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Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study

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Abstract
Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. Design. A preclinical and a clinical case-control trial. Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. Population. Pregnant and nonpregnant women and baboons receiving chemotherapy. Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry. Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state. Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy. Conclusions. Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long-term follow-up of women treated with chemotherapy during pregnancy is underscored.
Keywords
pharmacokinetics, Chemotherapy, pregnancy, baboon, RENAL-FUNCTION, PACLITAXEL, TISSUES, FORMULA

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Chicago
Van Calsteren, Kristel, René Verbesselt, Nelleke Ottevanger, Michael Halaska, Liesbeth Heyns, Rieta Van Bree, Ernst de Bruijn, et al. 2010. “Pharmacokinetics of Chemotherapeutic Agents in Pregnancy: a Preclinical and Clinical Study.” Acta Obstetricia Et Gynecologica Scandinavica 89 (10): 1338–1345.
APA
Van Calsteren, K., Verbesselt, R., Ottevanger, N., Halaska, M., Heyns, L., Van Bree, R., de Bruijn, E., et al. (2010). Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA, 89(10), 1338–1345.
Vancouver
1.
Van Calsteren K, Verbesselt R, Ottevanger N, Halaska M, Heyns L, Van Bree R, et al. Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study. ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA. 2010;89(10):1338–45.
MLA
Van Calsteren, Kristel, René Verbesselt, Nelleke Ottevanger, et al. “Pharmacokinetics of Chemotherapeutic Agents in Pregnancy: a Preclinical and Clinical Study.” ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA 89.10 (2010): 1338–1345. Print.
@article{2155132,
  abstract     = {Objective. To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents.
Design. A preclinical and a clinical case-control trial.
Setting. Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic.
Population. Pregnant and nonpregnant women and baboons receiving chemotherapy.
Methods. Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed chemotherapy regimens were administered in pregnant and nonpregnant baboons/women, followed by serial blood samplings. Drug plasma levels were determined using high performance liquid chromatography and atomic absorption spectrometry.
Main outcome measures. Area under the curve (AUC), maximal plasma concentration, terminal elimination half-life, clearance and distribution volume of each drug in pregnant and nonpregnant state.
Results. Intraindividual comparative pharmacokinetic data were obtained for doxorubicin and paclitaxel/platinum in three and two baboons, respectively. In the clinical trial, two patients were exposed to doxorubicin and one patient was exposed to paclitaxel/platinum during and after pregnancy. Furthermore, a pooled analysis was performed based on 16 cycles of pregnant and 11 cycles of nonpregnant women. Numbers of pregnant/nonpregnant patients were 5/2, 7/5, 4/4 and 2/2 for paclitaxel, doxorubicin, epirubicin and platinum, respectively. For all drugs tested in the preclinical and clinical study, a decreased AUC and maximal plasma concentration and an increased distribution volume and clearance were observed in pregnancy.
Conclusions. Although numbers were too small for statistical significance, pregnancy-associated physiologic alterations appear to lead to a decrease in plasma exposure of chemotherapeutic drugs. The importance of long-term follow-up of women treated with chemotherapy during pregnancy is underscored.},
  author       = {Van Calsteren, Kristel and Verbesselt, Ren{\'e} and Ottevanger, Nelleke and Halaska, Michael and Heyns, Liesbeth and Van Bree, Rieta and de Bruijn, Ernst and Chai, Daniel and Delforge, Michel and Noens, Lucien and Renard, Vincent and Witteveen, Els and Rob, Lukas and de Hoon, Jan and Amant, Fr{\'e}d{\'e}ric},
  issn         = {0001-6349},
  journal      = {ACTA OBSTETRICIA ET GYNECOLOGICA SCANDINAVICA},
  keyword      = {pharmacokinetics,Chemotherapy,pregnancy,baboon,RENAL-FUNCTION,PACLITAXEL,TISSUES,FORMULA},
  language     = {eng},
  number       = {10},
  pages        = {1338--1345},
  title        = {Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study},
  url          = {http://dx.doi.org/10.3109/00016349.2010.512070},
  volume       = {89},
  year         = {2010},
}

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