Journal Mobile Options
Table of Contents
Vol. 83, No. 1, 2009
Issue release date: December 2008

Pharmacokinetic Study of the Variability of Indinavir Drug Levels when Boosted with Ritonavir in HIV-Infected Children

Curras V. · Höcht C. · Mangano A. · Niselman V. · Mariño Hernández E. · Cáceres Guido P. · Mecikovsky D. · Bellusci C. · Bologna R. · Sen L. · Rubio M.C. · Bramuglia G.F.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

The aim of this work is to: (1) assess therapeutic drug monitoring of indinavir (IDV) during clinical routine practice in HIV-infected children, whose antiretroviral treatment includes IDV boosted with ritonavir (RTV), and (2) describe a possible relationship between IDV pharmacokinetics and MDR1 genotypes. In 21 ambulatory pediatric patients receiving IDV plus RTV, IDV plasma levels and MDR1 genotypes on exon 26 (C3435T) were determined. Nine of the 21 patients initially receiving 250 mg/m2 IDV yielded trough levels below 0.10 μg/ml (median: 0.21, range: 0.04–1.31 μg/ml). When the dosage was increased to 400 mg/m2 IDV plus 100 mg/m2 RTV b.i.d., all, except 1 patient, achieved levels above 0.10 μg/ml. Pharmacokinetic analysis showed higher volume of distribution median values related to the C/C genotype in comparison with C/T or T/T genotypes for exon 26 (4.57 vs. 1.20 and 1.50 l/kg, respectively; p = 0.002). Although a higher median value of clearance was observed with the C/C genotype, the difference was not statistically significant (1.43 vs. 0.27 and 0.42 l/h, respectively; p = 0.052). These results may be explained by a reduced absorption of the drug, related with lower plasma IDV levels in patients carrying the C/C genotype in exon 26.



Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Back D, Gatti G, Fletcher C, Garaffo R, Haubrich R, Hoetelmans R, Kurowski M, Luber A, Merry C, Perno CF: Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 2002;16:S5–S37.
  2. Hsu A, Granneman GR, Cao G, Carothers L, Japour A, El-Shourbagy T, Dennis S, Berg J, Erdman K, Leonard JM, Sun E: Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998;42:2784–2791.
  3. Doherty MM, Charman WN: The mucosa of the small intestine: how clinically relevant as an organ of drug metabolism? Clin Pharmacokinet 2002;41:235–253.
  4. Gottesman MM, Pastan I: Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem 1993;62:385–427.
  5. Chen CJ, Clark D, Ueda K, Pastan I, Gottesman MM, Roninson IB: Genomic organization of the human multidrug resistance (MDRl) gene and origin of P-glycoproteins. J Biol Chem 1990;265:506–514.
  6. Ambudkar SV, Dey C, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM: Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 1999;39:361–398.
  7. Makhey VD, Guo A, Norris DA, Hu P, Yan J, Sinko PJ: Characterization of the regional intestinal kinetics of drug efflux in rat and human intestine and in Caco-2 cells. Pharm Res 1998;15:1160–1167.
  8. Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR: Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissue. J Histochem Cytochem 1990;8:1277–1287.
  9. Thomas SA: Drug transporters relevant to HIV therapy. J HIV Ther 2004;9:92–96.
  10. Schuetz EG, Furuya KN, Schuetz JD: Interindividual variation in expression of P-glycoprotein in normal human liver and secondary hepatic neoplasms. J Pharmacol Exp Ther 1995;275:1011–1018.
  11. Fromm MF: The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans. Adv Drug Deliv Rev 2002;54:1295–1310.
  12. Owen A, Chandler B, Back D: The implications of P-glycoprotein in HIV: friend or foe? Fundam Clin Pharmacol 2005;19:283–296.
  13. Jelliffe RW, Schumitzky A, Van Guilder M, Liu M, Hu L, Maire P, Gomis P, Barbaut X, Tahani B: Individualizing drug dosage regimen: roles of population pharmacokinetic and dynamic models, bayesian fitting, and adaptative control. Ther Drug Monit 1993;15:380–393.
  14. Sheiner L, Beal S: Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-bayesian methods. J Pharm Sci 1982;71:1344–1348.
  15. Thomson A, Whiting B: Bayesian parameter estimation and population pharmacokinetics. Clin Pharmacokinet 1992;22:447–467.
  16. Anderson P, Lamba J, Schuetz E, Fletcher C: CYP3A5 and MDR1 (P-gp) polymorphisms in HIV-infected adults: associations with indinavir concentrations and antiviral effects. 11th Conf Retroviruses Opportun Infect, February 8–11, San Francisco, Calif., USA, 2004, abstract 619.
  17. Saitoh A, Singh KK, Powell CA, Fenton T, Fletcher CV, Brundage R, Starr S, Spector SA: An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS 2005;19:371–380.
  18. Verstuyft C, Marcellin F, Morand-Joubert L, Launay O, Brendel K, Mentré F, Peytavin G, Gérard L, Becquemont L, Aboulker JP; ANRS081 Study Group: Absence of association between MDR1 genetic polymorphisms, indinavir pharmacokinetics and response to highly active antiretroviral therapy. AIDS 2005;19:2127–2131.
  19. USCPACK version 10.7a. Los Angeles, University of Southern California, 1995.
  20. D’Argenio DZ, Schumitzky A: ADAPT II User’s Guide. Los Angeles, Biomedical Simulations Resource, University of Southern California, 1990.
  21. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I: Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 2001;69:169–174.
  22. Cressey TR, Plipat N, Fregonese F, Chokephaibulkit K: Indinavir/ritonavir remains an important component of HAART for the treatment of HIV/AIDS, particularly in resource-limited settings. Expert Opin Drug Metab Toxicol 2007;3:347–361.
  23. Collin F, Chêne G, Retout S, Peytavin G, Salmon D, Bouvet E, Raffi F, Garraffo R, Mentré F, Duval X: Indinavir trough concentration as a determinant of early nephrolithiasis in HIV-1-infected adults. Ther Drug Monit 2007;29:164–170.
  24. Anderson PL, Brundage RC, Kakuda TN, Fletcher CV: CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid. Clin Pharmacol Ther 2002;71:280–285.
  25. Langmann P, Zilly M, Weissbrich B, Desch S, Väth T, Klinker H: Therapeutic drug monitoring of indinavir in HIV-infected patients undergoing HAART. Infection 2002;30:13–16.
  26. Bergshoeff AS, Fraaij PL, van Rossum AM, Verweel G, Wynne LH, Winchell GA, Leavitt RY, Nguyen BY, de Groot R, Burger DM: Pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother 2004;48:1904–1907.
  27. van Rossum A, de Groot R, Hartwig N, Weemaes C, Head S, Burger D: Pharmacokinetics of indinavir and low-dose ritonavir in children with HIV-1 infection. AIDS 2000;14:2209–2210.
  28. Schumitzky A: Nonparametric EM algorithms for estimating prior distributions. Appl Math Comput 1991;45:143–157.

    External Resources

  29. Burger DM, van Rossum AM, Hugen PW, Suur MH, Hartwig NG, Geelen SP, Scherpbier HJ, Hoetelmans RM, Vulto AG, de Groot R: Pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents Chemother. 2001;45:701–705.
  30. Matheny C, Lamb M, Brouwer KL, Polack GM: Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy 2001;21:778–796.
  31. Sankatsing SU, Cornelissen M, Kloosterboer N, Crommentuyn KM, Bosch TM, Mul FP, Jurriaans S, Huitema AD, Beijnen JH, Lange JM, Prins JM, Schuitemaker H: Antiviral activity of HIV type 1 protease inhibitors nelfinavir and indinavir in vivo is not influenced by P-glycoprotein activity on CD4+ T cells. AIDS 2007;23:19–27.
  32. Solas C, Simon N, Drogoul MP, Quaranta S, Frixon-Marin V, Bourgarel-Rey V, Brunet C, Gastaut JA, Durand A, Lacarelle B, Poizot-Martin I: Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients. Br J Clin Pharmacol 2007;64:353–362.
  33. Bramuglia GF, Cortada CM, Curras V, Höcht C, Buontempo F, Mato G, Niselman V, Rubio M, Carballo M: Relationship between P-glycoprotein activity measured in peripheral blood mononuclear cells and indinavir bioavailability in healthy volunteers. J Pharm Sci 2008, E-pub ahead of print.
  34. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmöller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U: Functional polymorphisms of the human multidrug resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000;97:3473–3478.
  35. Fellay J, Marzolini C, Meaden ER, Back DJ, Buclin T, Chave JP, Decosterd LA, Furrer H, Opravil M, Pantaleo G, Retelska D, Ruiz L, Schinkel AH, Vernazza P, Eap CB, Telenti A: Response to antiretroviral treatment in HIV-1 infected individuals with allelic variants of the multidrug resistance transporter 1: a pharmacogenetics study. Lancet 2002;359:30–36.
  36. Solas C, Simon N, Drogoul MP, Quaranta S, Frixon-Marin V, Bourgarel-Rey V, Brunet C, Gastaut JA, Durand A, Lacarelle B, Poizot-Martin I: Minimal effect of MDR1 and CYP3A5 genetic polymorphisms on the pharmacokinetics of indinavir in HIV-infected patients. Br J Clin Pharmacol 2007;64:353–362.
  37. Kim R, Leake BF, Choo EF, Dresser GK, Kubba SV, Schwarz UI, Xie HG, McKinsey J, Zhou S, Lan LB, Schuetz JD, Schuetz EG: Identification of functionally variant MDR1 alleles among Americans and African Americans. Clin Pharmacol Ther 2001;70:189–199.
  38. Eichelbaum M, Fromm MF, Schwab M: Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit 2004;26:180–185.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50