Posaconazole Pharmacokinetics in Healthy Cats after Oral and Intravenous Administration

Abstract

BackgroundPosaconazole is the most active available azole antifungal drug, but absorption and pharmacokinetics are not available to guide dosing regimens in cats.ObjectiveTo determine the pharmacokinetics of posaconazole in cats given an IV solution and PO suspension.AnimalsSix healthy, adult research cats.MethodsAfter a 12‐hour fast, each cat received 15 mg/kg of posaconazole PO suspension with food. Four cats also received 3 mg/kg IV posaconazole after a 7‐day washout period. Plasma was collected at predetermined intervals for analysis using high‐pressure liquid chromatography (HPLC). Concentration data were analyzed using a 2‐compartment pharmacokinetic analysis for IV administration data and a 1‐compartment analysis with first‐order input for PO administration data using Phoenix® software.5 ResultsAfter IV dosing, volume of distribution (V SS) was 1.9 (0.3) L/kg (mean, standard deviation), terminal half‐life (T ½) was 57.7 (28.4) hours, and clearance was 28.1 (17.3) mL/kg/h. After PO dosing, peak concentration (C MAX) was 1.2 (0.5) μg/mL and T ½ was 38.1 (15.0) hours. Bioavailability of PO suspension was 15.9% (8.6). No adverse effects were observed with either route of administration.Conclusion and Clinical ImportanceDespite low PO absorption, these data allow for simulation of PO dosage regimens that could be explored in clinical studies. Two regimens can be considered to maintain targeted trough concentrations of 0.5–0.7 μg/mL as extrapolated from studies in humans: (1) 30 mg/kg PO loading dose followed by 15 mg/kg q48h, or (2) 15 mg/kg PO loading dose followed by 7.5 mg/kg q24h.

An atypical cause of sporotrichosis in a cat

“…However, the relevance of these data in S. pallida complex is unknown. Posaconazole has shown equivalence with itraconazole in both in vivo and in vitro trials [21], with readily achievable effective blood concentrations, fewer side effects, and with easier administration in cats due to a palatable liquid formulation [22]. Terbinafine is also very effective against Sporothrix spp., with low MICs and less impact on the liver, although S. pallida (reported by its former name, S. albicans ) appears to have higher MICs than other Sporothrix species [19].…”

“…Treatment of feline sporotrichosis poses challenges, particularly for S. brasiliensis infections which are known to be intrinsically more virulent and contagious in cats, and where nasal mucosal involvement, respiratory signs and high fungal loads in skin lesions are predictors of treatment failure despite overall low MICs to several antifungals [11], [19]. In contrast, considering that the predicted maximum concentration (C MAX) for posaconazole in cats given an oral loading dose of 15 mg/kg is 1.19 mg/L ± 0.52 mg/L [22], peak serum concentrations would, at best, be comparable to the MIC for this isolate (1 mg/L). Taken together with the delayed clinical response to therapy, we consider that posaconazole therapy, debulking surgery and the cat's adaptive immunological response to therapy all contributed to the eventual successful clinical outcome.…”

Pharmacokinetics of posaconazole in koalas (Phascolarctos cinereus) after intravenous and oral administration

“…: 57.7 ± 28.4 hr: p.o. : 38.7 ± 15.02 hr (Mawby et al., )] and humans [median terminal t 1/2 : 15–35 hr; p.o. : 20–66 hr (Li, Theuretzbacher, Clancy, Nguyen, & Derendorf, )].…”

“…: 20–66 hr (Li, Theuretzbacher, Clancy, Nguyen, & Derendorf, )]. The shorter t 1/2 in koalas might be explained by higher median CL (0.15 L hr −1 kg −1 ) and lower V ss (1.23, range 0.93–1.53 L/kg) compared to those in dogs [CL: 0.08 L hr −1 kg −1 ; Vd ss : 3.28; range 2.25–6.45 L/kg (Kendall & Papich, )] and cats [CL: 0.028 L hr −1 kg −1 ; Vd ss : 1.86 ± 0.299 L/kg (Mawby et al., )]. The t 1/2 of the oral posaconazole formulation was longer than that when oral fluconazole is administered to koalas [4.69, range: 2.47–8.01 hr (Black et al., )], which indicates that the oral posaconazole may have a convenient once‐daily dosing interval in koalas.…”

“…serotypes tested in vitro, including isolates with reduced fluconazole susceptibility (Thompson et al., ). It is registered for use in humans and is available as a 40‐mg/ml oral suspension, as delayed‐release tablets and as an intravenous infusion (Noxafil, MSD, Macquarie Park, NSW, Australia) and has been used to treat fungal infections in cats (Evans, Gunew, Marshall, Martin, & Barrs, ; Krockenberger et al., ; Mawby, Whittemore, Fowler, & Papich, ), dogs (Cook et al., ; Corrigan et al., ; Kendall & Papich, ), rabbits (Perfect, Cox, Dodge, & Schell, ) and rats (Ullmann et al., ) with minimal adverse effects. Therefore, the aim of this study was to document changes in plasma concentration of clinically normal koalas after a single oral bolus of 6 mg/kg.…”