Ignite Creation Date:
2024-05-05 @ 11:29 AM
Last Modification Date:
2024-10-26 @ 9:08 AM
Study NCT ID:
NCT00050180
Status:
COMPLETED
Last Update Posted:
2017-07-02
First Post:
2002-11-25
Brief Title:
Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers
Sponsor:
National Institutes of Health Clinical Center CC
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers
Status:
COMPLETED
Status Verified Date:
2012-05-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 VersedRegistered 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 1200 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
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 VersedRegistered 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 1200 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
Detailed Description:
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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 03-CC-0052 | None | None | None |