Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles.

A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg/kg (100 µL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t(lag) ) of 0.333 h in the 1.3 mg/kg group and 0 in the other two groups. The mean C(max) increased with dose and were 2.28, 2.67, and 4.71 ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg/kg dose groups, respectively. The mean AUC(0-LLOQ) from lowest to highest dose groups were 157, 268, and 645 ng·h/mL and were dose proportional with a R(2) value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg/kg (50 µL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg/kg group.

The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.

Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 µL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.

The pharmacokinetics of mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs.

The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL·h/kg, and the apparent volume of distribution at steady-state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose-proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t(½) ) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t(½) for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks.

Effects of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats.

Oral N-acetylcysteine (NAC), IV NAC, and IV sodium sulfate were evaluated as treatments for cats dosed orally with toxic sublethal doses of acetaminophen (APAP). Six cats were given single oral doses of 120 mg of APAP/kg of body weight and the respective antidote at 4.5, 8.5, and 12.5 hours after APAP dosing in 3 separate trials. The cats were given each antidotal treatment in random order with at least 3 weeks separating the individual APAP-treated trials. Clinical signs, plasma APAP half-lives, clinical chemical values, and APAP urinary excretion and metabolites were studied. Results were compared (P less than 0.05) with each other and with those of a control group of 6 cats given identical APAP doses, but given no antidotal treatment. At the dosage levels used, oral NAC, IV NAC, and IV sodium sulfate were equally effective antidotes, as measured by decreased methemoglobinemia, increased whole blood reduced glutathione, decreased APAP half-lives, and increased urinary excretion of the APAP-sulfate conjugate. All the antidotal treatments produced results significantly different from those in the control cats.

The effect of acetaminophen on methemoglobin and blood glutathione parameters in the cat.

Acetaminophen (APAP) was given orally to 6 mature cats (3 male and 3 female) in single progressive doses of 20 (low), 60 (medium), or 120 (high) mg APAP/kg body weight, each 3 weeks apart. Methemoglobin (MHB), reduced blood glutathione (GSH) and APAP blood concentrations, and blood NADH methemoglobin reductase and NADPH glutathione reductase activities were measured periodically for 8 days after dosing. A statistically significant increase in MHB formation (21.7% and 45.5%, respectively) occurred following the medium and high doses. NADH methemoglobin reductase activity at the high dose decreased significantly. Red blood cell GSH concentrations decreased significantly during the first 24 h after the high APAP dose and returned to normal by 192 h. NADPH glutathione reductase activity decreased significantly following the high dose, but not after the lower APAP doses.

The toxicity and biotransformation of single doses of acetaminophen in dogs and cats.

The biotransformation of single oral doses of acetaminophen (APAP) was studied in dogs an cats. Each animal received APAP at a no-effect (low), mildly toxic (medium), and severely toxic (high) dosage; dosages for each species were selected to produce similar clinical effects at each respective dosage. For dogs, these dosages were 100, 200, and 500 mg APAP/kg, while for cats, the similar effective dosages were 20, 60, and 120 mg APAP/kg. Plasma half-lives in dogs remained constant at the lower two dosages, but nearly tripled at the high dosage. The plasma half-lives in cats rose with increased dosage. Although the cats were given lower APAP dosages than the dogs, the plasma half-lives of cats were greater than those of the dogs at the medium and high dosages. Both species excreted about 85% of the administered single dose within the first 24 hr. APAP-glucuronide was the principal metabolite excreted in the urine of dogs; its fraction of the total metabolites excreted in urine remained constant at the three dose levels. In cats, APAP-sulfate was the major metabolite in urine at all three dosage levels, but the fraction of the total urinary metabolites represented by APAP-sulfate decreased as the dosage increased. Hepatic centrilobular pathology was seen in dogs, while cats had more diffuse liver pathologic changes. The results indicate that the cat is at increased risk from APAP exposure because of impaired glucuronidation and saturation of its sulfate conjugation pathway.

Acetaminophen and its toxicity.

Acetaminophen (APAP) is considered one of the safest of all minor analgesics, but when taken in large doses (greater than 10 g) toxicity occurs. Severely poisoned patients experience hepatic and/or renal failure. The major metabolic pathway of APAP is formation of glucuronide and sulfate conjugates. A minor pathway is formation of a reactive metabolite that conjugates with glutathione (GSH). When GSH is depleted, the reactive metabolite causes necrosis of hepatic and other tissues. Treatment of APAP toxicity involves supplying alternate sulfhydryl donors or inhibiting oxidative formation of the reactive metabolite. Estimation of plasma APAP levels is necessary for effective treatment.

Pathophysiological effects of paraquat intoxication in domestic ruminants: low dose studies.

Two studies, one in mixed breed feedlot calves and one in domestic goats, evaluated the effects of low doses of parentally administered paraquat dichloride on lung function and pulmonary structure. Calves were injected IV with 5 mg/kg paraquat and studied on days 3, 5, and 7 postinfusion. Goats were intoxicated IP with 10 mg paraquat/kg and studied on days 2, 4, 8, and 10. Each animal served as its own control. The two dosage regimes in calves and goats did not alter pulmonary function or blood gases (calf study only). Only goats intoxicated at the higher dose demonstrated histopathological paraquat-related structural changes.

Urinary metabolism of orally administered ortho-phenyl phenol in dogs and cats.

The urinary metabolites from repeated oral doses of 3.7 mg o-phenyl phenol (OPP) to mature and immature dogs and cats were studied. At both age levels, dogs excreted significantly more OPP as sulfate and glucuronide than did cats. Puppies produced 4 times the level of glucuronides than mature dogs. No such age differences were seen with glucuronide formation by cats, nor were there any age differences in either group of animals for sulfate formation. Some sex differences were observed in conjugation of OPP in cats and dogs. The dominant urinary excretion product of oral OPP administration was the unchanged OPP.