Keratinocyte Growth Factor
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of palifermin in human pregnancy have been located. The animal reproduction data suggest risk of developmental toxicity, but the embryo–fetal effects (growth restriction and death) might have been secondary to maternal toxicity. Importantly, the no-effect doses in two animal species were close to the human dose (based on body weight). A more informative dose comparison (BSA or AUC) was not provided by the manufacturer. The use of this agent by a pregnant patient implies that she also will receive or has received chemotherapy that is toxic to the bone marrow and oral mucosa, and possibly to her embryo or fetus as well. The addition of palifermin to decrease maternal oral mucosal toxicity and to allow a more rapid return to a normal intake of food and fluids appears to be an overall embryo–fetal benefit. In this context, although the absence of human pregnancy experience prevents an assessment of the potential for embryo–fetal harm, the maternal benefit appears to outweigh this unknown risk.
FETAL RISK SUMMARY
Palifermin, a water-soluble, 140 amino acid protein produced by recombinant DNA technology, is a human keratinocyte growth factor (KGF). It is indicated to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support (1). KGF is an endogenous protein in the fibroblast growth factor family. It binds to the KGF receptor that is present on epithelial cells in many tissues (e.g., throughout the gastrointestinal tract), resulting in proliferation, differentiation, and migration of epithelial cells. Palifermin is given as a daily IV bolus dose for 3 days before and after myelotoxic therapy (total of six doses). The elimination half-life is about 4.5 hours (range 3.3–5.7 hours) (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, IV doses 8 or more times the recommended human dose based on body weight (RHD) were associated with increased postimplantation loss, decreased fetal body weight, and/or increased skeletal variations. These doses also were maternal toxic (clinical signs and decreased body weight gain/food consumption). The no-effect dose for developmental toxicity was 4.8 times the RHD. Systemic toxicity in male and female rats was observed at a dose 5 times the RHD, and the fertility index was decreased at a dose about 16 times the RHD. In pregnant rabbits, increased postimplantation losses and decreased fetal body weights were observed at IV doses 2.5 times the RHD. This dose produced maternal toxicity similar to that observed in rats. The no-effect dose for developmental toxicity in the rabbit was equal to the RHD (1).
The carcinogenic potential of palifermin has not been studied in animals. Palifermin has been shown to enhance the growth of human epithelial tumor cell lines in vitro and to increase the rate of tumor cell line growth in a human xenograft model (1). No clastogenic or mutagenic effects were observed in assays (1).
It is not known if palifermin crosses the human placenta. The molecular weight of the protein (about 16,300) should preclude passive diffusion, but active transfer, such as occurs with immunoglobulins, is possible. Moreover, as an endogenous protein, KGF is present in the embryo and fetus.
BREASTFEEDING SUMMARY
No reports describing the use of palifermin during human lactation have been located. Although this protein has a high molecular weight (16,300), it might be excreted into breast milk, as are other proteins (e.g., antibodies). The effects of this exposure on a nursing infant are unknown, but palifermin would most likely be broken down to its constituent amino acids or fragments thereof in the infant’s digestive tract. However, because it stimulates the proliferation, differentiation, and migration of epithelial cells, including epithelial tumor cell lines, the best course is to stop breastfeeding when the mother is being treated. Moreover, the use of palifermin implies that the mother also has received or is receiving myelotoxic chemotherapy, and exposure of a nursing infant to these agents should be avoided.
Reference
1.Product information. Kepivance. Amgen, 2004.