Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.
Biopharm Drug Dispos
; 40(8): 265-275, 2019 Sep.
Article
en En
| MEDLINE
| ID: mdl-31292985
ABSTRACT
AR-67 is a lipophilic camptothecin analog currently under clinical investigation using a Cremophor EL based formulation. However, as potential toxicity limitations exist in the clinical use of Cremophor, an alternative cyclodextrin (SBE-ß-CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE-ß-CD based formulation was compared with the Cremophor EL formulation. PK studies were conducted following intravenous or oral administration of AR-67 in either Cremophor or SBE-ß-CD formulation in mice. Noncompartmental analysis was used to determine the plasma and tissue drug distribution. A non-linear mixed effects (population) PK model was developed to fit both the oral and intravenous data and to estimate key PK parameters. The effect of formulation was explored as a covariate in the PK model. AR-67 in the SBE-ß-CD formulation had similar plasma PK and biodistribution to that in the Cremophor EL formulation. The proposed two-compartment model described the plasma PK of AR-67 in both formulations adequately. AR-67 in the SBE-ß-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE-ß-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Camptotecina
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Compuestos de Organosilicio
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Excipientes
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Modelos Biológicos
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Antineoplásicos Fitogénicos
Límite:
Animals
Idioma:
En
Revista:
Biopharm Drug Dispos
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos