Evaluation of Teratogenic Profile of Combination of Lumacaftor and Ivacaftor in Sprague–Dawley Rats

Abstract

Background: The individual teratogenicity profiles of Lumacaftor and Ivacaftor are known, but the combined effects remain unexplored. Purpose: To evaluate the teratogenic profile of a combination of Lumacaftor and Ivacaftor in Sprague-Dawley Rats. Methods: This study adhered to the Committee for Control and Supervision of Experiments on Animals (CCSEA) and Organisation for Economic Co-operation and Development (OECD) guidelines. Sprague–Dawley rats were acclimated and housed individually under controlled conditions. A polygamous breeding scheme was implemented, and pregnant female rats were assigned to control, vehicle control or treatment group following OECD Test Guideline 414. Lumacaftor and Ivacaftor were administered to pregnant rats at various doses, such as MRHD, 5MRHD, 8MRHD and 10MRHD, from gestation days 6 to 17. Clinical observations, body weight and food consumption of pregnant rats were monitored. Postmortem examinations included caesarean section, reproductive performance (the number of corpora lutea, implantation sites, early and late resorptions and live foetuses) and assessment of foetal analysis. The foetal analysis incorporated external malformation evaluation, visceral examination and skeletal examination using alizarin red solution. Results: In pregnant rats exposed to Lumacaftor and Ivacaftor, the external examination was conducted on 206, 209, 199, 184, 198 and 201 foetuses in their respective groups, each consisting of 19 litters. Within this cohort, approximately 33% of foetuses underwent visceral examination. Additionally, across six groups approximately 50% of foetuses underwent skeletal examination. Importantly, no abnormalities were detected in skeletal, visceral or histopathological assessments across the treatment groups encompassing doses of a combination of Lumacaftor and Ivacaftor at MRHD, 5MRHD, 8MRHD and 10MRHD. Additionally, no significant morbidity or mortality related to the treatment was observed. Conclusion: In conclusion, the study indicates that the combination of Lumacaftor and Ivacaftor at doses equivalent to MRHD, 5MRHD, 8MRHD and 10MRHD did not induce significant teratogenic effects, affirming their safety during pregnancy in rats.