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

Abstract

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 clearance_RRT (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, clearance_RRT, drug degradation (effluent-half-life_doripenem: 13.5 h^-1) and adsorption (polysulphone adsorption capacity_teicoplanin: 31.2 mg) were assessed.

Conclusion: The IDP model allows accurate, precise and sensitive characterization of clearance_RRT, adsorption and degradation. Successful quantification of all aspects of clearance_RRT in clinical data demonstrated the benefit of the IDP model as compared to conventional approaches.

Keywords: adsorption; doripenem; pharmacokinetics; renal replacement therapy; teicoplanin.

Fig. 1

Schematic overview of the IDP model with reversible adsorption. Bold arrows indicate measurements, thin arrows mass transfer, dashed arrows mechanistic flows of the dialyzer. c_pl(pre), c_pl(post), c_effl.: concentration of pre- and post-filter plasma, of effluent and cumulated effluent; CL_body: Clearance mediated by the human body; CL_RRT: total RRT clearance; k_deg: degradation rate; corr: corrected; cum.: cumulated F_Ads, Ads_max and k_ads rev: fraction, maximal and reversible rate of adsorption; Q_effl., Q_bood adj.: effluent and adjusted blood flow rate.

Fig. 2

Power to detect RRT clearance by reduced, post-filter, effluent, cumulated effluent and IDP approach in four drug examples. Horizontal line indicates 80% power.

Fig. 3

Accuracy and precision of estimated RRT clearance by reduced, post-filter, effluent, cumulated effluent and IDP approach. Horizontal line indicates 20% relative bias (rBias) and 20% relative root mean squared error (rRMSE).

Fig. 4

Visual-predictive checks on doripenem concentrations in pre- and post-filter plasma, effluent and cumulated effluent and on volume of the cumulated effluent in the 5th, 50th and 95th percentile with the shaded area describing the 90% confidence interval.

Fig. 5

(a) individual fits teicoplanin in vitro, points: observation, solid lines: individual model fit, black: pre- filter plasma, red: post-filter plasma, green: effluent, dashed line: lower limit of quantification. (b) mass balance teicoplanin in vitro, solid lines: amount adsorbed to the dialysis membrane, dashed line: amount of drug in plasma, red: triacetate membrane, blue: polysulphone membrane. (c) individual fits teicoplanin in vivo, points: observation, solid lines: individual model fit, black: pre- filter plasma, red: post-filter plasma, green: effluent.