>   >   >   >  1993 Vol.21 no.12 (201-221)
Issue Vol.21 no.12 (201-221)
Title Safety.tolerance and pharmacokinetics of milrinone in phase I study in healthy male apanese subjects(2) -After intravenous infusion-
Author M.Tsunoo et al.

An intravenous continuous infusion study of milrinone (0.5 or 1.0 microg/kg/min for 120 minutes, and 5.0 microg/kg/min for 10 minutes +0.5 microg/kg/min for 110 minutes) was performed using a single blind design with a placebo as the control in healthy male adult subjects to evaluate its safety, tolerance and pharmacokinetics.

1) There were no clinically significant subjective symptoms, adverse objective findings or side-effects that were considered ascribable to the infusion.

2) The intravenous infusion had no effect on blood pressure in the supine position or pulse rate.

3) One subject receiving a dosage of 1.0 microg/kg/min exhibited ventricular extrasystoles in the Holter monitoring ECG, which disappeared within 2 hours after completion of the infusion. The event could hardly be related with (the drug, however, since this subject had experienced a similar episode nocturnally before the administration. Otherwise, no significant changes that were considered attributable to the drug were noted in any study subjects.

4) The intravenous infusion did not affect body temperature or clinical laboratory test parameters at any dosage levels.

5) In subjects receiving 1.0 microg/kg/min, the plasma levels of unchanged drug increased in proportion to an infusion rate while the area under the plasma unchanged drug concentration-time curve (AUC) increased dose-dependently, compared to those receiving 0.5 microg/kg/min. 6) In a group given 5.0 microg/kg/min for 10 minutes plus 0.5 microg/kg/min for 110 minutes, the plasma levels remained virtually constant from 30 minutes after the initiation of infusion till completion of the 120 minute infusion. Furthermore, these plasma levels were essentially comparable with the steady state concentration (C(ss)), observed in the 0.5 microg/kg/min dosage group. These findings indicated that the steady state of plasma drug concentration was reached early following the initiation of infusion when the drug was administered using these dosage regimens. From the present results, it is concluded that there is no problem of clinical concern in respect of the safety and tolerance of milrinone when administered by intravenous infusion within the limits of dosage used in this study. The pharmacokinetic profile of the drug determined in this intravenous infusion study was essentially consistent with that predicted from the results of a single-dose intravenous administration study.