Pharmacokinetics of fluconazole following intravenous and oral administration to koalas ( Phascolarctos cinereus )

Clinically normal koalas ( n  = 12) received a single dose of 10 mg/kg fluconazole orally (p.o.; n  = 6) or intravenously (i.v.; n  = 6). Serial plasma samples were collected over 24 h, and fluconazole concentrations were determined using a validated HPLC assay. A noncompartmental pharmacokinetic analysis was performed. Following i.v. administration, median (range) plasma clearance (CL) and steady‐state volume of distribution ( V ss ) were 0.31 (0.11–0.55) L/h/kg and 0.92 (0.38–1.40) L/kg, respectively. The elimination half‐life ( t 1/2 ) was much shorter than in many species (i.v.: median 2.25, range 0.98–6.51 h; p.o.: 4.69, range 2.47–8.01 h), and oral bioavailability was low and variable (median 0.53, range 0.20–0.97). Absorption rate‐limited disposition was evident. Plasma protein binding was 39.5 ± 3.5%. Although fluconazole volume of distribution ( V area ) displayed an allometric relationship with other mammals, CL and t 1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher ( t 1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of f AUC /MIC pharmacodynamic targets, fluconazole is predicted to be ineffective against Cryptococcus gattii in the koala as a sole therapeutic agent administered at 10 mg/kg p.o. every 12 h.