Understanding mirabegron toxicity in canine veterinary patients
With a high risk of toxicity and a short window for decontamination, this drug for overactive bladder in people should be on every veterinarian’s radar.
When Pet Poison Helpline began to receive calls about the drug mirabegron, the initial information we obtained regarding human safety gave many of us a temporary sigh of relief. However, after further investigation, we were alarmed to see how highly toxic this medication can be to dogs and how different the effects are between species.
Beta-3 adrenergic receptors are primarily located in adipose tissue and are used for lipolysis and thermogenesis. Their stimulation differentially inhibits insulin signaling and causes relaxation of the bladder wall. Mirabegron, a beta-3 adrenergic receptor agonist, works by relaxing the detrusor smooth muscle in the urinary bladder, thereby increasing bladder capacity and decreasing bladder contractions. In 2012, the drug, marketed under the trade name Myrbetriq, received FDA approval for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and urinary frequency. (The drug has been marketed in Japan since 2011 under the trade name Betanis.)
In addition to binding to beta-3 receptors, the drug is also believed to slightly cross-activate beta-1 receptors and very few beta-2 receptors. Tachycardia is often seen in humans and animals as a result of this cross-activation. It is thought that the tachycardia seen in dogs at low doses is a compensatory response due to the vasodilatory effects of beta-3 agonist stimulation. With higher doses, tachycardia is expected due to beta-1 agonist stimulation.
(GETTY IMAGES/SAWAYASU TSUJI)
Absorption and metabolism
Mirabegron is rapidly absorbed after oral administration. The primary site of absorption in rats is the small intestine and, to a lesser extent, the stomach and colon. The plasma Tmax value in dogs is 0.1 to 4 hours, with the rate being affected by food consumption. Drug absorption is decreased and absorption rate is prolonged if a meal has been ingested. The plasma half-life is four to 10 hours, and the oral bioavailability increases with increasing doses. While plasma protein binding in humans, rabbits and rodents is greater than 75 percent, there is only 61 to 62 percent binding in dogs.
Mirabegron is metabolized by the liver, which predominantly utilizes the cytochrome P450 enzyme, with enterohepatic recirculation present in rats. The route of elimination in dogs was not noted; however, there is both urinary and fecal elimination in rats, monkeys and humans. Placental and milk transmission was shown to occur in rats. Mirabegron does not readily cross the blood-brain barrier.
While mirabegron has been shown to have a low level of toxicity in humans, it has a high degree of toxicity to dogs. Toxicosis may be seen in dogs at doses as low as 0.3 mg/kg, with the maximum non-lethal dose being 3 mg/kg. This is especially concerning as the medication is supplied in 25 and 50 mg tablets. Therefore, one 25 mg tablet may prove toxic to virtually all dogs, as any weight less than 182 lbs (83 kg) results in an ingested dose greater than 0.3 mg/kg.
In dogs, clinical signs seen after low ingestion of mirabegron (0.3 mg/kg) include erythema to the skin, hypotension, tachycardia and disruption or destruction of the zygomatic salivary gland. With increased ingestion, clinical signs include electrocardiogram (ECG) disturbances such as increased PR or QRS intervals, ventricular tachycardia with fibrillation, and death.
Reversible hepatotoxicity was also shown to occur during a two-week repeat-dose study as well as in large, acute ingestion, causing a mild elevation in alkaline phosphatase (ALP) and alanine transaminase (ALT) levels. Hepatic histopathology changes included enlarged and yellow discoloration with mild to moderate hypertrophy, hepatocyte vacuolation, slight glycogen accumulation and mild lipid deposits. Damage to the salivary glands was shown to be partially or completely recovered in surviving patients. While central nervous system abnormalities were seen in rodents and monkeys, none were reported in dogs.
Due to the rapid absorption of mirabegron, clinical signs may be seen as soon as 30 minutes after ingestion, making the window for effective decontamination extremely small. Cardiovascular signs are expected to last an average of eight hours with doses greater than 0.3 mg/kg. Hepatic abnormalities and laboratory values show partial to complete resolution approximately two weeks after ingestion. Salivary gland function and structure also returned to normal within two weeks after ingestion.
The recommended treatment for mirabegron toxicity is as follows:
> Induce emesis, if ingestion is recent and the patient is asymptomatic.
> Perform a baseline complete blood count (CBC) and serum chemistry profile, with a focus on hepatic enzyme activity.
> Administer activated charcoal with a cathartic, followed by one dose of activated charcoal without a cathartic in six to eight hours.
> Provide IV fluid therapy at appropriate doses to help with blood pressure support and perfusion.
> Monitor heart rate, blood pressure and ECG changes closely.
> Consider giving beta-blockers for persistent tachycardia (> 180 bpm).
> Use hepatoprotectants with large ingestions (> 3 mg/kg) for two to three weeks.
Since January 1, 2014, the Pet Poison Helpline has received five calls regarding ingestion of mirabegron in dogs. All of the dogs were small breeds and weighed less than 8 kg. Of the five cases, only one was symptomatic with tachycardia at the time of evaluation by a veterinarian. Surprisingly, all of the drug ingestions were at doses greater than 3 mg/kg and no fatalities were noted. No further follow-up evaluations were obtained.
United States Food and Drug Administration. Pharmacology Review: Mirabegron. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202611Orig1s000PharmR.pdf.
Dr. Schmid is a graduate of Kansas State University and a staff veterinarian for Pet Poison Helpline.