In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model

Abstract

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy.Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma.Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min.Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Gentamicin Administration in Dialysis Patients: Before or After Hemodialysis?

“…This value is based on the plasma flow of the dialyzer because the gentamicin clearance is almost identical to the plasma flow, as the serum protein binding of gentamicin is almost zero. 17,18 This is in line with the findings of Vossen et al 19 who recently studied the clearance of gentamicin from different dialyzers. A variance of 25% for CL non-dialysis , CL dialysis , and Vd was used.…”

“…Simulations of septic patients were also performed using the model PK parameters of Franck et al, 20 who performed a similar study. Moreover, individual variants were simulated: CL dialysis , which is the variation within membranes, 19 measuring 90 mL/min and 188 mL/min and for obese patients weighing 90, 110, and 130 kg.…”

“…In our simulations, the CL dialysis (150 mL/min) was higher than that in other studies (80-134 mL/min) 13,14,30,31 because these studies were published between 2006 and 2013; currently, higher dialyzer blood flows are used (200-400 mL/ min). 19,32 Therefore, our simulations better reflect the modern dialysis technique, which favors a high blood flow through the dialyzer. In our study, an average blood flow of 250 mL/ min was calculated for plasma flow using a hematocrit of 0.4.…”

Practical considerations for individualizing drug dosing in critically ill adults receiving renal replacement therapy

“…33,34 For vancomycin, gentamicin, and tigecycline, a significant decrease in drug concentrations in the hemofiltration circuit was observed for the polyacrylonitrile membrane. 60,61 Additionally, adsorption is inversely correlated to effluent flow rate and, in the case of amikacin, results in a 17% decrease in adsorption rate per 1 L/min increase in the flow rate. 33,34 For vancomycin, adsorption seems lower, ranging from 4% to 12%.…”