Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers
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
- 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.
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers|
|Study Start Date:||November 2002|
|Study Completion Date:||August 2007|
|Primary Completion Date:||August 2007 (Final data collection date for primary outcome measure)|
The expression of P-glycoprotein, a transporter protein present in enterocytes as well as other cells involved in the absorption and distribution of HIV protease inhibitors, has been linked to a single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T. Individuals homozygous for the T allele have reduced P-gp expression compared to CC individuals. Preliminary studies by other investigators to determine the influence of MDR1 genotype on HIV protease inhibitor pharmacokinetics have yielded inconclusive results. The primary purpose of this study is to determine the relationship, if any, between MDR1 genotypes and plasma concentrations of the HIV protease inhibitors indinavir and saquinavir. Secondary objectives of this investigation will (1) assess the relationship between CYP3A4 activity and indinavir and saquinavir exposure and (2) characterize the relationship, if any, between P-gp expression on lymphocyte surfaces and MDR1 genotype. Up to 150 subjects will be screened to enroll a total of 63 healthy volunteers (21 subjects each in the CC, TT, and CT groups). Each subject will have blood drawn for P-gp expression analysis and MDR1 genotyping at screening. Next, subjects will receive oral midazolam 8 mg for CYP3A4 phenotyping; a single blood sample will be collected 4 hours after midazolam administration for determination of midazolam and 1-hydroxymidazolam. Between 7 and 28 days after midazolam administration, subjects will receive indinavir 800 mg every 8 hours for one day and a single 800 mg dose the next morning (dose #4). Between 7 and 28 days after indinavir administration, subjects will receive saquinavir soft-gel capsules 1200 mg three times daily for 3 days and a single dose on the morning of day 4 (dose # 10). Post-dose blood samples will be collected over 8 hours following dose #4 of indinavir and dose #10 of saquinavir. Indinavir and saquinavir pharmacokinetic parameters (primarily AUC and Cmax) will be compared across MDR1 genotype groups using ANOVA with post-hoc testing. 1-hydroxymidazolam: midazolam ratios will be correlated to indinavir and saquinavir AUCs as well as compared across MDR1 genotype groups. P-gp expression on lymphocyte surfaces will be determined by flow cytometry, quantified, and compared across MDR1 genotype groups. Data from this investigation will determine whether MDR1 genotype influences protease inhibitor plasma concentrations.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00050180
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Nicolas Wentzensen, M.D.||National Cancer Institute (NCI)|