Pharmacokinetics in Rats of N-Dimethylaminoacetyl-Partricin A 2-Dimethylaminoethylamide Diascorbate (SPK-843)

Abstract

Single- and multiple-administration trials in rats were performed in this study to assess the serum and tissue concentrations of SPK-843 (N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide diascorbate), a new polyene antibiotic with a heptaene structure. A dose of 1.25 mg/kg (roughly 1 mg/kg of free base) by intravenous route was used both for the single- and multiple-administration trials. The single-administration trial was carried out in comparison with amphotericin B (AmB) at intravenous doses of 1 mg/kg. Plasma samples were drawn at intervals from 15 min to 96 h after injection. The elimination half-lives were 22.15 and 18.15 h, and the area under the curve to infinity (AUC_0–∞) values were 35.52 and 10.33 µg·h·ml^–1, respectively, for SPK-843 and AmB. Both drugs showed an extensive tissue distribution, with higher uptake by the kidneys, followed by the liver, spleen and lungs for SPK-843, and higher uptake by the spleen, followed by the lungs, liver and kidneys for AmB. The multiple-administration trial (1.25 mg/kg/day for 7 days) led to sustained serum and tissue concentrations. On the seventh day, the rats were bled at intervals from 5 min to 96 h after dosing. The serum elimination half-life and AUC_0–∞ values were roughly twice those of the single-dose study (41.4 h and 72.1 µg·h·ml^–1, respectively). Also, the half-lifes and AUCs from 0 to ∞ of tissues were greater than those in the single-dose trial.

Efficacy of SPK-843, a Novel Polyene Antifungal, in a Murine Model of Systemic Cryptococcosis

“…SPK-843 is reported to have in vitro inhibitory activity equal to or better than that of AMB against Candida spp., C. neoformans, and Aspergillus spp. (4,7,8), and the pharmacokinetics of SPK-843 was well determined to possess a profile suitable for its therapeutic effect (1,2). In this work, we evaluated in a murine model of systemic cryptococcosis the treatment efficacy of SPK-843 compared to AMB and FLC.…”

Comparative Pharmacokinetics of Three Preparations of the New Antifungal SPK-843

“…This study compares the pharmacokinetics of three preparations of SPK-843 administered as single intravenous doses in 5% glucose solution (A) as the vehicle, as in previous tests [13], in 10% lipid emulsion at pH 5.3 (B) and in 10% lipid emulsion at pH 7.5 (C). This comparison was thought to be necessary, as lipidic vehicles may modify the bioavailability and tissue distribution of drugs, amphotericin B included [14][15][16]; further, the increase of pH to 7.5 may also change the partition of the free base of SPK-843 from the water to the oily phase of the emulsion and therefore the kinetic properties of the preparation.…”

Efficacy of SPK-843, a Novel Polyene Antifungal, in Comparison with Amphotericin B, Liposomal Amphotericin B, and Micafungin against Murine Pulmonary Aspergillosis

“…(6). The pharmacokinetics of SPK-843 was analyzed, and the drug was found to possess a suitable profile for its therapeutic effect (1,2). In this study, we evaluated the efficacy of SPK-843 compared to those of AMB, liposomal AMB (L-AMB) (AmBisome), and micafungin in experimental pulmonary aspergilloses.…”