Effect of Fluconazole, Clarithromycin, and Rifabutin on the Pharmacokinetics of Sulfamethoxazole-Trimethoprim and Dapsone and Their Hydroxylamine Metabolites

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000826

Collaborator

(none)

Enrollment

Locations

Patients Per Site

Study Details

Study Description

Brief Summary

To determine the effects of fluconazole and either rifabutin or clarithromycin, alone and in combination, on the pharmacokinetics of first sulfamethoxazole-trimethoprim and then dapsone in HIV-infected patients.

Although prophylaxis for more than one opportunistic infection is emerging as a common clinical practice in patients with advanced HIV disease, little is known about possible adverse drug interactions. The need exists to define pharmacokinetics and pharmacodynamic adverse interactions of the many combination prophylactic regimens that may be prescribed.

Condition or Disease	Intervention/Treatment	Phase
Bacterial Infections Mycoses HIV Infections	Drug: Clarithromycin Drug: Rifabutin Drug: Sulfamethoxazole-Trimethoprim Drug: Dapsone Drug: Fluconazole	Phase 1

Detailed Description

In Part A, patients receive sulfamethoxazole-trimethoprim (SMX/TMP) alone for 2 weeks, then in combination with fluconazole, rifabutin, or both drugs, each over 2-week periods in a randomly assigned order. Patients in Part B receive the same regimens except with clarithromycin substituted for rifabutin. In Part C, patients receive dapsone alone for 2 weeks, then in combination with fluconazole, rifabutin, or both drugs in the same manner as in Part A. Part D patients receive the same regimen as those in Part C, except with clarithromycin substituted for rifabutin. Patients are followed every 2 weeks.

Study Design

Study Type:

Interventional

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Effect of Fluconazole, Clarithromycin, and Rifabutin on the Pharmacokinetics of Sulfamethoxazole and Dapsone and Their Hydroxylamine Metabolites

Actual Study Completion Date :

May 1, 1999

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Concurrent Medication:

Allowed:

Antiretroviral therapy provided patient has been on a stable dose for at least 4 weeks prior to study entry.
Methadone for drug abuse programs provided patient has been on a stable dose for at least 4 weeks prior to the study.

Patients must have:

HIV infection.
CD4 count >= 200 cells/mm3.
No active opportunistic infection.

Prior Medication:

Allowed:

Antiretroviral therapy.
Methadone for drug abuse therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

Suspicion of gastrointestinal malabsorption problems (at discretion of investigator).
Known hypersensitivity to dapsone, SMX, or other sulfonamides, trimethoprim, clarithromycin, rifabutin or other rifamycins, fluconazole, or other azoles.
G-6-PD deficiency or methemoglobinemia (in Part C and D patients only).

Concurrent Medication:

Excluded:

Cytolytic agents.
Amiodarone.
Anesthetics, general.
Astemizole.
Azithromycin.
Barbiturates.
Carbamazepine.
Cimetidine.
Ciprofloxacin.
Cisapride.
Clarithromycin (except as required on study).
Clotrimazole.
Dexamethasone.
Disulfiram.
Erythromycin.
Fluoroquinolones.
Fluoxetine.
Gestodene.
Hydrochlorothiazide.
Hypoglycemics, oral.
Isoniazid.
Itraconazole.
Ketoconazole.
Levomepromazine.
Loratadine.
MAO inhibitors.
Methoxsalen.
Miconazole.
Nafcillin.
Narcotic analgesics.
Naringenin.
Nifedipine.
Norethindrone.
Pentazocine.
Phenothiazines.
Phenytoin.
Protease inhibitors.
Quinidine.
Ranitidine.
Rifabutin (except as required on study).
Rifampin.
Sedative hypnotics.
Sulfaphenazole.
Terfenadine.
Tranquilizers (unless allowed by investigator).
Tricyclic and tetracyclic antidepressants.
Troleandomycin.
Warfarin.

Concurrent Treatment:

Excluded:

Radiation therapy.

Prior Medication:

Excluded:

Cytolytic agents within 5 years prior to study entry.
Rifabutin and/or rifampin within 4 weeks prior to study entry.
Fluconazoles or other azoles within 4 weeks prior to study entry.
Glutathione, glutathione precursors, or related prodrugs within 2 weeks prior to study entry.