Abstract
BackgroundThe safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The recommended dose is 0.5 mg/kg subcutaneously once yearly.MethodsStudy 1: safety margin was evaluated as 3 treatments of PH 12 (0× (control); 1× (recommended dose); 3× (3 times recommended dose) and 5× (5 times recommended dose) in 12 months via clinical observations, body weights, food consumption, injection site observations, physical examinations, moxidectin tissue assay, pharmacokinetics, and clinical and anatomic pathology. Study 2: safety in breeding-age males was demonstrated by semen testing at 14-day intervals from Day 7 to Day 91 post-treatment (0× or 3×). Study 3: reproductive safety in females was demonstrated by monitoring dams and litters following treatments (0× or 3×) administered during breeding, gestation, or lactation. Study 4: safety in dogs surgically implanted with adult heartworms was evaluated by clinical and laboratory monitoring following treatment with 0× or 3× administered 61 days post-implantation. Study 5: safety in ivermectin-sensitive dogs (120 µg/kg SC) was by clinical monitoring for 1 week after administering 1×, 3× or 5×.ResultsStudy 1: slight swelling clinically detectable at some 3× and 5× injection sites was characterized microscopically as granulomatous inflammation, like tissue responses to medical implants, interpreted as non-adverse. Pharmacokinetics were dose-proportional and there was little or no systemic accumulation. Residual moxidectin mean (range) at 1× injection sites after 1 year was 16.0% (0.045–37.6%) of the administered mass. Studies 2 and 3: no effects were identified in reproductive indices (females) or semen quality characteristics (males). Study 4: PH 12 produced marked reductions in circulating microfilariae and lower numbers of adult heartworms, but no adverse clinical signs were identified. Study 5: there were no abnormal clinical signs at 1×, 3× or 5× overdoses of PH 12 in ivermectin-sensitive dogs.ConclusionsPH 12 has a > 5× safety margin in both normal and ivermectin-sensitive dogs, has no effects on canine reproduction, and is well tolerated in heartworm-positive dogs. The only treatment-related finding was non-adverse, granulomatous inflammation at the injection site.
Highlights
The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies
In the USA, ProHeart® 6 (PH 6) employs the same microsphere suspension as PH 12 at a lower dosage that protects against heartworm disease for 6 months
The expert reports will be briefly summarized in the “Discussion” section as they extend the interpretation of target animal safety of PH 12 in dogs
Summary
The safety of ProHeart® 12 (PH 12; extended-release injectable suspension; 10% moxidectin in glyceryl tristearate microspheres) was evaluated in four studies using Beagle dogs and one study using ivermectin-sensitive Collies. The heartworm preventative P roHeart® SR-12 (PH 12; Zoetis, Parsippany, NJ) is an extended-release microsphere suspension formulation of moxidectin that provides continuous heartworm prophylaxis for 1 year following subcutaneous injection. After introduction of PH 6 to the USA market, concerns were raised about severe anaphylactoid responses in the first 48 hours post-treatment. The former manufacturer (Fort Dodge Animal Health; Overland Park, KS, USA) initiated an extensive pharmacovigilance (PV) monitoring program, which included agreement to report all adverse reactions. Given the comparability between the PH 6 PV profile and that of PH 12 internationally, that owner non-compliance continues to be an issue with monthly-use heartworm preventative products, and that the once-yearly dose interval for PH12 provides inherently superior compliance, Zoetis elected to seek approval for marketing of PH 12 in the USA. The safety objectives for PH 12 studies outlined in this article and in McTier et al [1] were extended as feasible to elucidating the origin and incidence of hypersensitivityrelated responses if any should be observed
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