Aims: To investigate the pharmacokinetics and safety profile of JTP- 4819, (-)-(2S)-1-benzylaminocarbonyl-[(2S)-2-glycoloylpyrrolidinyl]-2- pyrrolidinecarboxamide, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Methods: JTP-4819 was given orally to 28 healthy male volunteers at single doses of 30 mg (n=6), 60 mg (n=6), 120 mg (n=6) and placebo (n=3) and multiple doses of 60 mg three times daily (n=5) and placebo (n=2) for 7 days to investigate its safety and pharmacokinetics following a preliminary safety evaluation of 3, 10 and 30 mg doses in six healthy volunteers. With the single dose of 60 mg, a cross-over study was conducted to examine the effect of food on the bioavailability of the drug. The concentrations of JTP-4819 in plasma and urine were determined by electrospray ionization-liquid chromatography/mass spectrometry (ESI-LC/MS) method. Results: In the multiple dose study, the cholinesterase activity was gradually increased and reached above the normal range on days 4 to 8 in all five subjects given JTP-4819 and gradually returned to normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of JTP-4819, but this remains to be verified. There were no other abnormal findings in objective symptoms and laboratory findings including blood pressure, heart rate, electrocardiogram, body temperature, haematology, blood chemistry and urinalysis. The C(max) of JTP- 4819 at 30, 60 and 120 mg in fasting state were 474, 887 and 1,649 ng ml- 1, respectively, at 1 h after administration, and the t( 1/4 ) was about 2 h. AUC increased in proportion to the given doses. The cumulative urinary recoveries within 24 h were approximately 66%. C(max) AUC, t( 1/4 ) and urinary recovery were not affected by food intake. In the multiple-dose study, there was no drug accumulation trend in plasma. Conclusions: These results indicate that JTP-4819 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events as we verified in healthy young male volunteers.
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