Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study.
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.
Van Calsteren
Kristel
K
Department of Obstetrics & Gynecology, Division of Gynecological Oncology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.
Verbesselt
René
R
Ottevanger
Nelleke
N
Halaska
Michael
M
Heyns
Liesbeth
L
Van Bree
Rieta
R
de Bruijn
Ernst
E
Chai
Daniel
D
Delforge
Michel
M
Noens
Lucien
L
Renard
Vincent
V
Witteveen
Els
E
Rob
Lukas
L
de Hoon
Jan
J
Amant
Frédéric
F
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
D000970:Antineoplastic Agents; D001761:Bleomycin; D015251:Epirubicin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel