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      The Effect of Hepatic Insufficiency on the Safety and Pharmacokinetics of Paricalcitol (Zemplar ®)

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          Background/Aims: Paricalcitol is highly protein bound, extensively metabolized and eliminated primarily by hepatobiliary excretion. This study was designed to determine if hepatic disease alters the pharmacokinetics or affects the safety of paricalcitol. Methods: Subjects with mild (n = 5) or moderate (n = 5) hepatic impairment, and subjects with normal hepatic function (n = 10) enrolled in and completed the study. Each subject was administered a single 0.24 µg/kg intravenous dose of paricalcitol, injected within 1 min. Results: For both total and unbound paricalcitol, there were no statistically significant differences in the pairwise comparisons between hepatic function groups in paricalcitol concentration at 5 min postdose (C<sub>5</sub>) or area under the plasma concentration-time curve from time zero to infinity (AUC<sub>0–</sub>∞), except C<sub>5</sub> of total paricalcitol between mild and moderate impairment groups (p = 0.02). Paricalcitol binding to plasma proteins was extensive in all hepatic function groups (mean values >99.7%); unbound fraction was greater in subjects with moderate impairment than either healthy subjects or subjects with mild impairment (p < 0.01). Paricalcitol appeared to be well tolerated both by healthy subjects and subjects with mild to moderate hepatic insufficiency. Conclusion: No adjustment of paricalcitol dose is required for subjects with mild to moderate hepatic impairment. However, caution should be exercised in extrapolating the results from this study to subjects with severe hepatic impairment.

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          Patterns of hepatitis C prevalence and seroconversion in hemodialysis units from three continents: the DOPPS.

          Hepatitis C virus (HCV) remains a problem within hemodialysis units. This study measures HCV prevalence and seroconversion rates across seven countries and investigates associations with facility-level practice patterns. The study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective, observational study of adult hemodialysis patients randomly selected from 308 representative dialysis facilities in France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States. Logistic regression was used to model odds of HCV prevalence, and Cox regression was used to model time from study entry to HCV seroconversion. Mean HCV facility prevalence was 13.5% and varied among countries from 2.6% to 22.9%. Increased HCV prevalence was associated with longer time on dialysis, male gender, black race, diabetes, hepatitis B (HBV) infection, prior renal transplant, and alcohol or substance abuse in the previous 12 months. Approximately half of the facilities (55.6%) had no seroconversions during the study period. HCV seroconversion was associated with longer time on dialysis, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), HBV infection, and recurrent cellulitis or gangrene. An increase in highly trained staff was associated with lower HCV prevalence (OR = 0.93 per 10% increase, P= 0.003) and risk of seroconversion (RR = 0.92, P= 0.07). Seroconversion was associated with an increase in facility HCV prevalence (RR = 1.36, P < 0.0001), but not with isolation of HCV-infected patients (RR = 1.01, P= 0.99). There are differences in HCV prevalence and rate of seroconversion at the country and the hemodialysis facility level. The observed variation suggests opportunities for improved HCV outcomes.
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            Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group.

            Hepatitis C virus (HCV) infection is common among patients with end-stage renal disease (ESRD). However, the effect of HCV infection on survival among ESRD patients, and the impact of renal transplantation on the course of HCV infection has not been adequately defined. Sera from patients on the renal transplant waiting list at the New England Organ Bank between November 1986 and June 1990 were tested for anti-HCV using a third generation ELISA. All anti-HCV positive patients and a 1:1 ratio of randomly selected anti-HCV negative patients comprised the study sample. Duration of follow-up was calculated from the date of the first available serum specimen until death, loss to follow-up or December 31, 1995, whichever occurred earlier. Multivariate analysis of risk factors for mortality was performed using a Cox proportional hazards model which included anti-HCV as a time-independent (baseline) variable, transplantation as a time-dependent (follow-up) variable, and independently significant baseline covariates. Anti-HCV was detected in 287 (19%) of 1544 patients in whom sera were available, and 286 anti-HCV negative patients served as controls. Complete information was available in 496 (87%) of these 573 patients. Median follow-up was 73 months (range 1 to 110 months), during which time 302 (61%) patients underwent renal transplantation and 154 (31%) patients died. For anti-HCV positive patients compared to anti-HCV negative patients, the relative risk of death (and 95% confidence intervals) from all causes was 1.41 (1.01 to 1.97) and due to liver disease or infection was 2.39 (1.28 to 4.48). For patients who underwent transplantation compared to those who remained on dialysis, the relative risk of death from all causes between 0 to 3 months, 3 to 6 months, seven months to four years, and after four years was 4.75 (2.76 to 8.17), 1.76 (0.75 to 4.13), 0.31 (0.18 to 0.54) and 0.84 (0.51 to 1.37), respectively. There was no interaction between the effect of anti-HCV status as baseline and subsequent transplantation (P = 0.93), meaning that the association between treatment modality and survival was similar among anti-HCV positive and negative patients, at all intervals after transplantation. We conclude that HCV infection at the time of referral for transplantation is associated with an increased risk of death, irrespective of whether patients remain on dialysis or undergo transplantation. Transplantation has a beneficial rather than adverse effect on long-term survival in anti-HCV positive patients. Hence, anti-HCV positive status alone is not a contraindication for renal transplantation.
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              The changing epidemiology of hepatitis C virus (HCV) infection in haemodialysis: European multicentre study.

              The high prevalence of anti-hepatitis C virus (HCV) antibodies in HD patients has been known since the early 1990s but its evolution over the last decade is poorly documented. All chronic HD patients from 15 Belgian units were tested at (re)start of HD and every 18 months for anti-HCV antibodies (ELISA 2 in May 1991 and November 1992, then ELISA 3 until May 2000). All chronic HD patients from HD units from eight other European countries, whose prevalence of anti-HCV (+) patients had been studied in 1991-1994 (and published except in one country), were tested for anti-HCV antibodies in 1999. Anti-HCV (+) prevalence decreased (P<0.001) from 13.5 (1991) to 6.8% (2000) in the Belgian cohort (n = 1710). Prevalence also decreased (P<0.05) in the participating units from France (42-30%), Sweden (16-9%) and Italy (28-16%), tended to decrease in the participating units from UK (7-3%, P = 0.058) and Hungary (26-15%, P = 0.057) but did not change (NS) in the participating units from Germany (7 to 6%), Spain (5 to 12%) and Poland (42 to 44%). In the Belgian cohort, the prevalence of anti-HCV(+) at (re)start of HD did not change significantly over 1991-2000. The prevalence of anti-HCV(+) in HD has decreased markedly over the last decade in the participating units from most European countries. This decrease should reduce further the risk of nosocomial and occupational HCV infection in HD and ultimately contribute to improved long-term prognosis of HD patients and kidney graft recipients.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                June 2006
                13 March 2006
                : 103
                : 3
                : c100-c105
                aAbbott Laboratories, Abbott Park, Ill., bAbbott Laboratories, Parsippany, N.J., cDepartment of Drug Metabolism and Pharmacokinetics, TAP Pharmaceutical Products Inc., Lake Forest, Ill., and dDepartment of Medicine and Cancer Center, Veterans Affairs Healthcare System and University of California, San Diego, Calif., USA
                92018 Nephron Clin Pract 2006;103:c100–c105
                © 2006 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: 2, References: 16, Pages: 1
                Self URI (application/pdf):
                Original Paper

                Cardiovascular Medicine, Nephrology

                Hepatic insufficiency, Liver, Drug safety, Paricalcitol


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