Protocol Number: 03-CC-0052

Title:

Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers

Number:

03-CC-0052

Summary:

This study will examine whether a particular type of gene (MDR1) in the body can affect blood levels of two protease inhibitors, indinavir and saquinavir, which are used to treat people with HIV. If blood levels of these drugs are too low or too high, they may not work well or may cause side effects in patients. This study will determine how MDR1 genes might affect absorption of these medicines.

Healthy normal volunteers between 18 and 50 years of age may be eligible for this study. Candidates will be screened with a medical history and blood and urine tests. The blood will be tested for:

-Routine laboratory values for assessing general health

-HIV

-MDR1 gene type

-Amount of P-glycoprotein (a protein made by the MDR1 gene) on T cells.

Participants will have blood drawn three more times, as follows:

-After one dose of the sedative midazolam (Versed® (Registered Trademark)): Participants will take an 8-milligram dose of midazolam syrup by mouth. Four hours later, a single blood sample will be drawn through a needle in an arm vein. This part of the study will assess the efficiency of a certain enzyme involved in metabolizing (breaking down) indinavir and saquinavir.

-After four doses of indinavir: About a week after taking the midazolam, participants will take 800 mg of indinavir (two capsules) 3 times a day (every 8 hours) for 1 day. The following morning they will come to the clinic, where a catheter (flexible plastic tube) will be placed in an arm vein for repeated blood draws. A blood sample will be drawn, and a fourth and final dose of indinavir will be given. Seven blood samples of about a teaspoon each will then be collected through the catheter over an 8-hour period to measure blood levels of the drug.

-After 10 doses of saquinavir: About a week after the last dose of indinavir, participants will start taking 1,200 mg (6 capsules) of saquinavir soft-gelatin capsules 3 times a day for 3 days. On the fourth day, participants will come to the clinic. A catheter will be inserted into an arm vein and about 4 teaspoons of blood will be collected for routine laboratory tests and to measure saquinavir levels. A urine sample will also be collected for routine tests. Participants will then receive the tenth and final dose of saquinavir, and eight blood samples of about a teaspoon each will be collected through the catheter over an 8-hour period.

Sponsoring Institute:

National Institutes of Health Clinical Center (CC)

Recruitment Detail

Type: Completed Study; data analyses ongoing

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria: This study is not currently recruiting new subjects. If you have questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.

Special Instructions:

Currently Not Provided

Keyword(s):

P-Glycoprotein

Protease Inhibitor

Antiretrovirals

Cytochrome P450

Drug Transporters

Recruitment Keyword(s):

Healthy Volunteer

HV

Condition(s):

Healthy

HIV Infections

Investigational Drug(s):

None

Investigational Device(s):

None

Interventions:

Drug: Midazolam

Drug: Indinavir

Drug: Saquinavir

Supporting Site:

Warren G. Magnuson Clinical Center

Contact(s):

This study is not currently recruiting new subjects. If you have questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.

Citation(s):

Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997 Sep 11;337(11):725-33.

Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. Pharmacotherapy. 1999 Jun;19(6):708-12.

Matheny CJ, Lamb MW, Brouwer KR, Pollack GM Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy. 2001 Jul;21(7):778-96. Review.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

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