Clinical pharmacokinetics and exposure-toxicity relationship of a folate-Vinca alkaloid conjugate EC145 in cancer patients.
J Clin Pharmacol
; 49(12): 1467-76, 2009 Dec.
Article
em En
| MEDLINE
| ID: mdl-19837906
ABSTRACT
The clinical pharmacokinetics and exposure-toxicity relationship were determined for EC145, a conjugate of folic acid and the Vinca alkaloid desacetylvinblastine hydrazide (DAVLBH), in cancer patients. EC145 plasma concentration and toxicity data were obtained from a first-in-man phase I study and analyzed by nonlinear mixed effect modeling with NONMEM. EC145 concentration-time profile after intravenous administration was well described by a 2-compartment model with a first-order elimination process from the central compartment. BSA was identified as a significant covariate on EC145 clearance, accounting for 14.6% of interindividual variation on EC145 clearance. Population estimates for the clearance, steady-state volume of distribution, distribution, and elimination half-lives were 56.1 L/h, 26.1 L, 6 minutes, and 26 minutes, respectively. Constipation and peripheral neuropathy were the most common and clinically relevant toxicities. The clearance and area under the concentration-time curve (AUC) were significant predictors for the incidence of EC145-induced constipation but not peripheral neuropathy. In conclusion, EC145 is rapidly distributed and eliminated in cancer patients. BSA is a statistically significant covariate on EC145 clearance, but its clinical relevance remains to be defined. EC145-induced constipation occurs at a higher frequency in the patients with lower EC145 clearance, where the drug exposure tends to be higher.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Alcaloides de Vinca
/
Ácido Fólico
/
Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
/
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Clin Pharmacol
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos