Pharmacokinetics and safety of bevacizumab administered in combination with cisplatin and paclitaxel in cynomolgus monkeys.

PURPOSE: Bevacizumab is the first anti-angiogenic monoclonal antibody approved for use in combination with chemotherapy for treatment of a variety of solid tumors. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with paclitaxel and cisplatin to cynomolgus monkeys, and to assess the pharmacokinetic and safety interactions between bevacizumab and the two chemotherapeutic agents. METHODS: Twenty male cynomolgus monkeys (Macaca fasicularis) were randomized to one of four treatment groups: vehicle, bevacizumab alone, cisplatin alone, and the combination of cisplatin and bevacizumab. Blood collection over serial time points allowed determination of the pharmacokinetic parameters of paclitaxel and bevacizumab and the maximum concentration (C (max)) for cisplatin. Drug concentrations were determined by graphite-furnace atomic absorption, high performance liquid chromatography, and enzyme-linked immunosorbent assay methods, for cisplatin, paclitaxel, and bevacizumab, respectively. RESULTS: AUC0-t values for bevacizumab when administered alone or in combination with chemotherapy were 6,747 +/- 1,872 and 7,366 +/- 1,599 microg/ml x day, respectively. AUC0-t values for paclitaxel with or without concomitantly administered bevacizumab were 10.9 +/- 2.9 and 10.3 +/- 3.7 microg/ml x day, respectively. No alterations in the C (max) of bevacizumab, paclitaxel, or cisplatin were observed between any of the treatment groups. As expected, based on their known safety profile, the administration of cisplatin and paclitaxel were associated with vomiting, decreased body weight, and transient decreases in white blood cell and absolute neutrophil counts; concomitant bevacizumab administration did not alter the incidence or severity of these toxicological effects. CONCLUSION: Pharmacokinetic estimates for bevacizumab, paclitaxel and cisplatin indicate that combination of bevacizumab with the two chemotherapeutic agents does not result in a pharmacokinetic interaction. Moreover, the addition of bevacizumab to the chemotherapy regimen did not appear to alter the safety profiles of cisplatin/paclitaxel in cynomolgus monkeys. Results from the present study supported the clinical development of bevacizumab treatment regimens in combination with the chemotherapeutic agents paclitaxel and cisplatin.

Concomitant administration of bevacizumab, irinotecan, 5-fluorouracil, and leucovorin: nonclinical safety and pharmacokinetics.

Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor approved for use in combination with 5-fluorouracil (5-FU)-based chemotherapy for first-line treatment of metastatic colorectal cancer. The Saltz regimen (irinotecan/5-FU/leucovorin [LV]) is a first-line treatment for this indication. The objective of this study was to evaluate the safety of bevacizumab when administered concomitantly with the Saltz regimen to cynomolgus monkeys, and to determine if the pharmacokinetics of bevacizumab, irinotecan, SN38 (the active metabolite of irinotecan), or 5-FU were affected by combined administration. Male cynomolgus monkeys were intravenously administered the Saltz regimen (125 mg/m2 irinotecan, 500 mg/m2 5-FU, 20 mg/m2 LV) alone (n = 4) or concomitantly with 10 mg/kg bevacizumab (n = 5) on days 1 and 8. All animals survived to euthanasia on day 15. Adverse effects associated with the Saltz regimen included diarrhea and neutropenia. Macroscopically, two animals from each group had small thymus glands that correlated microscopically with lymphoid depletion. Myeloid hypoplasia and/or erythroid hyperplasia was observed in the sternal bone marrow of most animals. These effects were considered to be associated with the Saltz regimen; concomitant bevacizumab administration did not alter the severity of these findings. Irinotecan and 5-FU were observed to be rapidly eliminated (t1/2 = 1 h and 0.5 h, respectively). Although the number of animals in each group was small and no statistical comparison between groups was performed, bevacizumab did not affect the disposition of either agent. These results indicate that bevacizumab can be safely administered in combination with the Saltz regimen without pharmacokinetic interaction.

Beneficial effects of intraventricularly administered BMP-7 following a striatal 6-hydroxydopamine lesion.

The present study was undertaken to investigate the effects of bone morphogenetic protein-7 (BMP-7), also named osteogenic protein-1 (OP-1), on the progression of a striatal 6-hydroxydopamine (6-OHDA) lesion. BMP-7, a member of the transforming growth factor-beta (TGF-beta) superfamily of proteins, has been shown to have protective effects in other animal models of neuronal damage. In this study, male Fischer 344 rats received striatal 6-OHDA lesions followed 1 week later by an intraventricular dose of BMP-7. No significant effect of BMP-7 treatment on spontaneous locomotor activity was observed, however BMP-7 significantly increased the density of tyrosine hydroxylase (TH) immunoreactivity (TH-ir) in the substantia nigra (SN) pars compacta, in the lesioned hemisphere [31.7+/-5.2 (optical density (O.D.) arbitrary units) control vs. 50.2+/-4.3 O.D. BMP-7-treated; p<0.05]. Interestingly, BMP-7 significantly increased TH-ir in the SN of the non-lesioned hemisphere (pars reticulata: 14.8+/-1.19 O.D. control vs. 36+/-2.6 O.D. BMP-7-treated, p<0.05; pars compacta: 29.0+/-4.9 O.D. control vs. 64.4+/-6.9 O.D. BMP-7-treated, p<0.001). A significant increase in DA concentration in the contralateral, non-lesioned hemisphere was also noted (113.2 ng/g control vs. 198.2 ng/g BMP-7-treated, p<0.01). In contrast to other intraventricularly administered neurotrophic factors, BMP-7 was not associated with an increase in the sensitivity to pain. These results suggest that BMP-7 is able to act as a dopaminotrophic agent without unwanted side effects and as such may be a useful pharmacological tool in the treatment of Parkinson's disease in humans.