Tolerance and Pharmacokinetics of Galliprant™ Administered Orally to Collies Homozygous for MDR1-1Δ.

The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P-gp transporter, in collies homozygous for MDR1-1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1-1Δ genotype from a commercial colony were used in the study, eight in the treated group and four as placebo-treated controls. The only treatment-related clinical sign was self-limiting vomiting (in 2/8 treated animals) and the only treatment-related clinical pathological changes seen were a slight decrease in serum albumin in one dog (2.6 g/dL; reference 2.7 to 3.9 g/dL) and total protein (5.1 g/dL; reference 5.5 to 7.7 g/dL). Absorption of grapiprant was rapid with a median Tmax of 1 h, Cmax of 5.2 µg/mL, AUC0-24 of 17.3 ± 7.1 h* µg/mL and median terminal t½ of 4.3 h after the first dose. To determine whether MDR1-1Δ animals handle grapiprant differently from normal dogs, a population pharmacokinetic analysis was performed utilizing data from the collies and historical beagle data. Volume of the peripheral compartment of collies was estimated to be 45% that of beagles, and clearance from the central compartment was 71% less in collies than in beagles. Self-liming vomiting events occurred at a numerically higher rate (2/8; 25%) in this group of P-gp-deficient dogs than seen in a clinical study (17%) composed of various dog breeds but limited numbers in this PK study make comparisons difficult. Grapiprant was otherwise well tolerated in collies homozygous for MDR1-1Δ despite increased drug exposure compared to dogs without this mutation.

Safety evaluation of the interchangeable use of robenacoxib in commercially-available tablets and solution for injection in cats.

BACKGROUND: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation. RESULTS: Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib. CONCLUSIONS: This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

Safety evaluation of the interchangeable use of robenacoxib (Onsior™) tablets and solution for injection in dogs.

BACKGROUND: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this safety study was to investigate the interchangeable use of two robenacoxib formulations in dogs using a novel study design alternating between oral tablets and subcutaneous injections. Thirty-two naïve healthy 4-month dogs were enrolled in this 88-day study and were randomized among four groups to be untreated or to receive robenacoxib at the highest recommended or elevated dose rates. The dogs were administered three 20-day treatment cycles each separated by a 14-day washout period. Each 20-day cycle was comprised of 10 days of once daily oral administration, 3 days of subcutaneous administration, followed by further 7 days of oral administration (Groups 2 to 4). The control group (Group 1) received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical and neurological examinations including ophthalmological examinations, electrocardiographic examinations and clinical pathology evaluations, food and water consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for pharmacokinetic evaluation. RESULTS: Blood concentrations of robenacoxib confirmed systemic exposure of all treated dogs. All dogs were in good health through study termination and there were no serious adverse events during the course of the study. No changes in body weight, food consumption, ophthalmic, neurological examinations, electrocardiograms, buccal mucosal blood times, clinical pathology or organ weight were attributable to robenacoxib formulation administration. Primary treatment-related abnormalities were of low incidence at all doses. They were confined to macroscopic and microscopic changes observed locally at the subcutaneous injection sites and microscopic findings within the gastrointestinal tract. These findings were as expected based on previous studies with robenacoxib solution for injection alone and the known properties of this class of compound and mode of administration. There were no adverse effects which could be attributed specifically to the interchangeable use of oral and injectable robenacoxib. CONCLUSIONS: Alternating regimens of robenacoxib tablets and solution for injection were well tolerated in healthy young dogs.