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      New AUC-Based Method to Estimate Drug Fraction Removed by Hemodialysis


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          Background: A supplemental dose is often necessary after hemodialysis depending on the amount of drug removed by hemodialysis. However, there are different methods of estimating this amount, and most methods ignore drug rebound after hemodialysis. In this report we present a new area under the concentration curve (AUC)-based method that provides an estimate of the drug fraction removed by hemodialysis including drug rebound. Methods: Valganciclovir, the oral prodrug of ganciclovir, was administered to 6 patients with end-stage renal disease. Hemodialysis was performed after 32 h. The fraction of ganciclovir removed by hemodialysis was estimated using the new AUC-based method, a classical method (using the slope on and off hemodialysis), the back-extrapolation method, and a reference model (a two-compartment model with zero-order input and first-order elimination). Results: The AUC-based method and the back-extrapolation method provided accurate estimates of the fraction of ganciclovir removed by hemodialysis (47 ± 6 and 46 ± 5%, respectively) compared to the reference model (49 ± 3%). The classical method, which does not account for the rebound of ganciclovir concentrations after hemodialysis, overestimated the removed fraction by 9% (58 ± 3%). Conclusions: The new AUC-based method and the back-extrapolation method accurately estimate the drug fraction removed by hemodialysis for drugs with a rebound after hemodialysis. The AUC-based method is more robust and as efficient compared to the back-extrapolation method.

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          Pharmacokinetics of valganciclovir and ganciclovir in renal impairment.

          Valganciclovir is the oral prodrug of ganciclovir. The pharmacokinetics of valganciclovir in patients with renal impairment is not known. Furthermore, it is not known whether there are any pharmacokinetic differences between patients who are positive for human immunodeficiency virus (HIV) and cytomegalovirus (CMV) and healthy subjects.
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            How to Calculate Clearance of Highly Protein-Bound Drugs during Continuous Venovenous Hemofiltration Demonstrated with Flucloxacillin

            Background: Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin – drugs which have formerly been characterized as not being dialyzable. Methods: The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described. Results: Flucloxacillin serum levels were significantly lowered (56.9 ± 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 ± 0.7 h, 117.2 ± 79.1 ml/min and 0.21 ± 0.09, respectively. These discrepancies can be explained by the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T > MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l. Conclusion: Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical ‘hemodialysis’ equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs.

              Author and article information

              Kidney Blood Press Res
              Kidney and Blood Pressure Research
              S. Karger AG
              April 2004
              12 August 2004
              : 27
              : 3
              : 172-176
              Department of Internal Medicine II, Division of Nephrology, University Hospital of Ulm, Ulm, Germany
              79806 Kidney Blood Press Res 2004;27:172–176
              © 2004 S. Karger AG, Basel

              Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

              Page count
              Figures: 2, Tables: 1, References: 13, Pages: 5
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/79806
              Self URI (text/html): https://www.karger.com/Article/FullText/79806
              Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
              NephroPharmacology 7 Meeting

              Cardiovascular Medicine,Nephrology
              Ganciclovir,Pharmacokinetics,Drug dose adjustment,End-stage renal disease,Extracorporeal drug removal,Hemodialysis,Removed fraction,Eliminated fraction,Rebound,Valganciclovir


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