Phase I study and clinical pharmacological study of muroctasin

In a first part a phase I clinical study on the immunomodulator N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin) in male healthy volunteers was performed to assess safety, immunological activities, and preliminary pharmacokinetics of the drug by subcutaneous administration. 1. Safety Slight increase (38 degrees C) in body temperature was observed in a high-dose group by subcutaneous administration. Redness was noted as a change in the injection site, but no dose-dependency was seen in this respect. No other noticeable subjective nor objective symptoms were detected. On the other hand, positive C-reactive protein (CRP) (1 case out of 35) and slight increase in gamma-glutamyl transpeptidase (gamma-GTP, 1 case out of 35) associated with the use of this drug were observed. But the causal relationship of gamma-GTP with this drug was not clear because the finding returned to normal value during the treatment. 2. Immunological activities and leucocyte count Mitogenic responses of lymphocytes were augmented after subcutaneous administration of this drug. Increase in peripheral leukocyte count was also observed. This was due to the increase in neutrophil count. 3. Pharmacokinetics Pharmacokinetic parameters (maximum serum levels, area under serum concentration-time curve, time to reach maximum blood level, biological half-life) were obtained after a single administration of 400 micrograms: Cmax: 6.93 +/- 1.32 ng/ml (mean +/- SE), AUC: 37.22 +/- 6.51 ng/ml/h, tmax: 1.32 +/- 0.26 h and t1/2: 2.7 +/- 0.8 h. The safety of subcutaneous administration of MDP-Lys (L18) injection has been confirmed in 35 male healthy volunteers. It was suggested that adequate doses for phase II studies in patients were 200 micrograms to 400 micrograms. In a second part a clinical pharmacological study (single subcutaneous administrations of 100 micrograms and 200 micrograms and multiple 5 day subcutaneous administration of 200 micrograms of MDP-Lys (L18) was performed on male healthy volunteers to assess pharmacokinetics, effect on leukocyte function and on immune system, and safety: 1. Pharmacokinetics a) serum concentration after single administration Cmax in 100 micrograms and 200 micrograms were 1.48 and 2.78 ng/ml, respectively. The AUC values were 6.71 and 15.62 ng/ml/h, respectively, with dose dependency.(ABSTRACT TRUNCATED AT 400 WORDS)