DEVELOPMENTAL TOXICITY OF IBUTILIDE FUMARATE IN RATS AFTER ORAL-ADMINISTRATION

In two Segment II Teratology studies, timed-pregnant Crl:CD[BR] (Sprag ue-Dawley) rats were treated orally (gastric intubation) on days 6-15 of gestation with ibutilide fumarate (ibutilide), a class III antiarrh ythmic that has been shown to increase the refractory period and actio n potential duration of myocardial cells. in the first study, ibutilid e does of 20, 40, and 80 mg/kg/day were tested. Although maternal toxi city was equivocal in the 80 mg/kg/day group, all 23 rats that conceiv ed had entirely resorbed liters when the animals were killed on day 20 of gestation. Similarly, 12 of 24 litters were completely resorbed in the 40 mg/kg/day group, with an 87.7% postimplantational toss. Of the surviving fetuses in this group, 48.6% had at least one malformation. The incidences of malformed pharynx and malformed palate, along with adactyly, were statistically significantly higher in this group than i n the control group. In addition, a significant (P < 0.05) increase in fetal malformations (5.7% of the fetuses), relative to the controls ( 0.8%), was found for the 20 mg/kg/day group. Since a no observed adver se effect level (NOAEL) was not found, a second teratology study was p erformed. In this study, the ibutilide doses were 5, 10, and 20 mg/kg/ day. The 20 mg/kg/day dose was again teratogenic with 9.2% of the fetu ses malformed, as compared to a control value of 1.0%. Also, the incid ences of scoliosis and interventricular septal defect were statistical ly significantly higher in this group. Although statistically signific ant differences were not detected, scoliosis was also found in the 10 mg/kg/day group (3 fetuses in 2 litters), along with a significant dos e-response trend for this malformation. As the result, the NOAEL for i butilide teratogenicity in rats was set at 5 mg/kg/day. This dose is 4 times the proposed maximum clinical dose (two 1 mg doses, each infuse d over 10 minutes, or 0.033 mg/kg for a 60 kg person), when corrected for 2.6% oral bioavailability in the rat at a dose of 10 mg/kg, as det ermined in separate studies. (C) 1996 Wilet-Liss, Inc.