DOSE REGIMEN ADJUSTMENT FOR MILRINONE IN CONGESTIVE-HEART-FAILURE PATIENTS WITH MODERATE AND SEVERE RENAL-FAILURE

This study was designed to test a proposed dose modification for intra venous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients wer e administered an intravenous loading dose of drug at 50 mu g kg(-1) o ver 10 min. This was followed by an 18 h maintenance infusion of milri none at 0.45 or 0.35 mu g kg(-1) min(-1) for the moderate (chromium-ED TA clearance of 31-75 mL min(-1), n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10-30 mL min(-1),n = 11), respect ively. Plasma and urine samples were collected for up to 34 h and anal ysed for parent drug by validated HPLC methods. The mean (+/- s.d.) st eady-state plasma concentrations of milrinone were within the therapeu tic range (100-300 ng mL(-1)) for both groups, with values of 239 +/- 71 ng mL(-1) and 269 +/- 32 ng mL(-1) for the moderate and severe pati ents, respectively. No statistical differences were observed between t he steady-state values for the two groups. With the exception of two p atients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-stat e levels, ranging between 308 and 353 ng mL(-1), that were not associa ted with any serious adverse events. As predicted for this highly rena lly cleared drug, there were differences (P < 0.001) in the total plas ma clearance (CL(p)), renal clearance (CL(r)), and plasma terminal hal f-life (t1/2) of drug, with values in the severe group being 44% lower , 75% lower, and about 134% longer respectively, when compared with th e moderate group. High (correlation coefficient > 0.8) and significant correlations (P < 0.001) were observed between CL(p) and CL(r) and th e degree of renal impairment (chromium-EDTA clearance). The apparent v olume of distribution was approximately 40% higher (P<0.01) in the sev ere group compared with that for the moderate group (moderates were 0. 443 +/- 0.155 Lkg(-1)). This volume difference suggests a decrease in the plasma protein-binding of milrinone because of the renal disease. The fraction of drug excreted in the urine was 0.705 +/- 0.100 for the moderate group and 0.320 +/- 0.089 for the severe group (P < 0.001). These results may suggest an increase in non-renal clearance of the co mpound, representing a partial compensation mechanism for the reduced renal function. In conclusion, this study has confirmed that the curre nt dose reductions recommended for the use of intravenous milrinone in CHF patients with impaired renal function will yield plasma concentra tions of the drug within the therapeutic range.