An Integrated Dialysis Pharmacometric (IDP) Model to Evaluate the Pharmacokinetics in Patients Undergoing Renal Replacement Therapy.

PURPOSE: Clearance via renal replacement therapy (RRT) can significantly alter the pharmacokinetic profile of drugs. The aim of this study was (i) to improve the use of clinical trial data and (ii) to provide a model that allows quantification of all aspects of drug elimination via RRT including adsorption to dialysis membranes and/or degradation of the drug in the dialysate. METHODS: An integrated dialysis pharmacometric (IDP) model was developed to simultaneously incorporate all available RRT information. The sensitivity, accuracy and precision of the IDP model was compared to conventional approaches in clinical trial simulations and applied to clinical datasets of teicoplanin and doripenem. RESULTS: The IDP model was more accurate, precise and sensitive than conventional plasma-concentration-based approaches when estimating the clearanceRRT (relative bias <1%). In contrast to conventional approaches, adsorption and degradation were quantifiable using the IDP model (relative bias: -1.1% and - 1.9%, respectively). Applied to clinical data, clearanceRRT, drug degradation (effluent-half-lifedoripenem: 13.5 h-1) and adsorption (polysulphone adsorption capacityteicoplanin: 31.2 mg) were assessed. CONCLUSION: The IDP model allows accurate, precise and sensitive characterization of clearanceRRT, adsorption and degradation. Successful quantification of all aspects of clearanceRRT in clinical data demonstrated the benefit of the IDP model as compared to conventional approaches.