The pharmacokinetics of maropitant, a novel neurokinin type-1 receptor antagonist, in dogs.
Maropitant is the first NK1 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/h.kg 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 (Cmax) occurred 0.75 h (tmax) 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.
Benchaoui
H A
HA
Veterinary Medicine Research and Development, Pfizer Ltd., Sandwich, Kent, UK. sandwich-cr.ahpdinfotemp@pfizer.com
Cox
S R
SR
Schneider
R P
RP
Boucher
J F
JF
Clemence
R G
RG
D000284:Administration, Oral; D000818:Animals; D000932:Antiemetics / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004285:Dogs / Q000378:metabolism*; D005260:Female; D007279:Injections, Subcutaneous / Q000662:veterinary; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000932:Antiemetics; D064729:Neurokinin-1 Receptor Antagonists; D011812:Quinuclidines; C518176:maropitant