Developmental toxicity and toxicokinetics of two endothelin receptor antagonists in rats and rabbits

Abstract

Embryo‐fetal development studies with toxicokinetic evaluations were conducted in rats and rabbits after oral or intravenous administration of two endothelin receptor antagonists. In the rat studies, females were administered SB‐217242 (0.01–300 mg/kg/day) orally or SB‐209670 (0.01–50 mg/kg/day) intravenously from days 6–17 postcoitus (pc). External and visceral fetal examinations were performed at necropsy on day 21 pc. Maternal body weight and food consumption were decreased only at 300 mg/kg/day SB‐217242. Embryolethality was seen at 300 mg/kg/day SB‐217242. Decreased fetal body weight occurred at 300 mg/kg/day SB‐217242 and 50 mg/kg/day SB‐209670. Dose‐dependent increases in the mean percentage of fetuses per litter with malformations were seen at ≥50 mg/kg/day SB‐217242 and ≥10 mg/kg/day SB‐209670. Craniofacial, great vessel, heart, and thyroid were the predominant malformations. In the rabbit studies, females were administered SB‐217242 (0.01–50 mg/kg/day) orally or SB‐209670 (0.01–25 mg/kg/day) intravenously from days 6–20 pc. There was no drug‐related effect on maternal body weight or food consumption. Embryolethality was observed at 50 mg/kg/day of SB‐217242. Dose‐related increases in the mean percentage of fetuses per litter with malformations were seen at ≥10 mg/kg/day SB‐217242 and ≥10 mg/kg/day SB‐209670. The malformations were similar to those observed in the rat studies, except that craniofacial development was not altered by SB‐209670. The malformations observed are consistent with the pattern of endothelin‐1 gene expression described in mouse embryonic pharyngeal arches and heart, and with the craniofacial and cardiovascular malformations observed in endothelin‐1‐deficient mice. Given the known role for endothelins in development, and concordant malformations in rats and rabbits observed in this study, teratogenicity is likely to be a class effect of endothelin receptor antagonists. Teratology 59:51–59, 1999. © 1999 Wiley‐Liss, Inc.

Update on endothelins - biology and clinical implications

“…Thus, ET-1/ETA interaction is essential in post-migratory cardiac neural crest cell development, without which aberrant branchial arch artery patterning results. Related to these observations in genetically engineered mice are teratogenicity studies during the preclinical phase of ETA receptor antagonists, which revealed developmental abnormalities that overlapped with the phenotype in mice with gene knockout for preproendothelin-1, and ETA mutants specifically with respect to brachial arch derivatives [29,30].…”

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

“…However, peripheral edema was more frequently observed with ambrisentan when compared to dual ERAs and therefore could hold a risk of intervention and treatment should be discontinued when considered necessary [48][49][50]. ET-1 has a role in various stages of embryo development and, therefore, treatment with ERAs has been observed to cause fetal harm [51,52]. Consequently, all approved ERAs hold a black-box warning for embryo-fetal toxicity and must not be administered to pregnant females [50,53].…”

Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension

“…1). Developmental toxicity studies with ERA's in the rat confirmed these malformations [23,24]. The pattern of fetal cardiovascular malformations is caused by the effect of ERA's on specific neural crest cells in pharyngeal arches 3, 4 and 6 that migrate to the cardiac outflow tract.…”

“…ET-1, ETA, and ET-B expressions are increased in the lungs of animals with experimental pulmonary hypertension [41][42][43]. It has also been demonstrated that administration of ERA's in several animal models resembling [20][21][22][23][24]63,[101][102][103][104]. Due to these preclinical teratogenic observations in rats, rabbits and mice, both FDA and EMA strongly contraindicate the treatment of ERA's during pregnancy as the risk involved outweighs beneficial treatment effects.…”