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Pharmacokinetic modeling of the blood‐stable camptothecin analog AR‐67 in two different formulations
Author(s) -
Liu Xiaoxi,
Adane Eyob,
Tang Fei,
Leggas Markos
Publication year - 2019
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2199
Subject(s) - pharmacokinetics , pharmacology , camptothecin , biodistribution , chemistry , bioavailability , distribution (mathematics) , excipient , population , oral administration , medicine , mathematics , in vitro , biochemistry , mathematical analysis , environmental health
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.