The pharmacokinetics of maropitant, a novel neurokinin type‐1 receptor antagonist, in dogs

Abstract

The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs. J. vet. Pharmacol. Therap. 30,[336][337][338][339][340][341][342][343][344] Maropitant is the first NK 1 receptor antagonist developed to treat and prevent emesis in dogs; it is administered by subcutaneous (s.c.) injection at 1 mg/kg, or orally (p.o.), in tablet form, at either 2 or 8 mg/kg depending on indication. The absolute bioavailability of maropitant was markedly higher (90.7%) following s.c. injection than after oral administration (23.7% at the 2 mg/kg dose and 37.0% at the 8 mg/kg dose). First-pass metabolism contributes to the low bioavailability of maropitant following oral administration. The difference in bioavailability between the two oral doses reflects the nonlinear kinetics characterizing the disposition of maropitant within the 2-8 mg/kg dose range. Systemic clearance of maropitant following intravenous (i.v.) administration was 970, 995 and 533 mL/hAEkg at doses of 1, 2 and 8 mg/kg, respectively. Nonproportional kinetics were observed for p.o. administered maropitant at doses ranging from 2 to 16 mg/kg but dose proportionality was demonstrated at higher doses (20-50 mg/kg). Linearity was also demonstrated following s.c. administration at 0.5, 1 and 2 mg/kg. Maximum plasma drug concentration (C max ) occurred 0.75 h (t max ) after s.c. administration at 1 mg/kg, and at 1.7 and 1.9 h after oral administration of 8 and 2 mg/kg doses, respectively. The apparent terminal half-life of maropitant was 7.75, 4.03 and 5.46 h after dosing at 1 mg/ kg (s.c.), 2 mg/kg (p.o.) and 8 mg/kg (p.o.), respectively. Feeding status had no effect on oral bioavailability. Limited accumulation occurred following once-daily administration of maropitant for five consecutive days at 1 mg/kg (s.c.) or 2 mg/ kg (p.o.). At the dose of 8 mg/kg (p.o.) once daily for two consecutive days, the mean AUC 0)24h (second dose) was 218% that of the first dose value. Urinary recovery of maropitant and its main metabolite was minimal (<1%), thus supporting the evidence that maropitant clearance is primarily hepatic.

Pharmacokinetics of single doses of maropitant citrate in adult horses

“…Maximum plasma maropitant concentrations after IV administration in horses (814 ± 137 ng/ml) were lower than that reported in dogs and cats, in which the maximum plasma concentrations following 1 mg/kg were 3650 ± 998 ng/ml and 1000 μg/ml, respectively (Benchaoui et al., ; Hickman et al., ). This is consistent with differences in volume of distribution (dogs: 4.4 ± 1.0, cats: 6.2, and horses: 6.5 ± 1.8 L/kg) (Benchaoui et al., ; Hickman et al., ). The elimination half‐life in horses (10.37 ± 2.07 hr) was intermediate between dogs (4.4–5.6 hr) and cats (16.5 hr) (Benchaoui et al., ; Hickman et al., ; Kenward, Elliott, Lee, & Pelligand, ).…”

“…It binds to neurokinin‐1 (NK‐1) receptors, with high concentrations in the emetic center of the brainstem. Maropitant citrate (Cerenia ™ , Zoetis Services LLC, Parsippany, NJ, USA) is a synthetic NK‐1 receptor antagonist that inhibits Substance P from binding to receptors and is used to treat nausea and emesis in dogs and cats (Benchaoui, Cox, Schneider, Boucher, & Clemence, ; Hickman et al., ). NK‐1 receptor antagonists have also been found to have anti‐inflammatory and visceral analgesic properties in models of bowel distension and chemical irritation (Laird et al., ; Okano, Ikeura, & Inatomi, ; Tsukamoto, Ohgoda, Haruki, & Inomata, ).…”

Efficacy of orally administered maropitant citrate in preventing vomiting associated with hydromorphone administration in dogs

“…Pharmacokinetic data 23 indicate that the plasma concentration of maropitant is maximal at 1.9 hours after oral administration of a 2.0 mg/kg dose. In those experiments, 32 orally administered maropitant administered to dogs at a minimum dose of 2.0 mg/kg 1 hour prior to administration of a known emetogen significantly reduced but did not eliminate the incidence of vomiting.…”

“…15,16 Vomiting may also be undesirable in certain clinical cases wherein increases in intraocular or intracranial pressure caused by vomiting may lead to increased patient morbidity. [23][24][25][26] Results of a previous study 9 in dogs indicate that maropitant citrate (1.0 mg/kg [0.45 mg/lb], SC) injected 1 hour prior to premedication with hydromorphone (0.1 mg/kg [0.045 mg/lb], IM) was effective in preventing vomiting and signs of nausea. It is used clinically to treat vomiting attributable to a wide range of clinical causes.…”

Interaction between maropitant and carprofen on sparing of the minimum alveolar concentration for blunting adrenergic response (MAC-BAR) of sevoflurane in dogs

“…Maropitant is a highly selected neurokinin (NK 1 ) receptor antagonist that blocks the pharmacological action of substance P in the central nervous system (CNS) [4, 5]. Maropitant provides antimemetic effects by preventing the substance P from binding with the NK 1 receptors located in the vomiting center and the chemo-trigger zone [5, 23].…”