Pharmacokinetic studies of maropitant citrate in different situation and clinical recommendations

Introduction

Maropitant citrate is a synthetic neurokinin-1 (NK-1) receptor antagonist developed as an antiemetic for use in dogs. The drug prevents emesis by selectively inhibiting the effect of substance P, a potent NK1 receptor agonist that is widely distributed both centrally and peripherally in the gastrointestinal tract. The NK-1 receptor antagonists are the standard of care in human cancer patients to prevent emesis associated with chemotherapy, and maropitant citrate is commonly administered clinically at 1 mg/kg intravenously (IV) or subcutaneously (SC) once daily for a broad range of emetic stimuli in dogs and cats. Maropitant citrate has also been investigated for anti-inflammatory, analgesic, and inhalant anesthesia sparing effects, related to the involvement of substance P in several other physiologic pathways.[1]This article mainly summarizes the pharmacokinetic studies of Maropitan citrate in different species under different administration methods.

1.In Rhode Island Red chickens following subcutaneous administration

Maropitant citrate is a synthetic neurokinin-1 receptor antagonist and substance P inhibitor used for control of emesis in dogs in cats. Maropitant citrate is used empirically in birds, despite a lack of pharmacokinetic data in avian species. The objective of this study was to determine the pharmacokinetic profile of a single dose of maropitant citrate 1 and 2 mg/kg subcutaneously (SC) in eight Rhode Island Red hens (Gallus gallus domesticus). A crossover study design was used with 1-week washout between trials. Blood samples were collected over 36 h after drug administration. Plasma concentrations were measured using liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were determined via non-compartmental analysis. The mean maximum plasma concentration, time to maximum concentration, and elimination half-life following 1 and 2 mg/kg SC were 915.6±312.8 ng/ml and 1195.2±320.2 ng/ml, 0.49±0.21 h and 1.6 ± 2.6 h, and 8.47±2.24 h and 8.58±2.6 h, respectively. Pharmacokinetic data suggests doses of 1 or 2 mg/kg SC may be administered every 12-24 h to maintain above target plasma concentration similar to dogs (90 ng/ml). These data provide a basis for further investigation of maropitant citrate pharmacokinetics and pharmacodynamics in birds.

2. single doses of maropitant citrate in adult horses

The purpose of this study was to determine the pharmacokinetic profile of maropitant citrate in seven adult horses after single intravenous (IV; 1 mg/kg) and intragastric (IG; 2 mg/kg) doses. A randomized, crossover design was performed. Serial blood samples were collected after dosing; maropitant citrate concentrations were measured using LC-MS/MS. Pharmacokinetic parameters were determined using noncompartmental analysis. The mean plasma maropitant citrate concentration 3 min after IV administration was 800±140 ng/ml, elimination half-life was 10.37±2.07 h, and volume of distribution was 6.54±1.84 L/kg. The maximum concentration following IG administration was 80 ± 40 ng/ml, and elimination half-life was 9.64±1.27 hr. Oral bioavailability was variable at 13.3±5.3%. Maropitant citrate concentrations achieved after IG administration were comparable to those in small animals. Concentrations after IV administration were lower than in dogs and cats. Elimination half-life was longer than in dogs and shorter than in cats. This study is the basis for further investigations into using maropitant citrate in horses.[2]

3. After oral administration of multiple doses in adult horses

Nausea is poorly understood in horses, and clinical use of NK-1 receptor antagonists has not been reported. This study aimed to determine the pharmacokinetics and safety of maropitant citrate after administration of multiple doses. Berryhill et al. hypothesized that maropitant concentrations would be similar at steady state tothose reported in dogs, with minimal adverse effects. Maropitant citrate was administeredat 4 mg/kg orally, once daily for 5 days in seven adult horses. Serial plasma maropitant citrate concentrations were measured by liquid chromatography-mass spectrometry. Noncompartmental pharmacokinetic parameters were determined. The maximum,minimum, and average concentrations of maropitant citrate achieved at steady state were 375.5±200, 16.8±7.7, and 73.5±45.1 ng/ml, respectively. The terminal elimination half-life was 11.6±1.4 hr, and the accumulation index was 1.3±0.07. Heartrate decreased between Day 1 and Day 5 (p=0.005), with three horses having heartrates of 20 beats per minute and atrioventricular block on Day 5. Pharmacokineticsof repeated maropitant citrate administration suggests the drug could be considered for use in healthy horses. Further investigation on the clinical relevancy of its cardiac effects is warranted.[3]

Clinical recommendations 

From the body of research and clinical studies above, there is a preponderance of evidence of the advantages of using maropitant as a preanesthetic agent in both dogs and cats, especially when used in conjunction with mu-agonists and in females undergoing OHE surgery. Maropitant prevents opioid-induced vomiting and decreases signs of nausea preop and post-op in females undergoing OHE surgery. For canine patients, 1.0 mg/kg SC administered 1 hour prior to hydromorphone has been shown to prevent vomiting and signs of nausea. To date, the studies evaluating the effectiveness of maropitant prior to morphine premedication have only allowed 20–45 minutes after maropitant administration, resulting in a significant decrease, but not complete elimination of, vomiting and signs of nausea. Since morphine is less lipid soluble than hydromorphone and may be a stronger emetogen than hydromorphone, the recommendation would be to allow the full 1 hour prior to morphine administration to allow full onset of action of maropitant SC. To minimize injection pain, opened vials of maropitant should be stored at refrigerated temperatures (36°F–46°F, 2°C–5°C) and administered immediately. Oral dosing (2.0–2.5 mg/kg) of maropitant in dogs 2 hours prior to hydromorphone administration is effective in preventing vomiting; however, it does not prevent signs of nausea and appears to actually increasethe severity of visible signs of nausea, including salivation,licking of lips, and increased swallowing.[4]

References

[1]Mones AB, Petritz OA, Knych HK, Sadar MJ, Thomson AE, Guzman DS. Pharmacokinetics of maropitant citrate in Rhode Island Red chickens (Gallus gallus domesticus) following subcutaneous administration. J Vet Pharmacol Ther. 2022;45(5):495-500. doi:10.1111/jvp.13082

[2]Berryhill EH, Knych H, Edman JM, Magdesian KG. Pharmacokinetics of single doses of maropitant citrate in adult horses. J Vet Pharmacol Ther. 2019;42(4):487-491. doi:10.1111/jvp.12768

[3]Berryhill EH, Knych H, Chigerwe M, Edman J, Magdesian KG. Pharmacokinetics of maropitant citrate after oral administration of multiple doses in adult horses. J Vet Pharmacol Ther. 2020;43(3):282-287. doi:10.1111/jvp.12844

[4]Hay Kraus BL. Spotlight on the perioperative use of maropitant citrate. Vet Med (Auckl). 2017;8:41-51. Published 2017 Aug 24. doi:10.2147/VMRR.S126469