Effect of hemopurification rate on doripenem pharmacokinetics in critically ill patients receiving high-flow continuous hemodiafiltration

Hemopurification is an effective therapy for acute kidney injury, defined as creatinine clearance less than 30 ml/min, which occurs frequently in the intensive care unit. These critically ill patients often have severe infectious complications and are thus often treated with antibiotics. However, the effect of hemopurification on the pharmacokinetics of antibiotics is not well understood. In this study, we investigated the pharmacokinetics of doripenem (DRPM) in critically ill patients with accompanying renal dysfunction undergoing continuous hemodiafiltration by high-volume filtration/high-flow dialysis (high-flow CHDF) and compared it to the pharmacokinetics of DRPM during conventional CHDF. We studied 8 patients (2 in the high-flow group and 6 in the conventional group) in whom DRPM was administered while performing CHDF for acute kidney injury. DRPM (250 mg) was intravenously infused over 1 h. For the conventional group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 500 ml/h, and filtration flow rate (Q(F)) of 300 ml/h. For the high-flow group, CHDF was performed at a blood flow rate (Q(B)) of 100 ml/min, dialysate flow rate (Q(D)) of 1500 ml/h, and filtration flow rate (Q(F)) of 900 ml/h. For both groups, a polysulfonehemofilter with a membrane area of 1.0 m(2) was used. Mean half-life, total body clearance, and clearance via hemodiafiltration of DRPM were 2.9 h, 118 ml/min, and 41.9 ml/min, respectively, in the high-flow group, and 7.9 h, 58 ml/min, and 13.5 ml/min in the conventional group. Clearance via hemodiafiltration increased approximately 3-fold by tripling the hemopurification rate. Therefore, CHDF parameters greatly affected DRPM pharmacokinetics in patients receiving CHDF. These results suggest that clearance via hemodiafiltration increases proportionally to the hemopurification rate. Thus, it is reasonable to conclude that DRPM dose must be increased to 1.0-1.5 g/day when performing high-flow CHDF.