PRESHIPMENT TESTING SUCCESS: RESOLUTION OF A NASAL SINUS GRANULOMA IN A CAPTIVE KOALA (<i>PHASCOLARCTOS CINEREUS</i>) CAUSED BY<i>CRYPTOCOCCUS GATTII</i>

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 (Vss ) were 0.31 (0.11-0.55) L/h/kg and 0.92 (0.38-1.40) L/kg, respectively. The elimination half-life (t1/2 ) 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 (Varea ) displayed an allometric relationship with other mammals, CL and t1/2 did not. Allometrically scaled values were approximately sevenfold lower (CL) and sixfold higher (t1/2 ) than observed values, highlighting flaws associated with this technique in physiologically distinct species. On the basis of fAUC/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.

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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

Black

Krockenberger

Kimble

et al. 2013

“…The pathogen responsible for cryptococcosis in koalas is Cryptococcus gattii, which is considered part of the Cryptococcus neoformans species complex (Chen, Meyer, & Sorrell, 2014). Medicines that have been used for the systemic treatment of cryptococcosis in koalas include fluconazole (FLC) (Govendir et al, 2016;Kido et al, 2012;Woods & Blyde, 1997;Wynne et al, 2012), itraconazole (ITC) (Kido et al, 2012;Woods & Blyde, 1997;Wynne et al, 2012), and ketoconazole (Woods & Blyde, 1997). A treatment protocol of daily FLC administration with additional administration of amphotericin has also been reported (Govendir et al, 2016;Kido et al, 2012;Woods & Blyde, 1997;Wynne et al, 2012).…”

Section: Antifungalsmentioning

confidence: 99%

Review of some pharmacokinetic and pharmacodynamic properties of anti‐infective medicines administered to the koala (Phascolarctos cinereus)

Govendir

2017

Although koalas are iconic Australian animals, no pharmacokinetic studies of any first-line medicines used to treat diseased or injured koalas had been published prior to 2010. Traditionally, medicine dosages suggested for this species underwent linear extrapolation from those recommended for domesticated species. The koala, a specialist folivore whose natural diet consists of almost exclusively Eucalyptus spp. foliage has anatomical and physiological adaptations for detoxifying their diet which also affect medicine pharmacokinetic profiles. This review addresses aspects of medicine absorption, clearance, and other indices (such as medicine binding to plasma proteins) of enrofloxacin/marbofloxacin and chloramphenicol used for the systemic treatment of chlamydiosis, and fluconazole ± amphotericin, and posaconazole for the treatment of cryptococcosis. Based on observations from published studies, this review includes suggestions to improve therapeutic outcomes when administering medicines to diseased koalas.

“…Medicines that have been used for the systemic treatment of clinical cryptococcosis in koalas include fluconazole (Govendir et al., ; Kido et al., ; Woods & Blyde, ; Wynne et al., ), itraconazole (Kido et al., ; Woods & Blyde, ; Wynne et al., ) and ketoconazole (Woods & Blyde, ). A treatment protocol of daily fluconazole administration with additional administration of amphotericin administered subcutaneously has also been reported (Govendir et al., ; Kido et al., ; Woods & Blyde, ; Wynne et al., ). Black, Krockenberger, Kimble, & Govendir, demonstrated that oral fluconazole administration alone at 10 mg/kg twice daily is unlikely to be effective against C. gattii .…”

Section: Introductionmentioning

confidence: 99%

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

Gharibi

Kimble

Vogelnest

et al. 2017

The pharmacokinetic profile of posaconazole in clinically normal koalas (n = 8) was investigated. Single doses of posaconazole were administered intravenously (i.v.; 3 mg/kg; n = 2) or orally (p.o.; 6 mg/kg; n = 6) with serial plasma samples collected over 24 and 36 hr, respectively. Plasma concentrations of posaconazole were quantified by validated high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis of data was performed. Following i.v. administration, estimates of the median (range) of plasma clearance (CL) and steady-state volume of distribution (V ) were 0.15 (0.13-0.18) L hr kg and 1.23 (0.93-1.53) L/kg, respectively. The median (range) elimination half-life (t ) after i.v. and p.o. administration was 7.90 (7.62-8.18) and 12.79 (11.22-16.24) hr, respectively. Oral bioavailability varied from 0.43 to 0.99 (median: 0.66). Following oral administration, maximum plasma concentration (C ; median: 0.72, range: 0.55-0.93 μg/ml) was achieved in 8 (range 6-12) hr. The in vitro plasma protein binding of posaconazole incubated at 37°C was 99.25 ± 0.29%. Consideration of posaconazole pharmacokinetic/pharmacodynamic (PK/PD) targets for some yeasts such as disseminated candidiasis suggests that posaconazole could be an efficacious treatment for cryptococcosis in koalas.