Antineoplastic (Tyrosine Kinase Inhibitor)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
The human pregnancy experience with lapatinib is very limited. The animal reproduction studies suggest moderate risk. The no-observed-effect-level (NOEL) in animals was ≤1 times the human clinical exposure based on AUC (HCE). Although the near absence of human pregnancy experience prevents a complete assessment of the embryo–fetal risk, the drug should be avoided in pregnancy. If it must be administered for the mother’s benefit, avoiding the period of organogenesis should be considered.
FETAL RISK SUMMARY
Lapatinib is an intracellular tyrosine kinase inhibitor that is indicated, in combination with capecitabine (see Capecitabine), for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress human epidermal receptor type 2 (HER2) and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab. There are no other agents in this subclass (see Appendix). Lapatinib is extensively metabolized to inactive metabolites. Plasma protein binding to albumin and α-1 acid glycoprotein is >99%. The terminal phase half-life following repeated dosing is 24 hours (1).
Reproduction studies have been conducted in rats and rabbits. Pregnant rats were given doses during organogenesis and through lactation that produced systemic exposures that were about 6.4 times the HCE. At this exposure, 91% of the pups died by the 4th day after birth, but this dose also caused maternal toxicity. When half of the dose was used (about 3.3 times the HCE), 34% of the pups died. The NOEL was about equal to the HCE. There were no teratogenic effects at the highest exposure, but minor anomalies observed were left-sided umbilical artery, cervical rib, and precocious ossification. In rabbits, maternal toxicity was observed at doses resulting in exposures that were about 0.07 and 0.2 times the HCE. Decreased fetal body weights and minor skeletal variations were noted at both doses, and abortions were observed at the higher dose (1).
Carcinogenicity studies have not been completed. Lapatinib was not clastogenic or mutagenic in a variety of assays. There were no effects on mating or fertility in female and male rats given doses producing exposures that were 6.4 and 2.6 times the HCE, respectively. However, in female rats, this exposure during breeding and through the first 6 days of gestation was associated with a significant decrease in the number of live fetuses. At about 3.3 times the HCE, there was a significant decrease in fetal body weights (1).
It is not known if lapatinib crosses the human placenta. Although the high plasma protein binding will inhibit transfer, the molecular weight (about 926 for the nonhydrated form) and the prolonged half-life suggest that embryo–fetus exposure will occur.
A 44-year-old woman with breast cancer conceived while being treated in a phase I clinical trial with lapatinib (2). During the previous 10 years, she had been treated with a number of antineoplastic agents, including cyclophosphamide, doxorubicin, fluorouracil, paclitaxel, trastuzumab, and vinorelbine. She also had undergone a left modified radical mastectomy, regional radiation, and 10 years of tamoxifen. When cancer was discovered in her right breast, she was enrolled in the clinical trial. She was initially treated with lapatinib 1500 mg/day, but the dose was reduced by 50% because of diarrhea and rash. Pregnancy was diagnosed at about 14 weeks’ gestation; conception was thought to have occurred in the 3rd or 4th week of study drug. A modified radical mastectomy was conducted to avoid further antineoplastic treatment. Because of disease progression, labor was induced, and the woman gave birth to a healthy, 2.6-kg female infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. At 18 months of age, the infant was doing well, having reached all developmental milestones on schedule (2).
BREASTFEEDING SUMMARY
No reports describing the use of lapatinib during lactation have been located. Although the high plasma protein binding (>99%) should inhibit excretion, the molecular weight (about 926 for the nonhydrated form) and the prolonged half-life (24 hours) suggest that the drug will be excreted into breast milk. Women receiving lapatinib should not breastfeed because of the potential for toxicity in a nursing infant. The most common toxicities in adults were severe diarrhea, nausea and vomiting, and rash.
References
1.Product information. Tykerb. GlaxoSmithKline, 2007.
2.Kelly H, Graham M, Humes E, Dorflinger LJ, Boggess KA, O’Neil BH, Harris J, Spector NL, Dees EC. Delivery of a healthy baby after first-trimester maternal exposure to lapatinib. Clin Breast Cancer 2006;7:339–41.