8
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Electronic supplementary material

          The online version of this article (10.1007/s11095-020-02832-w) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references8

          • Record: found
          • Abstract: found
          • Article: not found

          Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy.

          Continuous renal replacement therapy (CRRT), particularly continuous venovenous haemofiltration (CVVH) and continuous venovenous haemodiafiltration (CVVHDF), are gaining increasing relevance in routine clinical management of intensive care unit patients. The application of CRRT, by leading to extracorporeal clearance (CL(CRRT)), may significantly alter the pharmacokinetic behaviour of some drugs. This may be of particular interest in critically ill patients presenting with life-threatening infections, since the risk of underdosing with antimicrobial agents during this procedure may lead to both therapeutic failure and the spread of breakthrough resistance. The intent of this review is to discuss the pharmacokinetic principles of CL(CRRT) of antimicrobial agents during the application of CVVH and CVVHDF and to summarise the most recent findings on this topic (from 1996 to December 2006) in order to understand the basis for optimal dosage adjustments of different antimicrobial agents. Removal of solutes from the blood through semi-permeable membranes during RRT may occur by means of two different physicochemical processes, namely, diffusion or convection. Whereas intermittent haemodialysis (IHD) is essentially a diffusive technique and CVVH is a convective technique, CVVHDF is a combination of both. As a general rule, the efficiency of drug removal by the different techniques is expected to be CVVHDF > CVVH > IHD, but indeed CL(CRRT) may vary greatly depending mainly on the peculiar physicochemical properties of each single compound and the CRRT device's characteristics and operating conditions. Considering that RRT substitutes for renal function in clearing plasma, CL(CRRT) is expected to be clinically relevant for drugs with dominant renal clearance, especially when presenting a limited volume of distribution and poor plasma protein binding. Consistently, CL(CRRT) should be clinically relevant particularly for most hydrophilic antimicrobial agents (e.g. beta-lactams, aminoglycosides, glycopeptides), whereas it should assume much lower relevance for lipophilic compounds (e.g. fluoroquinolones, oxazolidinones), which generally are nonrenally cleared. However, there are some notable exceptions: ceftriaxone and oxacillin, although hydrophilics, are characterised by primary biliary elimination; levofloxacin and ciprofloxacin, although lipophilics, are renally cleared. As far as CRRT characteristics are concerned, the extent of drug removal is expected to be directly proportional to the device's surface area and to be dependent on the mode of replacement fluid administration (predilution or postdilution) and on the ultrafiltration and/or dialysate flow rates applied.Conversely, drug removal by means of CVVH or CVVHDF is unaffected by the drug size, considering that almost all antimicrobial agents have molecular weights significantly lower (<2000Da) than the haemofilter cut-off (30,000-50,000Da). Drugs that normally have high renal clearance and that exhibit high CL(CRRT) during CVVH or CVVHDF may need a significant dosage increase in comparison with renal failure or even IHD. Conversely, drugs that are normally nonrenally cleared and that exhibit very low CL(CRRT) during CVVH or CVVHDF may need no dosage modification in comparison with normal renal function. Bearing these principles in mind will almost certainly aid the management of antimicrobial therapy in critically ill patients undergoing CRRT, thus containing the risk of inappropriate exposure. However, some peculiar pathophysiological conditions occurring in critical illness may significantly contribute to further alteration of the pharmacokinetics of antimicrobial agents during CRRT (i.e. hypoalbuminaemia, expansion of extracellular fluids or presence of residual renal function). Accordingly, therapeutic drug monitoring should be considered a very helpful tool for optimising drug exposure during CRRT.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Population pharmacokinetics of total and unbound teicoplanin concentrations and dosing simulations in patients with haematological malignancy.

            To develop a pharmacokinetic model describing total and unbound teicoplanin concentrations in patients with haematological malignancy and to perform Monte Carlo simulations to evaluate target attainment of unbound trough concentrations with various dose regimens.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy.

              Caspofungin pharmacokinetics was assessed in 27 critically ill patients, including 7 on continuous venovenous hemofiltration (CVVH), 8 on continuous venovenous hemodialysis (CVVHD), and 13 not requiring continuous renal replacement therapy (CRRT). Caspofungin exposure during CRRT was very similar to that of the control group and comparable to that in healthy volunteers. Caspofungin clearance by CRRT was very low. Therefore, the standard dosage of caspofungin is probably adequate for critically ill patients undergoing CVVH or CVVHD.
                Bookmark

                Author and article information

                Contributors
                sebastian.wicha@uni-hamburg.de
                Journal
                Pharm Res
                Pharm. Res
                Pharmaceutical Research
                Springer US (New York )
                0724-8741
                1573-904X
                14 May 2020
                14 May 2020
                2020
                : 37
                : 6
                : 96
                Affiliations
                [1 ]GRID grid.9026.d, ISNI 0000 0001 2287 2617, Department of Clinical Pharmacy, Institute of Pharmacy, , University of Hamburg, ; Bundesstraße 45, 20146 Hamburg, Germany
                [2 ]GRID grid.22937.3d, ISNI 0000 0000 9259 8492, Division of Infectious Diseases and Tropical Medicine, Department of Internal Medicine I, , Medical University of Vienna, ; Vienna, Austria
                [3 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, University of Queensland Centre of Clinical Research, Faculty of Medicine, , The University of Queensland, ; Brisbane, Queensland Australia
                [4 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, ; Brisbane, Australia
                [5 ]GRID grid.1003.2, ISNI 0000 0000 9320 7537, University of Queensland Centre for Clinical Research, Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, , The University of Queensland, ; Brisbane, Australia
                [6 ]GRID grid.416100.2, ISNI 0000 0001 0688 4634, Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, ; Brisbane, Australia
                [7 ]GRID grid.411165.6, ISNI 0000 0004 0593 8241, Division of Anaesthesiology Critical Care Emergency and Pain Medicine, , Nîmes University Hospital, University of Montpellier, ; Nîmes, France
                Author information
                http://orcid.org/0000-0002-8773-4845
                Article
                2832
                10.1007/s11095-020-02832-w
                7225193
                32409892
                6eb78d28-d41b-44ff-bfe2-7724e9b4c36f
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 February 2020
                : 22 April 2020
                Funding
                Funded by: Universität Hamburg (1037)
                Categories
                Research Paper
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2020

                Pharmacology & Pharmaceutical medicine
                adsorption,doripenem,pharmacokinetics,renal replacement therapy,teicoplanin

                Comments

                Comment on this article