RESUMEN
BACKGROUND: ABT-751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma. OBJECTIVE: Determine a maximum tolerated dose for ABT-751, and assess long-term tolerability and activity in canine lymphoma. ANIMALS: Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non-Hodgkin's lymphoma. METHODS: Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long-term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells. RESULTS: The maximum tolerated dose of ABT-751 was 350 mg/m(2) PO q24h. Dose-limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m(2) PO q48h. ABT-751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs). CONCLUSION: ABT-751 was well tolerated at 350 mg/m(2) PO q24h for 7 days and then q48h thereafter. Activity of ABT-751 suggested a rationale for additional studies of ABT-751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.
Asunto(s)
Antimitóticos/administración & dosificación , Antimitóticos/efectos adversos , Enfermedades de los Perros/tratamiento farmacológico , Linfoma no Hodgkin/veterinaria , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Administración Oral , Animales , Antimitóticos/sangre , Estudios de Cohortes , Enfermedades de los Perros/patología , Perros , Relación Dosis-Respuesta a Droga , Femenino , Linfoma no Hodgkin/sangre , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , Masculino , Dosis Máxima Tolerada , Sulfonamidas/sangreRESUMEN
3-(1H-Indol-2-yl)phenyl)(3,4,5-trimethoxyphenyl)methanone (I-387) is a novel indole compound with antitubulin action and potent antitumor activity in various preclinical models. I-387 avoids drug resistance mediated by P-glycoprotein and showed less neurotoxicity than vinca alkaloids during in vivo studies. We examined the pharmacokinetics and metabolism of I-387 in mice as a component of our preclinical development of this compound and continued interest in structure-activity relationships for antitubulin agents. After a 1 mg/kg intravenous dose, noncompartmental pharmacokinetic analysis in plasma showed that clearance (CL), volume of distribution at steady state (Vd(ss)), and terminal half-life (t(1/2)) of I-387 were 27 ml per min/kg, 5.3 l/kg, and 7 h, respectively. In the in vitro metabolic stability study, half-lives of I-387 were between 10 and 54 min by mouse, rat, dog, monkey, and human liver microsomes in the presence of NADPH, demonstrating interspecies variability. I-387 was most stable in rat liver microsomes and degraded quickly in monkey liver microsomes. Liquid chromatography-tandem mass spectrometry was used to identify phase I metabolites. Hydroxylation, reduction of a ketone group, and O-demethylation were the major metabolites formed by the liver microsomes of the five species. The carbonyl group of I-387 was reduced and identified as the most labile site in human liver microsomes. The results of these drug metabolism and pharmacokinetic studies provide the foundation for future structural modification of this pharmacophore to improve stability of drugs with potent anticancer effects in cancer patients.
Asunto(s)
Antimitóticos/metabolismo , Benzofenonas/metabolismo , Indoles/metabolismo , Microsomas Hepáticos/metabolismo , NADP/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antimitóticos/sangre , Antimitóticos/síntesis química , Antimitóticos/farmacología , Benzofenonas/sangre , Benzofenonas/síntesis química , Benzofenonas/farmacología , Biotransformación , Perros , Estabilidad de Medicamentos , Semivida , Haplorrinos , Humanos , Hidroxilación , Indoles/sangre , Indoles/síntesis química , Indoles/farmacología , Inyecciones Intravenosas , Fase I de la Desintoxicación Metabólica , Fase II de la Desintoxicación Metabólica , Ratones , Microsomas Hepáticos/efectos de los fármacos , Ratas , Especificidad de la Especie , Relación Estructura-ActividadRESUMEN
A method has been developed for the quantitation of ABT-751, ABT-751 glucuronide, and ABT-751 sulfate in human plasma. ABT-751 and metabolites were separated from endogenous material on a C18 column with acetonitrile-ammonium acetate (2 mM) mobile phase containing formic acid (0.1%, v/v) using isocratic flow for 5 min. The analytes were monitored by tandem-mass spectrometry. Calibration curves were generated over the range of 20-5,000 ng/ml for ABT-751, ABT-751 glucuronide, and ABT-751 sulfate. A 20,000 ng/ml sample that was diluted 1:10 (v/v) with plasma was accurately quantitated. The method has been successfully applied to study the plasma pharmacokinetics of ABT-751 in humans.