, is in clinical trial phase II for soft tissue sarcoma [194,195,202]. Cemadotin is another analog of dolastatin 10 that reached clinical trial phase I, but was withdrawn because of its cardiovascular toxicity and myelotoxicity [203]. …”

Organismos marinhos como fonte de novos fármacos: histórico & perspectivas

“…Nos testes clínicos, a cemadotina (Quadro 3) mostrou-se segura nos estudos de fase 1 e melhorou a qualidade de vida de alguns pacientes com câncer de pulmão em fase 2, porém não demonstrou resultados objetivos contra os tumores. [119][120][121][122][123][124][125][126][127] A sintadotina (Quadro 3) é uma dolastatina de 3 a geração que age estabilizando microtúbulos, porém com um mecanismo singular, distinto das outras dolastatinas ou mesmo dos taxanos. O ILX-651 traz grandes vantagens, como ser ativo por via oral e possuir uma janela terapêutica maior que a da cemadotina.…”