1. Pharmacokinetic modeling of the blood-stable camptothecin analog AR-67 in two different formulations.
- Author
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Liu X, Adane E, Tang F, and Leggas M
- Subjects
- Animals, Antineoplastic Agents, Phytogenic pharmacokinetics, Camptothecin administration & dosage, Camptothecin pharmacokinetics, Glycerol analogs & derivatives, Glycerol chemistry, Male, Mice, Mice, Inbred C57BL, Organosilicon Compounds pharmacokinetics, Tissue Distribution, beta-Cyclodextrins chemistry, Antineoplastic Agents, Phytogenic administration & dosage, Camptothecin analogs & derivatives, Excipients chemistry, Models, Biological, Organosilicon Compounds administration & dosage
- 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-β-CD) based formulation has been proposed. Pharmacokinetic (PK) studies were conducted in mice and the SBE-β-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-β-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-β-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-β-CD formulation exhibited dose linearity following both oral and intravenous administration. Our studies indicate that SBE-β-CD is a viable alternative to Cremophor EL as a pharmaceutical excipient for formulating AR-67., (© 2019 John Wiley & Sons, Ltd.)
- Published
- 2019
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