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. 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.

How much platinum passes the placental barrier? Analysis of platinum applications in 21 patients with cervical cancer during pregnancy

“…19 Because of the inherent low molecular weight, most parts of the cytotoxic agentsmaycrosstheplacentaandreachthe fetus. Nevertheless, the exact transport mechanism is not known.…”

“…18 Several pharmacokinetic studies on animals have confirmed these hypotheses. [19][20][21] Despite the fact that platinum-based chemotherapy is the most frequently used systemic therapy in pregnant women with cervical cancer, only 1 small study and 1 case report have analysed maternofetal passage of cisplatinum. 22,23 It was therefore the intention of the present prospective study to extend the current literature data about the safety of chemotherapy during gestation and to reinforce our own results on in vivo measurement of platinum concentrations.…”

Treatment of lymphoma and cardiac monitoring during pregnancy

“…A study by Van Calsteren et al (6), suggested that serum levels of chemotherapy, including anthracyclines, measured in pregnant women, were lower compared with those in nonpregnant women although the differences were not statistically significant. Despite the lower serum levels, cardiotoxicity might have a more significant impact on the maternal cardiovascular system in a context of increased hemodynamic loading.…”

Taxanes during Pregnancy: Probably Safe, but Still to Be Optimized

“…To date, little is known about the optimal dosing regimen for taxanes in pregnant patients because clinical pharmacokinetic studies are scarce [7,8]. These data indicate that pregnant patients receiving paclitaxel had lower AUC and higher clearance compared to nonpregnant patients.…”