Impact of high-flux haemodialysis on the probability of target attainment for amoxycillin/clavulanic acid combination therapy

Introduction: High-flux dialysers are widely used in patients receiving haemodialysis due to increased permeability, solute flow and positive outcomes for patients. The clearances of small molecules, including amoxycillin (Amox)/clavulanic acid (Clav), are likely to increase during high-flux haemodialysis (HFHD). This will result in lower exposure and importantly, reduced efficacy. Objectives: This simulation study evaluates the likely impact of HFHD on the probability of target attainment (PTA) of Amox/Clav combination therapy. Methods: Using previously published pharmacokinetic parameters,(1, 2) Monte Carlo simulations (MCS) were performed in Berkeley Madonna (version 8.3.13) to produce concentration time profiles over 10 days in 1000 simulated patients. A four hour dialysis period occurred on days 2, 5, 7 and 9. To evaluate the likely effect of HFHD, the value for dialysis clearance (CLD) for Amox and Clav were obtained by doubling and quadrupling the CLD in low-flux haemodialysis.(1) MCS were performed using seven different regimens involving either oral Amox/Clav 875mg/125mg administered daily or 500mg/125mg twice daily. Free drug concentrations were calculated (20% protein binding for Amox and 30% for Clav) from the simulations. The following pharmacokinetic/pharmacodynamic (PK/PD) targets were used for PTA calculations. For Amox, this was: the time the free concentration was above the minimum inhibitory concentration for ≥50% of the dosing period (%ƒT>MIC).(3) For Clav, the PK/PD target was the time the free concentration was above 0.1mg/L for ≥45% of the dosing period (%ƒT>0.1mg/L).(4) A further PTA was calculated when patients fulfilled both PK/PD targets. Results: For Amox, over 90% of simulated patients had ≥50%ƒT>MIC across the MIC range (1-8mg/L) for most of the dosing regimens. When CLD was doubled or quadrupled, the exceptions were regimens where Amox/Clav was dosed daily or when dialysis occurred within 2 hours of the administered dose. Similarly, with Clav, when CLD was doubled or quadrupled, less than 90% of simulated patients achieved the PK/PD target for regimens where there were 24-hours between consecutive doses or when dialysis occurred within 2 hours of the administered dose. Regimens where Amox/Clav were dosed twice daily, and where dialysis did not occur within 2 hours of dose administration, achieved both PK/PD targets in over 90% of simulated patients. Discussion: The simulations suggest that if CLD is doubled or quadrupled with HFHD that twice daily dosing of Amox/Clav in patients receiving HFHD should result in sufficient concentrations to effectively treat infections. However, concentrations may be affected by the the time dialysis occurs in relation to when the dose is administered. It would suggest that a PK clinical trial and a physiologically based PK extracorporeal model are required to confirm these findings. References: 1. Davies BE et al. Br J Clin Pharmacol. 1988;26(4):385-90. 2. Horber FF et al. Antimicrob Agents Chemother. 1986;29(4):614-9. 3. Lodise TP et al. Pharmacotherapy. 2006;26(9):1320-32. 4. Lowdin E et al. Clin Microbiol Infect. 2002;8(10):646-53.