Plasma pharmacokinetic profile of fluralaner (Bravecto™) and ivermectin following concurrent administration to dogs

Abstract

BackgroundFluralaner is a novel systemic ectoparasiticide for dogs providing immediate and persistent flea, tick and mite control after a single oral dose. Ivermectin has been used in dogs for heartworm prevention and at off label doses for mite and worm infestations. Ivermectin pharmacokinetics can be influenced by substances affecting the p-glycoprotein transporter, potentially increasing the risk of ivermectin neurotoxicity. This study investigated ivermectin blood plasma pharmacokinetics following concurrent administration with fluralaner.FindingsTen Beagle dogs each received a single oral administration of either 56 mg fluralaner (Bravecto™), 0.3 mg ivermectin or 56 mg fluralaner plus 0.3 mg ivermectin/kg body weight. Blood plasma samples were collected at multiple post-treatment time points over a 12-week period for fluralaner and ivermectin plasma concentration analysis.Ivermectin blood plasma concentration profile and pharmacokinetic parameters Cmax, tmax, AUC∞ and t½ were similar in dogs administered ivermectin only and in dogs administered ivermectin concurrently with fluralaner, and the same was true for fluralaner pharmacokinetic parameters.ConclusionsConcurrent administration of fluralaner and ivermectin does not alter the pharmacokinetics of either compound. Based on the plasma pharmacokinetic profile and the clinical observations, there is no evident interaction between fluralaner and ivermectin, and co-administration does not increase the risk of ivermectin associated neurotoxicity.

Investigation of pharmacokinetic interaction between ivermectin and praziquantel after oral administration in healthy dogs

“…ng/ml and 137 ng/ml, respectively. When AUC and C max values were normalized to same dose, our parameters were similar to previously reported values in Beagle dogs at different doses (0.069-0.3 mg/ kg) (Al-Azzam, Fleckenstein, Cheng, Dzimianski, & McCall, 2007;Dunn et al, 2011;Walther, Allan, & Roepke, 2015), but lower than in cross-bred dogs at 0.2 mg/kg dose (Gokbulut, Karademir, Boyacioglu, & McKellar, 2006) and in Beagle dogs at 0.6 mg/kg dose (Magalhães et al, 2016) after oral administration. Significant differences of the AUC in these studies may be related to the affinity to fatty tissues due to high lipophilicity of ivermectin, P-pg transport F I G U R E 1 Comparative mean (± SD) plasma concentration profiles for ivermectin (IVM) obtained after its administration (0.4 mg/kg) either alone or co-administered with praziquantel (PZQ, 10 mg/kg) both given by the oral route to dogs (n = 6) TA B L E 1 Plasma pharmacokinetic parameters obtained after the oral administration of ivermectin (0.4 mg/kg) to dogs either alone or co-administered with praziquantel (10 mg/kg) (mean ± SD, n = 6) b…”

“…ng/ml and 137 ng/ml, respectively. When AUC and C max values were normalized to same dose, our parameters were similar to previously reported values in Beagle dogs at different doses (0.069–0.3 mg/kg) (Al‐Azzam, Fleckenstein, Cheng, Dzimianski, & McCall, ; Dunn et al., ; Walther, Allan, & Roepke, ), but lower than in cross‐bred dogs at 0.2 mg/kg dose (Gokbulut, Karademir, Boyacioglu, & McKellar, ) and in Beagle dogs at 0.6 mg/kg dose (Magalhães et al., ) after oral administration. Significant differences of the AUC in these studies may be related to the affinity to fatty tissues due to high lipophilicity of ivermectin, P‐pg transport activity, and entering the enterohepatic circulation (Canga et al., ; Hennessy & Alvinerie, ).…”

“…Mealey and Meurs (2008) have reported a relatively high percentage of mixed-breed dogs with the ABCB1 mut/ mut (7/238 [3%]) or ABCB1 mut/wt (19/238 [8%]) genotype. The T max and t 1/2λz (14.0 and 110 hr, respectively) were determined considerably longer in our study than previously reported values in dogs for ivermectin (Al-Azzam et al, 2007;Dunn et al, 2011;Gokbulut et al, 2006;Magalhães et al, 2016;Walther et al, 2015). This can be explained by the formulation of ivermectin.…”

“…Furthermore, the hardness and friability of the tablets also affect the dissolution. Also, different T max values may be related to differences in feeding time (Paulson et al., ; Walther et al., ). Studies in different animal species have shown that feeding time may alter the pharmacokinetics of anthelmintic drugs.…”

“…Studies have been carried out to determine the interaction between ecto/endoparasitic drugs and ivermectin for oral administration in dogs. It was determined that spinosad and pyrantel pamoate changed ivermectin plasma pharmacokinetic but fluralaner did not (Clark, Daurio, Skelly, Cheung, & Jeffcoat, ; Dunn et al., ; Walther et al., ). In the current research, no statistically ( p > 0.05) significant pharmacokinetic changes were observed for ivermectin after its oral co‐administration with praziquantel in dogs.…”