Date of Award

12-2011

Document Type

Thesis

Degree Name

Master of Science (MS)

Program

Pharmaceutical Science

Research Advisor

Clinton F. Stewart, Pharm.D.

Committee

Bernd Meibohm, Ph.D. John C. Panetta, Ph.D. Clinton F. Stewart, Pharm.D.

Keywords

Bevacizumab, Pharmacokinetics, Rhabdomyosarcoma, Topotecan

Abstract

Increasing evidence suggests that inhibition of vascular endothelial growth factor (VEGF) can transiently normalize tumor vasculature, thereby improving delivery of systemic chemotherapy. Bevacizumab (BEV), an anti-VEGF antibody, has been shown to transiently normalize tumor vasculature by increasing tumor vessel maturity, decreasing tumor vessel permeability, and increasing tumor oxygenation in an Rh30 orthotopic rhabdomyosarcoma xenograft model. However, the effects of BEV on the pharmacokinetics of TPT and the antitumor activity of TPT have not been evaluated. This study aimed to investigate the effect of BEV on TPT systemic and tumoral pharmacokinetics and to determine how these changes affect the efficacy of TPT in the Rh30 mouse model. Mice bearing Rh30 orthotopic xenografts were treated with BEV alone (5 mg/kg), TPT alone (2 mg/kg) or a combination of the two administered intravenously with different schedules. The pharmacokinetics of TPT, including TPT intratumoral penetration, as well as the efficacy of the monotherapy and combination therapy were evaluated. Population pharmacokinetic modeling and covariate analysis of TPT pharmacokinetics were performed using the maximal likelihood expectation maximization (MLEM) method in ADAPT 5 to predict the plasma and tumor concentration-time profile, to estimate the pharmacokinetic parameters of individual mouse and mice population, and to evaluate the effect of BEV on TPT systemic and tumoral pharmacokinetics. Tumor penetration was assessed by the tumor-to-plasma ratio of area under concentration-time curve (AUC). Tumor volume before and after the treatment were measured to evaluate the antitumor activity of the treatment regimen, and to assess the effect of BEV on the antitumor activity of TPT in Rh30 xenografts. Covariate analysis showed a single dose of BEV was associated with the increased systemic elimination rate and clearance of TPT. Furthermore, a single dose BEV had a time-dependent effect on the tumor elimination rate of TPT. The elimination rate of TPT from tumor compartment increased when it was given 1 day after a single dose of BEV and gradually decreased to control level when TPT was given 3 days and 7 days after a single dose of BEV. Multiple doses of BEV had no effect on TPT pharmacokinetics. TPT penetration was not altered after administering multiple doses of BEV, but a single dose of BEV produced a trend in changes of TPT penetration. Tumor efficacy was not dependent on the schedule of BEV and TPT. TPT significantly enhanced the antitumor activity of combination therapy while pre-treatment of BEV did not alter the antitumor activity of TPT. Tumor efficacy in MDBT groups was mainly due to the multiple doses of BEV and the antitumor activity of TPT was diminished. The present work provides crucial insights into the effect of coadministration of BEV on the pharmacokinetic changes and antitumor activity of TPT. The increased TPT systemic elimination and clearance after single dose of BEV treatment may be due to the altered renal clearance by VEGF. The increased TPT elimination from tumor tissue after 1 day pre-treatment of BEV may be caused by a normalization of tumor vasculature. The overall effect of BEV on TPT pharmacokinetics as well as TPT penetration is determined by the net balance of the pharmacologic changes of tumor microenvironment by BEV. And the antitumor activity of combination is determined by the balance between angiogenesis inhibition-induced tumor cell starvation and the tumor cytotoxicity due to the exposure to cytotoxic drugs. This study highlights the complexity of pharmacokinetic (PK) and pharmacodynamic (PD) interaction that may take place when antiangiogenic agent and cytotoxic drug are combined and cautions that more consideration and mechanistic investigation should be made before using a combination of anti-angiogenic agents with cytotoxic drugs for cancer treatment.

DOI

10.21007/etd.cghs.2011.0143

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