Gastrointestinal Agent (Laxative)
PREGNANCY RECOMMENDATION: No Human Data—Probably Compatible
BREASTFEEDING RECOMMENDATION: No Human Data—Probably Compatible
PREGNANCY SUMMARY
No reports describing the use of linaclotide during human pregnancy have been located. Although the animal reproduction data are reassuring, the comparisons to human doses were based on body weight and may not be interpretable. Nevertheless, the absence of quantifiable plasma concentrations of linaclotide and its active metabolite suggest that clinically significant amounts of these agents will not cross to the embryo or fetus.
FETAL RISK SUMMARY
Linaclotide, guanylate cyclase-C agonist, and its active metabolite act locally on the luminal surface of the intestinal epithelium. The parent drug is a 14-amino-acid peptide. Linaclotide is indicated in adults for treatment of irritable bowel syndrome with constipation and for chronic idiopathic constipation. Both linaclotide and its active metabolite are minimally absorbed with plasma concentrations below the limit of quantitation (1).
Reproduction studies have been conducted in rats, rabbits, and mice. In rats and rabbits, oral doses up to 20,000 and 8000 times, respectively, the maximum recommended human dose of about 5 mcg/kg/day based on a 60-kg body weight (MRHD) produced no maternal toxicity and no effects on embryo–fetal development. In mice, oral doses at least 8000 times the MRHD caused severe maternal toxicity including death, reduction of gravid uterine and fetal weights, and effects on fetal morphology. A dose 1000 times the MRHD in mice was not maternal toxic and caused no adverse effects on embryo–fetal development (1).
In 2-year studies, linaclotide was not carcinogenic in rats and mice. Assays for mutagenicity also were negative and the drug had no effect on fertility or reproductive function in male and female rats (1).
It is not known if linaclotide or its active metabolite cross the human placenta. The molecular weight of the parent drug (about 1527) and the absence of quantifiable concentrations of either agent suggest that exposure of the embryo or fetus will be nil. However, both agents are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and cross the placenta.
BREASTFEEDING SUMMARY
No reports describing the use of linaclotide during human lactation have been located. The molecular weight of the parent drug (about 1527) and the absence of quantifiable plasma concentrations of linaclotide or its active metabolite suggest that excretion into breast milk of clinically significant amounts of either agent is unlikely. However, both agents are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids and these may be absorbed and excreted into milk. Nevertheless, the use of linaclotide during breastfeeding appears to be compatible.
Reference
1.Product information. Linzess. Forest Pharmaceuticals, 2012.