PACLITAXEL
Antineoplastic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
Paclitaxel produces embryo–fetal toxicity, including teratogenicity, in animals. In addition, the drug was clastogenic with in vitro and in vivo tests. In animals, compared with the free drug, liposome encapsulation of paclitaxel appears to markedly increase the dose at which toxicity and teratogenicity are observed. Whether this also would occur in human pregnancy is not known. The human pregnancy experience is limited to use in the 2nd and 3rd trimesters. No fetal or newborn toxicity have been reported following this use. Based on the animal data, the use of paclitaxel during organogenesis should be avoided if possible. Use after this period appears to be relatively low risk, but the fetus should be monitored appropriately. (See Carboplatin for additional data.)
FETAL RISK SUMMARY
Paclitaxel, an antineoplastic agent, is indicated for the treatment of advanced ovarian cancer but also is used in other malignancies. The drug is a natural product obtained by extraction from Taxus brevifolia (Pacific yew tree) (1,2). Paclitaxel is an antimicrotubule agent, an action that results in the inhibition of the normal reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. It is in the same subclass of taxoids as docetaxel and cabazitaxel. The pharmacokinetics of paclitaxel are markedly affected by the dose and infusion rate with elimination half-lives varying from approximately 13 to 53 hours. Approximately 89%–98% of the agent is protein bound (1). The free commercial form of paclitaxel contains the vehicle polyoxyethylated castor oil (also known as polyoxyl 35 castor oil) (1,2).
Reproduction studies in pregnant rabbits at doses about 0.2 times the maximum recommended human daily dose based on BSA (MRHDD) caused embryo and fetal toxicity (increased resorptions and intrauterine deaths). However, maternal toxicity was observed at this dose. No teratogenic effects were noted at a dose about 0.07 times the MRHDD, but the teratogenic potential of higher doses could not be assessed because of extensive fetal mortality (1).
The carcinogenic potential of paclitaxel has not been studied. The drug was not mutagenic in one test but was clastogenic in vitro (human lymphocytes) and in vivo (micronucleus test in mice). Fertility in male and female rats was impaired at doses about 0.04 times the MRHDD, and at this dose, increased embryo and fetal toxicity was observed (1).
Interestingly, a 1995 research report concluded that some, paclitaxel-induced, embryotoxicity in animals might be due to the polyoxyethylated castor oil vehicle (2). In an experiment with chick embryos, the researchers compared free paclitaxel containing the vehicle with liposome-encapsulated paclitaxel. At a dose of 1.5 mcg per egg, 60% of the embryos either died or were malformed. A 20-fold higher dose was required to produce the same degree of toxicity with the liposome-encapsulated product (2).
In a follow-up to the above study, the same group of researchers compared the developmental toxicity in rats of free and encapsulated paclitaxel (3). Free paclitaxel, at a dose of 10 mg/kg (approximately 0.4 times the MRHDD) given IV once on gestation day 8 (determined to be the most sensitive day for the production of paclitaxel-induced malformations), produced maternal toxicity and resorption of all embryos in surviving dams. At 2 mg/kg (about 0.08 times the MRHDD) of free paclitaxel, embryo–fetal toxicity (increased resorptions and reduced fetal weight) and anomalies (exencephaly, anencephaly, ventral wall defects, facial clefts, anophthalmia, diaphragmatic hernia, and malformations of the kidney, cardiovascular system, and tail) were observed (3). In contrast, no toxicity or anomalies were observed with a 2 mg/kg IV dose of encapsulated paclitaxel. At 10 mg/kg, toxicity and malformations were noted that were similar to those observed with the free drug at 2 mg/kg. Thus, encapsulation appeared to increase the dose needed to produce toxicity and malformations (3). However, encapsulation of paclitaxel could markedly increase or decrease the amount of drug crossing the placenta to the fetus. The authors of the study cited examples in perfused in vitro human placentas in which liposome encapsulation reduced placental transfer. In contrast, they also cited studies in intact rats and rabbits that have shown that encapsulation enhanced placental transfer, possibly by a process involving placental intracellular sequestration and degradation of liposomes (3).
Although the molecular weight (about 854) suggests that paclitaxel will cross the placenta, the extensive protein binding might limit the exposure of the embryo or fetus. Of interest, in an in vitro model, paclitaxel slowly crossed the human placenta to the fetal side (4).
In a novel case report, a 21-year-old woman was diagnosed with metastatic ovarian cancer that was initially treated with surgery that left her uterus, right fallopian tube, and ovary in situ (5). She was then enrolled into a phase I transplant protocol and received three cycles of paclitaxel (225 mg/m2
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