Tissue Distribution of Anidulafungin in Neonatal Rats

Abstract

Anidulafungin, an echinocandin, is currently approved for treatment of fungal infections in adults. There is a high unmet medical need for treatment of fungal infections in neonatal patients, who may be at higher risk of infections involving bone, brain, and heart tissues. This in vivo preclinical study investigated anidulafungin distribution in plasma, bone, brain, and heart tissues in neonatal rats. Postnatal day (PND) 4 and PND 8 Fischer (F344/DuCrl) rats were dosed subcutaneously once with anidulafungin (10 mg/kg) or once daily for 5 days (PND 4-8). Plasma and tissue samples were collected and anidulafungin levels were measured by liquid chromatography-tandem mass spectrometry. The mean plasma Cmax and AUC0-24 values were consistent with single-dose plasma pharmacokinetics (dose normalized) reported previously for adult rats. Observed bone concentrations were similar to plasma concentrations regardless of dosing duration, with bone-to-plasma concentration ratios of approximately 1.0. Heart concentrations were higher than plasma, with heart to plasma concentration ratios of 1.3- to 1.8-fold. Brain concentrations were low after single dose, with brain-to-plasma concentration ratio of approximately 0.23, but increased to approximately 0.71 after 5 days of dosing. Tissue concentrations were nearly identical after single-dose administration in both PND 4 and PND 8 animals, indicating that anidulafungin does not appear to differentially distribute in this period in neonatal rats. In conclusion, anidulafungin distributes to bone, brain, and heart tissues of neonatal rats; such results are supportive of further investigation of efficacy against infections involving bone, brain, and heart tissues.

Anidulafungin and Micafungin Concentrations in Cerebrospinal Fluid and in Cerebral Cortex

“…In infants with meningitis, daily high doses of 8-10 mg/kg of micafungin resulted in CSF concentrations of 0.80-1.80 µg/ml (15). In neonatal rats, anidulafungin brain concentrations of 1.60 µg/g and 4.40 µg/g were measured (16). Along with the higher dosage, the immaturity of the blood brain might explain the higher penetration into CSF and brain.…”

Tissue Penetration of Antifungal Agents

“…Anidulafungin concentrations in the bone of neonatal rats after a single dose are less than those in plasma, with a bone/plasma concentration ratio of 0.21 (175). No data are available for caspofungin or micafungin, although these drugs have been used to treat a few patients with bone/joint infections, in combination with AmBd or a triazole.…”

Antifungal drugs: An updated review of central nervous system pharmacokinetics

“…Ripp and colleagues found AND concentration in brain tissue corresponding to 21% of the concentration found in plasma. 81 Brain concentrations in adult rats were low at early time points, but increased over time. 81,82 These current data indicate that AND penetrates the BBB in rats, but at a relatively slow rate.…”

“…81 Brain concentrations in adult rats were low at early time points, but increased over time. 81,82 These current data indicate that AND penetrates the BBB in rats, but at a relatively slow rate. The distribution of AND observed in brain tissue in this study might be considered unexpected because of its large MW and amphiphilic nature.…”

“…There are scarce studies about AND in the CNS in animal models. Ripp and colleagues found AND concentration in brain tissue corresponding to 21% of the concentration found in plasma 81 . Brain concentrations in adult rats were low at early time points, but increased over time 81,82 .…”