Metabolic Agent (Growth Hormone Receptor Antagonist)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The limited human data, as well as the animal data, suggest that use of pegvisomant during human pregnancy represents a low risk of embryo–fetal harm.
FETAL RISK SUMMARY
Pegvisomant, an analog of human growth hormone (GH) that has been structurally altered to act as a GH antagonist, is given as a daily SC injection. The protein is covalently bound to various amounts of polyethylene glycol (PEG) polymers to reduce its clearance rate. Pegvisomant is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-1 (IGF-1). The mean serum elimination half-life is about 6 days (1).
Reproduction studies have been conducted in rabbits. No evidence of teratogenic effects was observed with SC doses up to 10 times the maximum human therapeutic dose based on BSA (MHTD) during organogenesis. However, at the highest dose, a slight increase in postimplantation loss was observed (1).
In long-term studies for carcinogenic potential in rats, an increase in malignant fibrous histiocytoma at injection sites in male rats but not in female rats was observed. The tumors were thought to have been caused by irritation and the high sensitivity of the rat to repeated SC injections. Multiple assays for mutagenicity were negative. There was no effect on fertility or reproductive performance of female rabbits at SC doses up to 10 times the MHTD (1).
It is not known if pegvisomant crosses the human placenta. Although the elimination half-life is prolonged, the protein is bound to various amounts of PEG polymers yielding predominant molecular weights of 42,000–52,000. This suggests that little if any of the drug will cross to the embryo–fetus. In a case discussed below, analysis of a cord blood sample at term revealed a minimal concentration of the protein.
A 2006 case report described the use of pegvisomant (20 mg SC daily) in a 29-year-old woman with active acromegaly who underwent in vitro fertilization (2). A positive pregnancy test was documented 2 weeks later and pegvisomant was discontinued. She eventually gave birth to a healthy, 3.5-kg male infant who was physically and developmentally normal at 1 year of age (2).
Another case report described the use of pegvisomant throughout the pregnancy of a 26-year-old woman with acromegaly (3). The woman conceived during the 13th month of pegvisomant therapy while receiving 15 mg/day. The dose was increased to 20 mg/day at 1 month and to 25 mg/day at 3 months for the remainder of the pregnancy. At 40 weeks’ gestation, she underwent a cesarean section to give birth to 3.8 kg female infant with Apgar scores of 9 and 9. The infant’s weight, length, and head circumference were at the 75th percentile. GH and IGF-1 concentrations in cord blood were within the normal range and a pegvisomant concentration was minimal (112 ng/mL). These findings suggested that pegvisomant had no effect on fetal GH or IGF-1 interactions. At 6 months of age, the infant was healthy and achieving normal developmental milestones (3).
A 2005 review of acromegaly pharmacotherapy stated that pegvisomant should not be used in pregnancy (4). However, no studies of the drug in pregnancy were cited. In contrast, a 2012 review of acromegaly concluded that treatment of the disease in pregnancy does not cause teratogenicity or significant complications (5).
BREASTFEEDING SUMMARY
No reports describing the use of pegvisomant during human breastfeeding have been located. However, in a case report discussed earlier, a mother receiving 25 mg/day of the protein had undetectable concentrations (<50 ng/mL) in her milk (4). The timing of the sample relative to the last dose or the time after birth was not reported. The concentration of GH in her breast milk was 0.6 ng/mL, whereas the GH concentration in three milk samples from normal healthy mothers was consistently <0.1 ng/mL (4).
In the above study, the undetectable pegvisomant concentration in milk is consistent with the high molecular weights (42,000–52,000) of PEG-bound pegvisomant. Moreover, even if some of the protein is excreted into milk, it would most likely be digested in the infant’s gut and not absorbed.
References
1.Product information. Somavert. Pharmacia & Upjohn, 2010.
2.Qureshi A, Kalu E, Ramanathan G, Bano G, Croucher C, Panahloo A. IVF/ICSI in a woman with active acromegaly: successful outcome following treatment with pegvisomant. J Assist Reprod Genet 2006;23:439–42.
3.Brian SR, Bidlingmaier M, Wajnrajch MP, Weinzimer SA, Inzucchi SE. Treatment of acromegaly with pegvisomant during pregnancy: maternal and fetal effects. J Clin Endocrinol Metab 2007;92:3374–7.
4.Biermasz NR, Romijn JA, Pereira AM, Roelfsema F. Current pharmacotherapy for acromegaly: a review. Expert Opin Pharmacother 2005;6:2393–405.
5.Cheng S, Grasso L, Martinez-Orozco JA, Al-Agha R, Pivonello R, Colao A, Ezzat S. Pregnancy in acromegaly: experience from two referral centers and systematic review of the literature. Clin Endocrinol (Oxf) 2012;76:264–71.