Received for publication December 11, 2006.
Revised January 24, 2007.
Accepted for publication January 25, 2007.

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

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 promising, there has not been any attempt to define optimal metronomic dosing regimens by integrating pharmacokinetic (PK) with pharmacodynamic (PD) measurements. This study was aimed at comparing the PK and PD of temozolomide (TMZ) following MD and CD regimens. In vivo studies were carried out in xenografted athymic rats treated with either 18 mg/kg/d TMZ for 5 days or 3.23 mg/kg/d 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, 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 interstitial fluid pressure (IFP) and tumor size compared to vehicle control treatment, demonstrating a comparable effectiveness of MD and CD regimens. Using real-time PCR and Western blot analyses, some differences were noted in expression levels of VEGF and HIF-1 suggesting that the MD regimen may be superior to the CD regimen by preventing tumors from progressing towards 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.

Key words: angiogenesis, glioma tumor model, metronomic chemotherapy, microdialysis, pharmacokinetics, temozolomide

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