Safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs
Authors: Mathur Sheerin , Malpas Phyllis B , Mahabir Sean , Boucher Joseph , Pullins Aleah , Gagnon Genevieve , McTier Tom L. , Maeder Steven 
Published: January 2023

Background
Assessment of the safety of heartworm preventatives in dogs with pre-existing, patent, heartworm (Dirofilaria immitis) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of 3 consecutive monthly treatments of Simparica Trio.
Methods
Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate) and once infection was patent, were randomized equally among 3 groups to receive negative control, 1X, or 3X of the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56 as whole tablets to achieve the maximum recommended label dose 2.4 mg/kg of sarolaner + 10 mg/kg pyrantel + 48 µg/kg (0.048 mg/kg) moxidectin. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption, and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts, and D. immitis antigen testing. At the end of the study the heart, lungs, and pleural and peritoneal cavities were examined for adult D. immitis worms.
Results
Simparica Trio was generally well-tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in 1X and 3X groups throughout the 3-month study. Fever (> 104°F/40°C) was recorded in one 1X and one 3X dog one day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/mL at study start (Day 0) to > 20,000/mL at Day 28 and remained above 20,000/mL for the duration of the study. The least squares mean of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1X group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares mean of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3X group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was fewer than 10 per sex in all groups with 90%, 85%, and 75% of live adult heartworms recovered in control, 1X, and 3X treatment groups, respectively. Low numbers of dead adult worms were recovered in 1X and 3X, with none in control. Following each dose, the moxidectin and sarolaner AUC and Cmax had close to dose proportional increases.
Conclusions
This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well-tolerated when administered to heartworm-positive dogs at 1X, and 3X the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity, but resulted in no clinical sequelae.