Calcium Receptor Agonist
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Two reports described the use of cinacalcet late in the 3rd trimester, but information on the newborn condition was provided only in one case. Cinacalcet is the first member of a new drug class, so there are no other comparable agents. Moreover, therapy in most patients will be prolonged (months). Animal data do show developmental toxicity (growth restriction) but maternal toxicity also was evident. The near absence of human pregnancy experience prevents a more complete assessment of the embryo–fetal risk. Nevertheless, if a woman’s condition requires cinacalcet, it should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Cinacalcet increases the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. It is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis. It also is indicated for the treatment of hypercalcemia in patients with parathyroid carcinoma. Cinacalcet is rapidly and extensively metabolized to inactive metabolites. The terminal half-life is 30–40 hours and plasma protein binding is 93%–97% (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, no teratogenicity was observed with daily oral doses that produced exposures up to four times those resulting with a human dose of 180 mg/day based on AUC (HE). Decreased fetal weights were observed with daily doses producing exposures that were less than one to four times the HE, but maternal toxicity (decreased food consumption and body weight gain) also was noted. Daily doses that produced exposures less than the HE given during gestation through lactation revealed no evidence of adverse fetal or pup (postweaning) effects. When higher doses were given (two to three times the HE), maternal signs of hypocalcemia (periparturient mortality and early postnatal pup death) and reductions in postnatal maternal and pup weight were noted. In pregnant rabbits, daily oral doses that produced exposures less than the HE revealed no evidence of fetal harm, but maternal toxicity (reduced food consumption and body weight gain) was observed (1).
No evidence of carcinogenic effects was observed in long-term studies in mice and rats.
Assays for mutagenicity were negative. In fertility studies in male and female rats, only daily doses producing exposures greater than four times the HE were associated with slight toxicity (decreases in food consumption and body weight) (1).
It is not known if cinacalcet crosses the human placenta. The drug crosses the rabbit placenta (1). The molecular weight (about 358 for the free base) and long terminal half-life suggest that the drug will cross to the embryo and fetus. However, the extensive metabolism and high plasma protein binding should decrease the exposure to the parent drug.
A 2009 case report described a pregnant 40-year-old woman with severe primary hyperparathyroidism (2). She presented at 32 weeks’ gestation with hypertension and hypercalcemia. Treatment with cinacalcet (240 mg/day) and calcitonin (100 mcg SC every other day) decreased the serum calcium. A planned cesarean section delivery was conducted at 34 weeks. No information on the newborn was provided, except that the cord blood had elevated calcium as compared to the mother’s blood, indicating that the physiological calcium gradient between the mother and the child had not been disrupted by cinacalcet (2).
In a 2013 report, a 21-year-old woman with primary hyperparathyroidism attributable to parathyromatosis presented with markedly elevated total calcium and ionized calcium levels at 14 weeks’ gestation (3). She underwent surgery at 22 weeks to remove hypercellular parathyroid tissue. Because of persistent hypercalcemia that was increasing, cinacalcet (30 mg/day) was started at 33 weeks’ gestation and was successful in decreasing the calcium levels. At 38 weeks, a cesarean section delivered a healthy male infant. Other than that he was doing well at 6 weeks of age; no other details about the infant were provided (3).
BREASTFEEDING SUMMARY
No reports describing the use of cinacalcet during human lactation have been located. The molecular weight (about 358 for the free base) and long terminal half-life (30–40 hours) suggest that the drug will be excreted into breast milk. However, the extensive metabolism and high plasma protein binding (93%–97%) should decrease the amount of parent drug in milk. The effect of this exposure on a nursing infant is unknown, but nausea/vomiting, the most common toxicity observed in adults, and hypocalcemia are potential adverse effects. The latter toxicity is particularly worrisome because of an infant’s high requirements for calcium during bone accretion.
References
1.Product information. Sensipar. Amgen, 2007.
2.Horjus C, Groot I, Telting D, van Setten P, van Sorge A, Kovacs CS, Hermus A, de Boer H. Cincacalcet for hyperparathyroidism in pregnancy and puerperium. J Pediatr Endocrinol Metab 2009;22:741–9.
3.Edling KL, Korenman SG, Janzen C, Sohsman MY, Apple SK, Bhuta S, Yeh MW. A pregnant dilemma: primary hyperthyroidism due to parathyromatosis in pregnancy. Endo Pract 2013;6:1–15.