Antineoplastic (Antiandrogen)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of enzalutamide in human pregnancy have been located. However, such reports are unlikely because of the indication. Animal reproductive studies have not been conducted. If the drug was used in pregnancy, the mechanism of action suggests that it could cause fetal harm. A 2013 study concluded that the androgen receptor was a key regulator for myometrial cell proliferation and disruption of myometrial growth could affect the outcome of pregnancy and labor (1).
FETAL RISK SUMMARY
Enzalutamide is an oral antineoplastic that is given daily (160 mg/day). It is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. The drug undergoes hepatic metabolism to an active and inactive metabolites. Enzalutamide is 97%–98% bound to plasma proteins, primarily to albumin, whereas the active metabolite is 95% bound to plasma protein. The mean terminal half-life after a single dose in patients is 5.8 days (range 2.8–10.2 days). After a single 160 mg dose in healthy volunteers, the mean terminal half-life for the active metabolite was about 7.8–10.6 days (2).
Reproduction studies in animals have not been conducted (2).
Long-term animal studies to evaluate the potential for carcinogenicity have not been conducted. The drug was not mutagenic in multiple assays. In a long-term study in male rats, atrophy of the prostate and seminal vesicles was observed at dose that was equal to the human exposure based on AUC (HE). In dogs, hypospermatogenesis and atrophy of the prostate and epididymides was observed at a dose that was 0.3 times the HE (2).
It is not known if enzalutamide or its active metabolite cross the human placenta. The molecular weight (about 464) and the long elimination half-life suggest that the drug will cross to the embryo–fetus, although the high plasma protein binding (97%–98%) might limit the amount crossing.
BREASTFEEDING SUMMARY
No reports describing the use of enzalutamide during human lactation have been located. However, such reports are unlikely because of the indication. Nevertheless, if the drug was used during breastfeeding, the molecular weight (about 464) of the parent drug and its long mean elimination half-life (5.8 days; range 2.8–10.2 days) in patients suggest that the drug will be excreted into breast milk, although the high plasma protein binding (97%–98%) might limit the amount excreted.
References
1.Liu L, Li Y, Xie N, Shynlova O, Challis JRG, Slater D, Lye S, Dong X. Proliferative action of the androgen receptor in human uterine myometrial cells—a key regulator for myometrium phenotype programming. J Clin Endocrinol Metab 2013;98:218–27.
2.Product information. Xtandi. Astellas Pharma US, 2012.