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 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-1␣, 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.

Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice

“…However, the half-life of 4-OH-CPA would suggest that blood levels >0.013 Ag/mL prevail for the majority of a However, only early time points (up to 96 h) were analyzed. In another study, the plasma and tumor levels of the oral alkylating agent temozolomide, given in a LDM regimen to rats, are very similar at days 1 and 28 of dosing (45). This is not entirely unexpected because temozolomide undergoes spontaneous hydrolysis at physiologic pH to form its active metabolite instead of being metabolized, as is the case for CPA.…”

Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule

“…Patients were followed until first progression, at which point they received adjuvant chemotherapy with conventional TMZ at 150 mg/m 2 to 200 mg/m 2 given on 5 days of each 28-day cycle. The median number of conventional TMZ cycles administered was 6 (range, [4][5][6][7][8][9][10][11][12]. At the time of second progression, while still on conventional temozolomide, a change to continuous treatment with TMZ at 50 mg/m 2 was offered.…”

“…7 Both conventional and continuously delivered TMZ have been shown to have similar pharmacokinetic properties, linear kinetics, and similar cytotoxic activity when tested in xenograft models of glioma. 8 Short-term continuous delivery of TMZ (75 mg/ m 2 daily for 6 weeks) has been shown to be effective and well tolerated during initial therapy when combined with fractionated external beam RT for GBM. 1 After completion of this chemoradiation regimen, patients are offered the conventional adjuvant TMZ 150 mg/m 2 to 200 mg/m 2 regimen on 5 days of each 28-day cycle.…”

Metronomic chemotherapy regimens in oncology

“…В метрономных режимах применяется обычно в дозе 75 мг / м 2 , хотя дозировки варьируют по данным различных исследований [65,74]. В пред-клинических работах темозоломид в метрономных режимах наиболее активен в отношении глиом и ме-ланомы [66,67,75,76].…”