European Journal of Clinical Pharmacology

, Volume 63, Issue 5, pp 479–483 | Cite as

Effect of efavirenz on the pharmacokinetics of ketoconazole in HIV-infected patients

  • Somchai Sriwiriyajan
  • Werawath Mahatthanatrakul
  • Wibool Ridtitid
  • Sutep Jaruratanasirikul
Pharmacokinetics and Disposition



To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients.


Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16.


Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. Cmax and AUC0−24 were significantly decreased by 44 and 72%, respectively. The T ½ was significantly shorter by 58%.


Efavirenz has a strong inducing effect on the metabolism of ketoconazole.


Drug interaction Efavirenz Ketoconazole HIV-infected patients Pharmacokinetics 



We acknowledge and appreciate the financial support of this study by the Prince of Songkla University and would like to thank to Miss Stefania Vignotto and Mr. David Brown for checking our English. The experiments comply with the current laws of the country in which we were performed.


  1. 1.
    Department of Health and Human Services (2006) Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents-October 10, 2006. Assessed December 20, 2006
  2. 2.
    Heel RC, Brogden RN, Carmine A, Morley PA, Speight TM, Avery GS (1982) Ketoconazole: a review of its therapeutic efficacy in superficial and systemic fungal infections. Drugs 23:1–36PubMedGoogle Scholar
  3. 3.
    Adkins JC, Noble S (1998) Efavirenz. Drugs 56:1055–1064PubMedCrossRefGoogle Scholar
  4. 4.
    Yuen KH, Peh KK (1998) Simple high-performance liquid chromatographic method for determination of ketoconazole in human ploasma. J Chromatogr B 715:436–440CrossRefGoogle Scholar
  5. 5.
    Ellepola AN, Samaranayake LP (2000) Oral candidal infections and antimycotics. Crit Rev Oral Biol Med 11:172–198PubMedCrossRefGoogle Scholar
  6. 6.
    Thai Ministry of Public Health (2002) National guidelines for the clinical management of HIV infection in children and adults, 7th edn. Garnsadsana, BangkokGoogle Scholar
  7. 7.
    Teanpaisan R, Nittayananta W, Chongsuvivatwong V (2000) Biotypes of oral Candida albicans isolated from AIDS patients and HIV-free subjects in Thailand. J Oral Pathol Med 29:193–199PubMedCrossRefGoogle Scholar
  8. 8.
    Van Roey J, Haxaire M, Kamya M, Lwanga I, Katabira E (2004) Comparative efficacy of topical therapy with a slow-release mucoadhesive buccal tablet containing miconazole nitrate versus systemic therapy with ketoconazole in HIV-positive patients with oropharyngeal candidiasis. J Acquir Immune Defic Syndr 35:144–150PubMedCrossRefGoogle Scholar
  9. 9.
    Gascoigne EW, Barton GJ, Michaels M, Meuldermans WH (1981) The kinetics of ketoconazole in animals and man. Clin Res Rev 1:177–187Google Scholar
  10. 10.
    Brass C, Galgiani JN, Blaschke TF, Defelice R, O’Reilly RA, Stevens DA (1982) Disposition of ketoconazole, an oral antifungal, in human. Antimicrob Agents Chemother 21:151–158PubMedGoogle Scholar
  11. 11.
    Lamson M, Robinson P, Gigliotti M, Myers WM (1998) The pharmacokinetic interaction of nevirapine and ketoconazole. In: Abstr 12th World AIDS Conf, abstr 12218. Geneva, p 55Google Scholar
  12. 12.
    Berry M, Mulcahy F, Merry C, Gibbons S, Back D (1999) Pharmacokinetics and potential interactions and amongst antiretroviral agents used to treat HIV infection. Clin Pharmacokinet 36:289–304CrossRefGoogle Scholar
  13. 13.
    Clarke SM, Mulcahy FM, Tjia J, Reynolds HE, Gibbon SE, Berry MG, Back DJ (2001) The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 51:213–217PubMedCrossRefGoogle Scholar
  14. 14.
    Aarnoutse RE, Grintjes K, Telgt DS, Stek M Jr, Hugen PW, Reiss P, Koopmans PP, Hekster YA, Burger DM (2002) The influence of efavirenz on the pharmacokinetics of a twice-daily combination of indinavir and low-dose ritonavir in healthy volunteers. Clin Pharmacol Ther 71:57–67PubMedCrossRefGoogle Scholar
  15. 15.
    Dailly E, Allavena C, Raffi F, Jolliet P (2005) Pharmacokinetic evidence of the induction of lopinavir metabolism by efavirenz. Br J Clin Pharmacol 60:32–34PubMedCrossRefGoogle Scholar
  16. 16.
    Gerber JG, Rosenkranz SL, Fichtenbaum CJ, Vega JM, Yang A, Alston BL, Brobst SW, Segal Y, Aberg JA (2005) Effect of efavirenz on the pharmacokinetics of simvastatin, atorvastatin, and pravastatin: results of AIDS Clinical Trials Group 5108 Study. J Acquir Immune Defic Syndr 39:307–312PubMedCrossRefGoogle Scholar
  17. 17.
    Berruet N, Sentenac S, Auchere D, Gimenez F, Farinotti R, Fernandez C (2005) Effect of efavirenz on intestinal p-glycoprotein and hepatic p450 function in rats. J Pharm Pharmaceut Sci 8:226–234Google Scholar
  18. 18.
    Mouly S, Lown KS, Kornhauser D, Joseph JL, Fiske WD, Benedek IH, Watkin PB (2002) Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in human. Clin Pharmacol Ther 72:1–9PubMedCrossRefGoogle Scholar
  19. 19.
    Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW (2002) Interaction of Common Azole Antifungals with P-glycoprotein. Antimicrob Agents Chemother 46:160–165PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Somchai Sriwiriyajan
    • 1
  • Werawath Mahatthanatrakul
    • 2
  • Wibool Ridtitid
    • 2
  • Sutep Jaruratanasirikul
    • 1
  1. 1.Department of Medicine, Faculty of MedicinePrince of Songkla UniversitySongkhlaThailand
  2. 2.Department of Pharmacology, Faculty of SciencePrince of Songkla UniversitySongkhlaThailand

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