Abstract
Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drug-protein binding. In this work, we propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. We used a mechanistic model to assess the removal of phenytoin and carbamazepine during HD with or without binding-competition. We simulated dialytic removal of (1) phenytoin, initial concentration 70 mg/L, using 2000 mg aspirin, (2) carbamazepine, initial concentration 35 mg/L, using 800 mg ibuprofen, in a 70 kg patient. The competitor drug was infused at constant rate. For phenytoin (~ 13% free at t = 0), HD brings the patient to therapeutic concentration in 460 min while aspirin infusion reduces that time to 330 min. For carbamazepine (~ 27% free at t = 0), the ibuprofen infusion reduces the HD time to reach therapeutic concentration from 265 to 220 min. Competitor drugs with longer half-life further reduce the HD time. Binding-competition during HD is a potential treatment for drug toxicities for which current recommendations exclude HD due to strong drug-protein binding. We show clinically meaningful reductions in the treatment time necessary to achieve non-toxic concentrations in patients poisoned with these two prescription drugs.
Highlights
Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drugprotein binding
Initial albumin concentration was 4.3 g/dL (650 μM); the blood and dialysate flow rates were 250 and 500 mL/min, respectively; dialyzer specifications used were for an Optiflux F180NR dialyzer with a surface area of 1.8 m 2
Starting from a serum phenytoin concentration of 70 mg/L, conventional HD requires 460 min to bring the patient within the therapeutic range, while HD with aspirin requires only 330 min
Summary
Hemodialysis (HD) has limited efficacy towards treatment of drug toxicity due to strong drugprotein binding. We propose to infuse a competitor drug into the extracorporeal circuit that increases the free fraction of a toxic drug and thereby increases its dialytic removal. The competitor drug (D) will compete with toxic drug (T) for the same binding site on protein, and increase the free fraction of T, leading to its enhanced dialytic removal. Competitive binding provides significantly higher dialytic clearance of protein-bound uremic toxins in chronic HD patients[5] The superiority of this proposed method over conventional HD, hemodiafiltration, and ideal membrane adsorption (ideal hemoperfusion) has been illustrated in computer simulations of intra-dialytic removal of protein-bound uremic toxins (PBUTs)[6].
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