Pharmacokinetics of losigamone, a new antiepileptic drug, in healthy male volunteers.

Losigamone (AO-33), a new potential antiepileptic drug, was tested in 52 healthy male volunteers in 4 placebo-controlled phase I studies. In study 1 single doses of 100, 200, 300, 500, 700, and 1,000 mg losigamone were given as a fast releasing capsule to 12 subjects. The pharmacokinetics of losigamone measured after administration of 100, 300, and 700 mg was linear. Clearance and t1/2 were about 350 ml/min and 4 h, respectively, the Cmax values of 0.7, 1.7, and 4.4 micrograms/ml were reached after 2.5 h. In study 2,500 mg losigamone were given as a fast release capsule for 6 days (t.i.d.) to 12 subjects. There was a small but statistically significant decrease for the AUC but no change in t1/2, Cmax or tmax comparing single dose kinetics on day 1 and 8. There appeared to be no change in caffeine clearance on days 1 and 9. Study 2 was repeated in 20 volunteers with a film-coated tablet. Pharmacokinetic parameters appeared to be unaffected by this change in galenical formulation. In study 4 daily doses of 400, 1,200, and 1,800 mg losigamone were given 28 days to 24 subjects. The kinetics of caffeine and antipyrine were compared on days 1 and 29. With the exception of t1/2 for antipyrine in the 400 mg group there was no statistically significant change in pharmacokinetic parameters. Generally, losigamone was well tolerated and no serious adverse side-effects occurred. In some subjects a reversible increase in transaminases was observed.

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