The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283)

Helen R. Winter, Carol B. Trapnell, John T. Slattery, Mark Jacobson, Debra L. Greenspan, Thomas Hooton, Jashvant D. Unadkat

Research output: Contribution to journalArticle

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Abstract

Sulfamethoxazole hydroxylamine formation, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)-infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection. HIV-1-infected subjects (CD4 + count ≥200 cells/mm 3) were enrolled in a 2-part (A and B), open-label drug interaction study (Adult AIDS Clinical Trial Group [AACTG] 283). In part A (n = 9), subjects received cotrimoxazole (1 tablet of 800 mg sulfamethoxazole/160 mg trimethoprim daily) alone for 2 weeks and then, in a randomly assigned order, cotrimoxazole plus either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 12) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. In part A, fluconazole decreased the area under the plasma concentration-time curve (AUC), percent of dose excreted in 24-hour urine, and formation clearance (CL f) of the hydroxylamine by 37%, 53%, and 61%, respectively (paired t test, P < .05). Rifabutin increased the AUC, percent excreted, and CL f of the hydroxylamine by 55%, 45%, and 53%, respectively (P < .05). Fluconazole plus rifabutin decreased the AUC, percent excreted, and CL f of the hydroxylamine by 21%, 37%, and 46%, respectively (P < .05). In part B the fluconazole data were similar to those of part A. Overall, clarithromycin had no effect on hydroxylamine production. If the exposure (AUC) to sulfamethoxazole hydroxylamine is predictive of sulfamethoxazole toxicity, then rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole will decrease the rates of adverse reactions to sulfamethoxazole in HIV-infected subjects.

Original languageEnglish
Pages (from-to)313-322
Number of pages10
JournalClinical Pharmacology and Therapeutics
Volume76
Issue number4
DOIs
StatePublished - Oct 1 2004
Externally publishedYes

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Rifabutin
Clarithromycin
Fluconazole
Virus Diseases
Acquired Immunodeficiency Syndrome
Clinical Trials
HIV
Sulfamethoxazole
Hydroxylamine
Area Under Curve
Sulfamethoxazole Drug Combination Trimethoprim
HIV-1
Trimethoprim
sulfamethoxazole hydroxylamine
CD4 Lymphocyte Count
Drug-Related Side Effects and Adverse Reactions
Drug Interactions
Tablets
Oxidative Stress
Urine

ASJC Scopus subject areas

  • Pharmacology

Cite this

The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). / Winter, Helen R.; Trapnell, Carol B.; Slattery, John T.; Jacobson, Mark; Greenspan, Debra L.; Hooton, Thomas; Unadkat, Jashvant D.

In: Clinical Pharmacology and Therapeutics, Vol. 76, No. 4, 01.10.2004, p. 313-322.

Research output: Contribution to journalArticle

Winter, Helen R. ; Trapnell, Carol B. ; Slattery, John T. ; Jacobson, Mark ; Greenspan, Debra L. ; Hooton, Thomas ; Unadkat, Jashvant D. / The effect of clarithromycin, fluconazole, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with human immunodeficiency virus infection (AACTG 283). In: Clinical Pharmacology and Therapeutics. 2004 ; Vol. 76, No. 4. pp. 313-322.
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abstract = "Sulfamethoxazole hydroxylamine formation, in combination with long-term oxidative stress, is thought to be the cause of high rates of adverse drug reactions to sulfamethoxazole in human immunodeficiency virus (HIV)-infected subjects. Therefore the goal of this study was to determine the effect of fluconazole, clarithromycin, and rifabutin on sulfamethoxazole hydroxylamine formation in individuals with HIV-1 infection. HIV-1-infected subjects (CD4 + count ≥200 cells/mm 3) were enrolled in a 2-part (A and B), open-label drug interaction study (Adult AIDS Clinical Trial Group [AACTG] 283). In part A (n = 9), subjects received cotrimoxazole (1 tablet of 800 mg sulfamethoxazole/160 mg trimethoprim daily) alone for 2 weeks and then, in a randomly assigned order, cotrimoxazole plus either fluconazole (200 mg daily), rifabutin (300 mg daily), or fluconazole plus rifabutin, each for a 2-week period. Part B (n = 12) was identical to part A except that clarithromycin (500 mg twice daily) was substituted for rifabutin. In part A, fluconazole decreased the area under the plasma concentration-time curve (AUC), percent of dose excreted in 24-hour urine, and formation clearance (CL f) of the hydroxylamine by 37{\%}, 53{\%}, and 61{\%}, respectively (paired t test, P < .05). Rifabutin increased the AUC, percent excreted, and CL f of the hydroxylamine by 55{\%}, 45{\%}, and 53{\%}, respectively (P < .05). Fluconazole plus rifabutin decreased the AUC, percent excreted, and CL f of the hydroxylamine by 21{\%}, 37{\%}, and 46{\%}, respectively (P < .05). In part B the fluconazole data were similar to those of part A. Overall, clarithromycin had no effect on hydroxylamine production. If the exposure (AUC) to sulfamethoxazole hydroxylamine is predictive of sulfamethoxazole toxicity, then rifabutin will increase and clarithromycin plus fluconazole or rifabutin plus fluconazole will decrease the rates of adverse reactions to sulfamethoxazole in HIV-infected subjects.",
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