The effect of sheep breed, age, and gender on the pharmacokinetics and efficacy of monepantel, an amino-acetonitrile derivative

Abstract

This analysis investigated the influence of breed and gender on the pharmacokinetics of monepantel, and influence of breed, age, and gender on its efficacy against gastrointestinal nematodes of sheep. In a comparison of pharmacokinetic profiles from two studies, Merino lambs had significantly greater maximum concentrations of monepantel and monepantel sulfone, and faster times to reach these concentrations than Dorset cross lambs. Males had a statistically greater area under the curve (0-504 h) than females for monepantel sulfone. The biological relevance of these relatively small differences is unclear because efficacy was not evaluated in these studies. For efficacy, a breed effect existed for some nematodes when sheep were treated at a sub-optimum dose (1.25 mg/kg). There were no gender effects between sheep infected with adult parasites and treated at 1.25 mg/kg but there were differences between females and males treated at this dose when infected with fourth-stage larvae of Haemonchus contortus, Teladorsagia circumcincta, Trichostrongylus colubriformis, and Cooperia curticei. There were no breed or gender differences for sheep treated at the recommended dose (2.5 mg/kg). There was a potential trend for declining efficacy with increasing animal age for fourth-stage Trichostrongylus axei. This analysis demonstrated that, similarly to what is observed with other anthelmintics, the pharmacokinetics and efficacy of monepantel can vary with factors like breed, age, and gender. Identifying these covariates is important for understanding inter-individual variability in drug response. While further investigation is warranted, correctly treating sheep at the recommended dose of 2.5 mg/kg appears to mitigate any associated risk.

In vivoselection forHaemonchus contortusresistance to monepantel

“…This change in breed also resulted in faster development of resistance, as observed in the mean round of selection/week rates (0.42 vs. 0.13). These results possibly reflect the differences in parasitic resistance between Santa Ines and Ile de France sheep breeds, but also the breed influence on the pharmacokinetics of monepantel, as reported for Merino and Dorset lambs (Hosking et al ., 2010). Influence of sheep breed on resistance establishment was also observed under field conditions, where selective treatments of Ile de France, but not of Santa Ines sheep, resulted in monepantel resistance in H. contortus (Albuquerque et al ., 2017).…”

Monepantel: the most studied new anthelmintic drug of recent years

“…In terms of the effect of breed on pharmacokinetics of MOP, Merino sheep had a significantly higher C max and lower T max compared with the Dorset cross lambs. There were no significant differences in the AUC (Hosking et al 2010 b ). The MOP and MOP.SO 2 pharmacokinetic parameters are summarized in Tables 2 and 3.…”

“…Sampling times varied among the studies (Karadzovska et al . 2009; Hosking et al 2010 b , c ; Kinsella et al 2011). Fecal samples were collected using bag attached over the anus of the animal.…”

“…The animals were allocated to several different groups based on sex, breed, dose and administration of MOP (Karadzovska et al . 2009; Hosking et al 2010 b , c ). In the first study, sheep (mixed-sex) were divided into three groups based on route of administration ( per oral by a conventional drenching technique, intra-ruminal and intra-abomasal injection, in the same dose 0·8 mg kg −1 ) (Hosking et al 2010 c ).…”

“…Pharmacokinetic studies of MOP and its main metabolite MOP sulfone (MOP.SO 2 ) were performed in three studies using 20, 32 and 36 helminthnaive lambs (4-8 months of age, mixed-sex and weighing 30-50 kg). The animals were allocated to several different groups based on sex, breed, dose and administration of MOP (Karadzovska et al 2009;Hosking et al 2010b, c). In the first study, sheep (mixed-sex) were divided into three groups based on route of administration ( per oral by a conventional drenching technique, intra-ruminal and intra-abomasal injection, in the same dose 0•8 mg kg − 1 ) (Hosking et al 2010c).…”