Nexgard or Bravecto chewable flea and tick protection

BCSnob wrote:
I did a google search on +MDR1 (name of mutation for "ivermectin sensitivity") and each of the drug names (+fluralaner and +afoxolaner); the "+" requires these terms to be found in the websites.


Safety of fluralaner (Bravecto), a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration
Walther FM, Paul AJ, Allan MJ, Roepke RK, Nuernberger MC.
Parasit Vectors. 2014 Mar 6;7:86. doi: 10.1186/1756-3305-7-86.

Abstract

BACKGROUND:
Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies.

METHODS:
Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment.

RESULTS:
No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose.

CONCLUSIONS:
Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration.




CVMP assessment report for NexGard
Pharmacokinetics
The applicant provided pharmacokinetic studies following oral administration in dogs.
Afoxolaner is rapidly absorbed from the gastrointestinal tract. In dogs administered doses varying from 1 to 4 mg/kg bw, Tmax ranged from 2 to 12 hours; the mean Cmax ranged from 538 (1 mg/kg bw) to 2,147 ng/ml (4 mg/kg bw); the mean half-life ranged from 7.7 to 17.8 days; and, the mean AUCinf ranged from 7225 (1.0 mg/kg bw) to 30,107 day?ng/ml (4.0 mg/kg bw). After oral administration of 2.5 mg afoxolaner/kg bw bioavailability was calculated to be approximately 74%.
For the pivotal pharmacokinetic parameters, there was no significant difference between the fed and fasted state.
While a dose-dependent increase was seen for AUCinf and Cmax at doses up to 40 mg/kg bw, maximum plasma concentrations increased less than proportionally at higher doses (100 mg/kg bw and more). The dose proportionality is limited for afoxolaner due to solubility limited absorption.

In ivermectin sensitive Collies, Cmax was markedly higher at a dose of 25 mg/kg bw compared to studies using Beagles receiving 20 mg/kg bw, 14,000 ± 4,000 ng/ml and 7,690 ± 1,920 ng/ml respectively. Also, afoxolaner appeared to have a longer half-life in Collies (mean of 33 days at a dose of 25 mg/kg bw) than in Beagles. However, there were no serious adverse events observed following the dose of 25 mg/kg bw (i.e. 10x the therapeutic dose) administered to Collie dogs. Using the longest half-life of 47.7 days, and the maximum exposure dose (following recommended use) of 6.3 mg/kg bw, the highest steady state afoxolaner plasma concentrations predicted in Collie dogs would not exceed the maximum exposure (100 mg/kg bw and higher) achieved in toxicology studies in the target animal.