BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

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
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