BEVACIZUMAB EFFECT ON TOPOTECAN PHARMACOKINETICS ...

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Figure 9. The effect of treatment regimen on Ke and Kte A: Higher Ke associated with SDBT; B: Differential Kte associated with the timing of SDBT. 39
variability for Kte decreased from 308%to 162%. However, the pharmacokinetic analysis showed that the use of MDBT had no effect on the pharmacokinetics of TPT in plasma and tumor compartment. The results of this analysis indicated that SDBT was associated with higher systemic elimination rate of TPT given after BEV compared to TPT given alone. In addition, the elimination rate of TPT from tumor compartment was dependent upon the schedule of BEV and TPT: increased after 1 day treatment of BEV and gradually decreased after 3 days and 7 days treatment of BEV. SDBT did produce a trend toward higher intratumoral exposure and penetration of TPT given 1 day after BEV administration compared to either TPT given alone or TPT given 3 days and 7 days after BEV, however, the current experiment had a low power to identify the significant increase in intratumoral exposure and penetration of TPT after 1 day pre-treatment of BEV. 2.3.2 The antitumor activity of the combination therapy In the SDBT groups, as shown in Figure 10, TPT significantly enhanced the antitumor activity of BEV when comparing final tumor volume between group B vs groups 1D BT (mean±SD: 1525±322 vs 1019±199, p
Page 1 and 2: BEVACIZUMAB EFFECT ON TOPOTECAN PHA
Page 3 and 4: ACKNOWLEDGEMENTS I would like to th
Page 5 and 6: overall effect of BEV on TPT pharma
Page 7 and 8: 2.3.1 The effect of BEV on the phar
Page 9 and 10: LIST OF FIGURES Figure 1. TPT effic
Page 11 and 12: SDBT Single dose of bevacizumab tre
Page 13 and 14: hypertension and the pathologic ext
Page 15 and 16: 1.1.3 Strategies to improve drug pe
Page 17 and 18: 1.2.2 Role of vascular endothelial
Page 19 and 20: enhanced the tumor response to conv
Page 21 and 22: non-favorable sites [109]. So devel
Page 23 and 24: low sensitivity. Additionally, it r
Page 25 and 26: tumor distribution of TMZ in V+ SC
Page 27 and 28: over-pruned microvessel [146, 147].
Page 29 and 30: 1.7 Summary Although the overall su
Page 31 and 32: CHAPTER 2. THE EFFECT OF BEVACIZUMA
Page 33 and 34: 2.2.4 Tumor model and treatment Ort
Page 35 and 36: Table 1. (SDBT) TPT penetration stu
Page 37 and 38: Figure 2. TPT penetration plus effi
Page 39 and 40: Figure 3. A pharmacokinetic model f
Page 41 and 42: 2.2.10 Statistical analyses For eac
Page 43 and 44: Figure 6. Representative plasma and
Page 45 and 46: Figure 7. The effect of BEV on the
Page 47 and 48: Figure 8. The effect of BEV on the
Page 49: Table 6. Population PK parameters o
Page 53 and 54: Figure 11. The effect of different
Page 55 and 56: efflux transporters. TPT is a campt
Page 57 and 58: Furthermore, although the volume of
Page 59 and 60: 19. Sleeman, J., A. Schmid, and W.
Page 61 and 62: 56. ElBayoumi, T.A. and V.P. Torchi
Page 63 and 64: 91. Ma, J. and D.J. Waxman, Combina
Page 65 and 66: 125. Hao, M., et al., Pharmacokinet
Page 67 and 68: 154. Dickson, P.V., et al., Bevaciz
Page 69 and 70: 188. Tian, Q., et al., Topotecan is

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