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In vivo toxicity and bioavailability of taxol (R) and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC

Wim Bouquet-Geerardyn, Wim Ceelen (UGent) , Els Adriaens (UGent) , Ana Almeida (UGent) , Thomas Quinten, Filip De Vos (UGent) , Piet Pattyn (UGent) , Marc Peeters (UGent) , Jean Paul Remon (UGent) and Chris Vervaet (UGent)
(2010) ANNALS OF SURGICAL ONCOLOGY. 17(9). p.2510-2517
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Abstract
Background. Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol (R). Materials and Methods. The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol (R) and Pad/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of <= 10% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min. Results. Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol (R). Hyperthermia yielded no significant differences in bio-availability data. Conclusion. These results showed that both formulations had a similar toxicity profile but differed significantly in bioavai lability.
Keywords
PHARMACEUTICAL APPLICATIONS, HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY, PERITONEAL CARCINOMATOSIS, CREMOPHOR EL, SAFETY EVALUATION, OVARIAN-CANCER, DRUG-DELIVERY, DISPOSITION, RATIONALE, COMPLEXES

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Chicago
Bouquet-Geerardyn, Wim, Wim Ceelen, Els Adriaens, Ana Almeida, Thomas Quinten, Filip De Vos, Piet Pattyn, Marc Peeters, Jean Paul Remon, and Chris Vervaet. 2010. “In Vivo Toxicity and Bioavailability of Taxol (R) and a Paclitaxel/beta-cyclodextrin Formulation in a Rat Model During HIPEC.” Annals of Surgical Oncology 17 (9): 2510–2517.
APA
Bouquet-Geerardyn, W., Ceelen, W., Adriaens, E., Almeida, A., Quinten, T., De Vos, F., Pattyn, P., et al. (2010). In vivo toxicity and bioavailability of taxol (R) and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC. ANNALS OF SURGICAL ONCOLOGY, 17(9), 2510–2517.
Vancouver
1.
Bouquet-Geerardyn W, Ceelen W, Adriaens E, Almeida A, Quinten T, De Vos F, et al. In vivo toxicity and bioavailability of taxol (R) and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC. ANNALS OF SURGICAL ONCOLOGY. 2010;17(9):2510–7.
MLA
Bouquet-Geerardyn, Wim, Wim Ceelen, Els Adriaens, et al. “In Vivo Toxicity and Bioavailability of Taxol (R) and a Paclitaxel/beta-cyclodextrin Formulation in a Rat Model During HIPEC.” ANNALS OF SURGICAL ONCOLOGY 17.9 (2010): 2510–2517. Print.
@article{1193730,
  abstract     = {Background. Peritoneal carcinomatosis (PC) remains a dreaded clinical syndrome and a common evolution of gastrointestinal and ovarian cancers. In recent years, hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has emerged as a promising strategy in the management of PC. In this study, a novel paclitaxel (Pac) formulation was investigated for its toxicity and bioavailability during HIPEC compared with Taxol (R). Materials and Methods. The maximum tolerated dose (MTD) after HIPEC of both formulations (Taxol (R) and Pad/RAME-beta-CD) was determined. MTD was defined as the highest nonlethal dose with a reduction in body weight of {\textlangle}= 10\% over 2 weeks. Blood parameters (red blood cell and white blood cell count, creatinine, ALT, and GGT) were evaluated over 20 days. Bioavailability of both Pac formulations after HIPEC was determined under normothermic (37 degrees C) and hyperthermic (41 degrees C) conditions for 90 min. Results. Following HIPEC, both formulations had a similar MTD: 0.24 mg paclitaxel per ml. Red blood cell count decreased to a minimum after 10 days and was not fully recovered after 20 days for both formulations. White blood cell monitoring showed a significant increase in neutrocytes at day 10 and 15 for the Pac/RAME-beta-CD formulation. Liver and kidney parameters did not change significantly. Bioavailability data of Pac/RAME-beta-CD showed a 40-fold increase of the area under the curve (AUC) of plasma concentrations compared with Taxol (R). Hyperthermia yielded no significant differences in bio-availability data. Conclusion. These results showed that both formulations had a similar toxicity profile but differed significantly in bioavai lability.},
  author       = {Bouquet-Geerardyn, Wim and Ceelen, Wim and Adriaens, Els and Almeida, Ana and Quinten, Thomas and De Vos, Filip and Pattyn, Piet and Peeters, Marc and Remon, Jean Paul and Vervaet, Chris},
  issn         = {1068-9265},
  journal      = {ANNALS OF SURGICAL ONCOLOGY},
  keyword      = {PHARMACEUTICAL APPLICATIONS,HYPERTHERMIC INTRAPERITONEAL CHEMOTHERAPY,PERITONEAL CARCINOMATOSIS,CREMOPHOR EL,SAFETY EVALUATION,OVARIAN-CANCER,DRUG-DELIVERY,DISPOSITION,RATIONALE,COMPLEXES},
  language     = {eng},
  number       = {9},
  pages        = {2510--2517},
  title        = {In vivo toxicity and bioavailability of taxol (R) and a paclitaxel/beta-cyclodextrin formulation in a rat model during HIPEC},
  url          = {http://dx.doi.org/10.1245/s10434-010-1028-x},
  volume       = {17},
  year         = {2010},
}

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