Developmental Toxicity in the Pregnant Rabbit by theClass III Antiarrhythmic Drug Sotalol

Abstract

The purpose of this study was to investigate the potential of sotalol to cause developmental toxicity in the pregnant rabbit. Sotalol is a b-adrenoceptor blocking drug which also has class III antiarrhythmic properties via Ikr channel blockade. Experiment 1: Nine pregnant New Zealand White rabbits were given doses of either 300, 225, or 150 mg/kg of sotalol during gestational days, called Days, 13-16 which resulted in total litter loss. Experiment 2: A single dose of sotalol, 100 or 150 mg/kg was administered during Days 8-17 to 15 rabbits. Dosing on Day 8, 9, or 10 resulted in a slightly higher incidence of embryonic death compared to historical controls. There was marked increased embryonic death of 55-90% (four does with total litter loss), decreased number of live foetuses per litter, and elevated mean foetal weight after dosing during Days 12-16. Experiment 3: 16 pregnant rabbits were administered single doses of sotalol of either 100, 85, 75, 60 or 50 mg/kg on Day 14. The main finding was increased embryonic death, which ranged from total litter loss to ∂30% at 50 mg/kg. At 50 mg/kg, the maternal C max , AUC 1-24 hr , and t 1/2 were approximately 45 mM, 340 mmol¿hr/l, and 6 hr, respectively. In conclusion, sotalol treatment resulted in embryonic death in the rabbit in early pregnancy in the same way as has been seen for other drugs with Ikr blocking properties (class III antiarrhythmics) in rodents. The observed developmental toxicity in the rabbit is most likely secondary to embryonic arrhythmia as has been shown in rodent studies. The results may indicate that Ikr blocking agents are developmental toxicants across species including man.

Pregnancy Outcomes in Women With Congenital Heart Disease

“…Class III antiarrhythmic agents such as sotalol have been shown to increase the incidence of embryonic deaths in animal studies. 16 Of live offspring, the 7% rate of cardiac anomalies is identical to a previously reported recurrence rate in mothers with congenital heart disease 4 and 10-fold higher than the population at large. 17 The primary cardiac event rate of 19.4% observed in this study is comparable to the 23.5% incidence described in a large cohort of pregnant women with heart disease, of whom 19.1% had underlying congenital heart malformations.…”

Maternal cardiac arrhythmias during pregnancy and lactation

“…Sotalol may be teratogenic, although data are inconclusive. 52,53 Given these ambiguities it is not a first choice antiarrhythmic; however in some difficult cases its use is warranted and complications are rare. Close fetal monitoring is essential.…”

Effect of Rythmol (propafenone HCl) administration during pregnancy in Wistar rats

“…We showed that there was a significant difference between the mean number of viable fetuses in the treated pregnant females and those in the control pregnant rats. This corresponded with Skold and Danielsson [47] who investigated the potential of sotalol, which is a 3-adrenoceptor blocking drug that has family III antiarrhythmic characteristics through IBr channel blockade that can lead to toxicity during the pregnancy of rabbits. This study's results revealed that only one dose of sotalol, 100 or 150 mg/kg on Days 8, 9, or 10 generated a slightly greater rate of dead embryos parallel to historic control animals.…”