Evaluation of the safety in dogs of long-term, daily oral administration of capromorelin, a novel drug for stimulation of appetite.

The objective of the study was to evaluate the safety of capromorelin, a ghrelin agonist that stimulates appetite and causes increased body weight and the release of growth hormone (GH). Beagle dogs (n = 32) received either oral placebo or 0.3, 7, or 40 mg/kg capromorelin once daily for 12 consecutive months. Safety was evaluated by physical examinations, including ECG and ophthalmic examinations, and comprehensive clinical pathology. Serum levels of capromorelin, GH, and insulin-like growth factor 1 (IGF-1) were measured periodically. Necropsies and histopathological evaluations were performed at study termination. As expected, GH and IGF-1 levels were mildly increased in capromorelin-treated dogs. Adverse events were limited to mild emesis and loose stools in all groups and excess salivation among some dogs receiving higher capromorelin doses. Clinical pathology testing was generally normal, although blood lipids and alkaline phosphatase levels were moderately increased among dogs receiving capromorelin. Treated dogs had slightly longer post-treatment PR intervals seen on ECG, but with no changes in cardiac histopathology. Postmortem findings were normal. Drug-related increases in liver weight were linked to overall increases in body weight. Capromorelin was well tolerated in dogs at daily doses up to 40 mg/kg for 12 months, demonstrating a wide safety margin.

Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs.

A new anti-inflammatory drug for pain (grapiprant) was recently shown to have minimal side effects following chronic (9-month) daily oral dose of 6 or 50 mg/kg suspension. The current study compares the pharmacokinetics of the formulation used in the chronic safety study to those of the tablet formulation that will be marketed upon FDA approval. Sixteen Beagle dogs were randomized to receive single doses of either 6 or 50 mg/kg grapiprant as both suspension and table formulations within a cross-over design with a 15-day washout. Clinical observations were vomiting in one high-dose suspension dog and loose stools in two dogs, one in each 6 mg/kg formulation group. For both formulations, grapiprant reached a maximum concentration within two hours. The tablet formulation had better bioavailability, with AUClast values 34% higher at 6 mg/kg and 64% higher at 50 mg/kg compared to the suspension. Results on Day 0 were similar to those reported on Day 15, suggesting little to no accumulation. Using conversion factors of 1.34 and 1.64, these findings suggest that the 6 and 50 mg/kg suspension doses are equivalent to 4.5 and 30 mg/kg tableted doses, respectively. Combining these findings with the 9-month safety study demonstrates that safety was evaluated at doses approximately 15-fold above the demonstrated therapeutic dose of 2 mg/kg and 10-fold over the 'safety dose', defined as the maximum dose a dog of any body weight could receive when dosed at 2 mg/kg with whole or half-tablets.

Differential effects of microsomal enzyme-inducing chemicals on the hepatic expression of rat organic anion transporters, OATP1 and OATP2.

The organic anion transporting polypeptides, Oatp1 (Slc21a1) and Oatp2 (Slc21a5), mediate hepatic uptake of cardiac glycosides. Previously, we demonstrated that chemicals that increase cytochrome P450s differentially affect hepatic uptake of cardiac glycosides. We postulated that increased uptake of cardiac glycosides observed after pretreatment of animals with phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN) occurs via increased hepatic expression of Oatp1 and/or Oatp2. Male Sprague-Dawley rats were injected with PB, PCN, 3-methylcholanthrene (3-MC), or vehicle for 4 days. Branched-DNA (bDNA) signal amplification and Western blot analyses were used to assess hepatic Oatp1 and Oatp2 mRNA and protein, respectively. The expression of Oatp1 was not increased by any chemical treatment. Increases in Oatp2 expression were observed from livers of rats treated with PB and PCN, in which PCN caused a robust elevation of Oatp2 mRNA and protein. Oatp2 expression was suppressed in response to 3-MC. To determine the temporal effects of PCN treatment on the expression of Oatp2, rats were administered PCN, livers were extracted at various times, and Oatp2 expression was analyzed. Maximal expression of Oatp2 mRNA was observed at 24 hours and remained elevated, whereas the amount of Oatp2 protein increased throughout the 96-hour interval. The finding that Oatp2 expression increases in response to PB and PCN is consistent with our previous findings that PB and PCN enhance hepatic uptake of cardiac glycosides. These results suggest that Oatp2, but not Oatp1, is inducible by PB and PCN, which imparts the increased capacity of the liver to extract cardiac glycosides from the plasma.