title: Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.
abstract: OBJECTIVE
  To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents.
  
  
  METHODS
  A preclinical and a clinical case-control trial.
  
  
  METHODS
  Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Obstetrics & Gynecology, Division of Gynecological Oncology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Calsteren
authors.forename: René
authors.initials: R
authors.lastname: Verbesselt
authors.forename: Nelleke
authors.initials: N
authors.lastname: Ottevanger
authors.forename: Michael
authors.initials: M
authors.lastname: Halaska
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Heyns
authors.forename: Rieta
authors.initials: R
authors.lastname: Van Bree
authors.forename: Ernst
authors.initials: E
authors.lastname: de Bruijn
authors.forename: Daniel
authors.initials: D
authors.lastname: Chai
authors.forename: Michel
authors.initials: M
authors.lastname: Delforge
authors.forename: Lucien
authors.initials: L
authors.lastname: Noens
authors.forename: Vincent
authors.initials: V
authors.lastname: Renard
authors.forename: Els
authors.initials: E
authors.lastname: Witteveen
authors.forename: Lukas
authors.initials: L
authors.lastname: Rob
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001761:Bleomycin / Q000493:pharmacokinetics; D016190:Carboplatin / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000493:pharmacokinetics; D015251:Epirubicin / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D023421:Models, Animal; D017239:Paclitaxel / Q000493:pharmacokinetics; D010215:Papio; D011247:Pregnancy / Q000097:blood / Q000378:metabolism*; D013054:Spectrophotometry, Atomic; D014747:Vinblastine / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D001761:Bleomycin; D015251:Epirubicin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel