Preclinical Pharmacokinetic and Pharmacodynamic Evaluation of Metronomic and Conventional Temozolomide Dosing Regimens

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Abstract
Metronomic dosed (MD) chemotherapy as opposed to conventional dosed (CD) chemotherapy is considered an alternate strategy to target angiogenesis and limit host toxicity. Although this approach is promising, there has not been any attempt to define optimal metronomic dosing regimens by integrating pharmacokinetic (PK) with pharmacodynamic (PD) measurements. The aim of this study was to compare the pharmacokinetics and pharmacodynamics of temozolomide [TMZ, 8-carbamoyl-3-methylidazo(5,1-d)-1,2,3,5-terrazin-4(3H)-one] after MD and CD regimens. In vivo studies were carried out in xenografted athymic rats treated with either 18 mg/kg/day TMZ for 5 days or 3.23 mg/kg/day TMZ for 28 days. PK studies were performed on the first and last days of dosing. PD measurements consisted of gene and protein expression of various angiogenic markers, tumor size, tumor pH, and interstitial fluid pressure (IFP). The results demonstrated that the PK parameters (total clearance, volume of distribution, and tumor/plasma accumulation) were quite similar for MD and CD groups, consistent with the linear PK properties of TMZ. Both TMZ treatment schedules caused a significant decrease in IFP and tumor size compared with vehicle control treatment, demonstrating comparable effectiveness of MD and CD regimens. Using real-time polymerase chain reaction and Western blot analyses, some differences were noted in expression levels of vascular endothelial growth factor and hypoxia inducible factor-1α, suggesting that the MD regimen may be superior to the CD regimen by preventing tumors from progressing to a proangiogenic state. In conclusion, several PK/PD factors contributing to the antitumor activity of the MD TMZ therapy have been identified and form a foundation for further investigations of low-dose TMZ regimens.