Pharmacokinetic/pharmacodynamic modeling of etoposide tumor growth inhibitory effect in Walker-256 tumor-bearing rat model using free intratumoral drug concentrations.
Eur J Pharm Sci
; 97: 70-78, 2017 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-27816627
The purpose of this study was to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model linking etoposide free tumor and total plasma concentrations to the inhibition of solid tumor growth in rats. Walker-256 tumor cells were inoculated subcutaneously in the right flank of Wistar rats, which were randomly divided in control and two treated groups that received etoposide 5 or 10mg/kg i.v. bolus every day for 8 and 4days, respectively, and tumor volume was monitored daily for 30days. The plasma and intratumoral concentrations-time profiles were obtained from a previous study and were modeled by a four-compartment population pharmacokinetic (popPK) model. PK/PD analysis was conducted using MONOLIX v.4.3.3 on average data and by mean of a nonlinear mixed-effect model. PK/PD data were analyzed using a modification of Simeoni Tumor Growth Inhibition (TGI) model by introduction of an Emax function to take into account the concentration dependency of k2variable parameter (variable potency). The Simeoni TGI-Emax model was capable to fit schedule-dependent antitumor effects using the tumor growth curves from the control and two different administered schedules. The PK/PD model was capable of describing the tumor growth inhibition using total plasma or free tumor concentrations, resulting in higher k2max (maximal potency) for free concentrations (25.8mL·µg-1·day-1 - intratumoral vs. 12.6mL·µg-1·day-1 total plasma). These findings indicate that the plasma concentration may not be a good surrogate for pharmacologically active free tumor concentrations, emphasizing the importance of knowing drug tumor penetration to choose the best antitumor therapy.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma 256 de Walker
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Carga Tumoral
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Modelos Animais de Doenças
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Etoposídeo
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Inibidores do Crescimento
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Antineoplásicos Fitogênicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Brasil
País de publicação:
Holanda