BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

Furthermore, although the volume of distribution in tumor compartment is not identical
to tumor volume, it may serve as an early indicator of the therapeutic response. In our PK
study, we used population modeling and covariate analysis to assess the effect of BEV on
the volume of distribution of TPT in tumor compartment at the day of TPT
administration. The results indicated that the use of BEV significantly decreased the
volume of distribution in tumor compartment, which was confirmed by the tumor
efficacy study in a different cohort of mice─a significant tumor volume reduction was
observed when compared the combination therapy to monotherapy after two weeks of the
initial treatment. Last, the combination therapy with a single dose of BEV and TPT did
enhance the tumor response; however, the combination therapy with multiple doses of
BEV and TPT did not benefit antitumor activity. TPT alone had the least antitumor
activity, while multiple BEV only had similar antitumor activity when combing TPT.
This result clearly indicated that multiple doses of BEV dominated the tumor response
and the antitumor activity caused by a single dose of TPT was diminished.
In summary, in the present study we observed significant changes in TPT
disposition after a single BEV dose in our orthotopic RMS model. In brief, a single dose
of BEV had significant effect on the systemic elimination and clearance of TPT, and
time-dependently regulated TPT elimination from tumor compartment. Though a
substantial antitumor activity after a single dose of BEV and TPT combination was
detected, BEV did not alter TPT penetration or exposure into tumor tissue. Furthermore,
TPT penetration and efficacy were not affected after multiple doses of BEV
administration. Although using drug penetration and antitumor activity as the end points
of the study, we were unable to identify the optimal schedule of the combination therapy.
However, our results provide crucial insights into the effect of coadministration of BEV
on TPT PK changes. The overall effects of anti-angiogenic agents on tumor vasculature
and microenvironment, resulting in the net balance of the antiangiogenesis-mediated
pharmacologic actions may be the determinants for the cytotoxic drug penetration.
Cytotoxic drugs may reversely sensitize the antitumor activity of the anti-angiogenic
agents. This study highlights the complexity of PKPD interaction that may take place
when antiangiogenic agents and cytotoxic drugs are combined and cautions that careful
consideration and more mechanistic investigation should be made before the usage of the
combination of anti-angiogenic agents with cytotoxic drugs for cancer treatment.
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