Experimental toxicology of ASTA Z 7557 (INN mafosfamide)

Abstract

The LD 50 of Z 7557 in mice was between 500 and 625 mg/kg after i.v. and around 2310 mg/kg after oral administration. The corresponding LD 10 was around 435 mg/kg (i.v.) or 1100-1250 mg/kg (p.o.), respectively. The LD 50 values in rats were in the range of 250-310 mg/kg after i.v. administration and around 1000-1250 mg/kg if given orally. With repeated daily i.v. injections only 70% of the daily dose contributed to lethality. A second administration of Z 7557 to rats after reversal of all toxic signs from the first administration induced the same symptoms and degree of toxicity as the initial injection. Reversible myelosuppression was the predominant feature of toxicity in mice and rats, but at equimolar doses this myelotoxicity was less than half that of cyclophosphamide (CP). First signs of immunosuppression were seen only at 100 mg/kg i.v.. No severe urotoxicity was observed in rats with single i.v. doses up to 192 mg/kg. This might be due to the fast and complete renal excretion of the thiol moiety of Z 7557, whereas the activated oxazaphosphorine component occurred in the urine only to a much smaller amount, as could be shown by a pilot pharmacokinetic study. In conclusion, Z 7557 appeared to have an overall tolerance in rats and mice similar to cyclophosphamide but was clearly less toxic with respect to the bone marrow, the immune system and the urinary tract.

Phase-I study of mafosfamide-cyclohexylamine (ASTA-Z-7557, NSC 345 842) and limited phase-I data on mafosfamide-lysine

“…In vitro and in vivo the two mafosfamide salts show the same antitumor activity and there are no differences in their pharmacokinetic behavior (1,3). Patient entry criteria and follow up examinations were the same as for the previous study but doses were escalated more rapidly.…”

“…Preclinical toxicity studies were done in rodents and dogs (1,3). The predominant toxicity in rodents was myelosuppression.…”