The average concentration at steady state

was approximately 260 ng/mL and was similar after each dose. Experimental data show low accumulation with a ratio of AUC0-Inf (Dose #3) to AUC0-Inf (Dose #1) of approximately 1.0. The ratio for Cmax in this study was 1.3 (a 30% increase from Dose #1 to Dose #3). The half-life was comparable after each of the 3 monthly doses. The simulation assuming linear kinetics agrees with the measured plasma concentrations ( Fig. 3). These results are consistent with those observed by Shoop et al. (2014) following 5 monthly doses of afoxolaner to dogs. Maximum afoxolaner plasma concentrations for the fed dogs averaged 1366 ± 276 ng/mL, and the time to maximum concentration was between 2 and 24 h for most dogs. Fasted dogs had maximum afoxolaner plasma concentrations of 1453 ± 374 ng/mL, and selleck screening library the time to maximum concentration was 2 h for all 5 dogs in this treatment group. The overall exposure (AUCInf) was not affected by the prandial state of the dogs (13.0 ± 2.9

and 10.9 ± 2.6 μg day/mL for fed and fasted dogs, respectively). C  max, AUC0-TlastAUC0-Tlast and AUC0-Inf increased proportionally CP-868596 solubility dmso with dose, indicating linear pharmacokinetics over the range of 1.0–4.0 mg/kg when afoxolaner chews were administered orally in PK Study 1. Table 3 shows the parameters from the Power Model fit for PK Study 1. Including the Cmax and AUC0-Inf values from

PK Study 5 reveals that afoxolaner exhibited close to linear kinetics for absorption, elimination and distribution processes (ADME) over the Mephenoxalone range of 1–40 mg/kg. The data were obtained from two different studies and therefore are not included in one statistical analysis; nonetheless, the log Cmax versus Dose and Log AUC0-Inf versus Dose graphs covering the full range of doses tested are given in Fig. 4. Examples of the flea and tick efficacy as a function of plasma concentration are given in Fig. 5A and B, respectively. A direct relationship between plasma concentration and percent of effectiveness relative to control dogs was modeled using a Sigmoidal Emax model. The EC90 afoxolaner concentrations was estimated to be: 23 ng/mL (24 h post infestation) for C. felis and ≥100 ng/mL (48 h post infestation) for R. sanguineus and D. variabilis. The physicochemical properties of any drug affect its ability to cross cell membranes and therefore govern the absorption, tissue distribution, and elimination of the drug in vivo. The molecular size, solubility, degree of ionization (indicated by pKa), and relative solubility in lipid and aqueous environments (indicated by the lipid:water partition coefficient, i.e., log P or log D) are therefore important parameters for understanding pharmacokinetic behavior (Jenkins and Cone, 1998).