product introduction :::
SPK-843 new antifungal agent
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A NEW INJECTABLE ANTIFUNGAL AGENT
The new salt diascorbate SPK-843
In vitro and in vivo activity
Pharmacodynamic and safety studies
Pharmacokinetic studies
Toxicology and mutagenicity
The new salt diascorbate, SPK-843
As the ascorbic acid has been advantageously added to the pharmaceutical
formulation of SPA-S-753, so greatly improving the stability of the injectable
solution thanks to its antioxidant properties, it has been tought to directly
modify SPA-S-753 by chemical route to give the corresponding diascorbate
salt.
The new salt, namely N-dimethylaminoacetyl-partricin A 2-dimethylaminoethylamide
diascorbate salt, has been coded as SPK-843 or SPA-S-843 (Encl.45a, 45b).
Most of the tests carried out with SPA-S-753 have been repeated with SPK-843
quite confirming - as expected - the previous results.
In vitro and in vivo activity
Exemplifying data are given for the in vitro (Encl. 46, 47, 47a, 47b, 47c, 47d, 47e) and in vivo (Encl. 48-53, 53a, 53b, 61) antifungal activity, also showing much higher therapeutic activity than the lipid formulations of amphotericin B and than the triazoles.
Pharmacodynamic and safety studies
Pharmacodynamic and safety studies have been repeated confirming that SPK-843 tolerance is quite better than that of amphotericin B, even at much higher doses, including f.i. the lack of any pyrogenic effect (Encl.54).
Pharmacokinetic studies
Pharmacokinetic studies in rats by i.v. route showed high drug concentrations and half-life values for serum and particularly for tissues. Low dosages or intermittent administrations may be foreseeable in human therapy to avoid high tissue drug accumulation (Encl. 55, 55a).
Toxicology and mutagenicity
Acute toxicity tests of SPK-843 have been carried out on rats and mice,
even in comparison with amphotericin B and with SPA-S-753, confirming the
expected values of DL50 (Encl.56, 57), and were then repeated in rats under
GLP condition with single and 4-week repeated administration (Encl. 57a,
57b). In the Cynomolgus monkey GLP tests have been performed with single
and then with 2-week i.v. administration, to select the doses for longer
treatment trials (Encl. 58, 59).
Preliminary and then complete data on an i.v. 4-week repeated dose toxicity
study are also available, confirming a reduced nephrotoxicity in comparison
to that of amphotericin B, while some liver toxicity has also been evidenced
probably due to very high liver and other tissue drug accumulation (Encl.60,
60a).
The peripheral blood micronucleus test in mice and the reverse mutation test in bacteria did not show any mutagenetic effect, while the in vitro chromosomal aberration test in CHL/IU cells showed some degree of chromosomal aberration, which was however noticed only at the maximum dose and for prolonged incubation (Encl. 60b, 60c, 60d), and was not confirmed by a similar test with the diaspartate salt SPA-S-753 (Encl. 45).