HealthyPhase 4NCT00050180
Influence of the MDR1 Genotype on Blood Levels of Indinavir and Saquinavir in Healthy Volunteers
A Phase 4 study testing Midazolam, Indinavir and Saquinavir in people with Healthy and HIV Infections, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Healthy, HIV Infections
- What is being tested?
- Midazolam, Indinavir and Saquinavir
- How many people
- 81 participants
- Where
- 1 siteUnited States
- Study dates
- 22 Nov 2002to 24 Aug 2007
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Males and females between the ages of 18 and 60 years.
- Healthy by medical history and physical exam
- Laboratory values within established guidelines for participation in clinical studies: AST less than or equal to 2 times ULN (upper limit of normal); Serum creatinine less than or equal to ULN; hemoglobin greater than or equal to 11 g/dL.
- Ability to abstain from ingesting grapefruit or grapefruit juice 72 hours prior to, and the days of midazolam phenotyping and indinavir and saquinavir administration.
- Negative serum pregnancy test for females of child-bearing potential.
- Females of child-bearing potential are able and willing to practice abstinence or use other effective methods of birth control during Phase II of study that do not include oral contraceptives.
Who cannot join
- Concomitant routine therapy with any prescription, over the counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation.
- Subjects must be off oral contraceptives for at least 30 days prior to blood collection for P-gp expression analysis; they must also be off oral contraceptives for at least 30 days prior to midazolam phenotyping, and indinavir and saquinavir administration.
- Intermittent (PRN) use of acetaminophen and non-steroidal anti-inflammatory medications (i.e. ibuprofen) will be allowed during the study; these medications should not be taken prior to, or within 4 hours of midazolam administration on Day 0. These medications should not be taken during indinavir and saquinavir administration until all blood samples for pharmacokinetic analyses of the respective drugs have been obtained.
- Subjects will be allowed to take a multivitamin with minerals, or equivalent, once daily if they desire to do so.
- Inability to obtain venous access for sample collection.
- Presence of Diabetes mellitus, Human immunodeficiency virus (HIV) infection, cardiac disease (hypertension; congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency), respiratory disease (asthma requiring chronic treatment; chronic obstructive pulmonary disease) or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigator.
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- Positive pregnancy test or breastfeeding female.
- The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
- Drug or alcohol use that may impair safety or adherence.
- History of intolerance or allergic reaction (rash; hives; swollen lips; difficulty breathing) to indinavir, saquinavir or midazolam.
- Inability or unwillingness of females of child-bearing potential, to use a non-hormonal (barrier) method of contraception throughout the study (e.g. condom diaphragm etc.).
- Current cigarette smoker or regular smoker within the past 6 weeks.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics 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:
Read more
- 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.
Read the 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.
- Conditions
- Healthy, HIV Infections
- Being tested
- Midazolam, Indinavir, Saquinavir
- Keywords
- P-Glycoprotein, Protease Inhibitor, Antiretrovirals, Cytochrome P450, Drug Transporters, Healthy Volunteer, HV
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MidazolamDrug
IndinavirDrug
SaquinavirDrug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Nov 2002 (estimated)
- Study start22 Nov 2002
- Primary completion24 Aug 2007
- Study completion24 Aug 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Enrolment
- 81 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institutes of Health Clinical Center (CC)
- Sponsor type
- US National Institutes of Health
- Investigators
- Nicolas Wentzensen, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00050180
- Sponsor's protocol ID
- 030052
- Other IDs
- 03-CC-0052
- Status last verified
- 3 May 2012
- First submitted
- 25 Nov 2002
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
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. doi: 10.1056/NEJM199709113371101.
PubMed 9287227Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. Pharmacotherapy. 1999 Jun;19(6):708-12. doi: 10.1592/phco.19.9.708.31544.
PubMed 10391416Matheny CJ, Lamb MW, Brouwer KR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy. 2001 Jul;21(7):778-96. doi: 10.1592/phco.21.9.778.34558.
PubMed 11444575
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Influence of MDR1 Genotype on Indinavir and Saquinavir Pharmacokinetics in Healthy Volunteers
- ClinicalTrials.gov ID
- NCT00050180
- Acronym / sponsor ID
- 030052
- Conditions
- Healthy, HIV Infections
- Keywords
- P-Glycoprotein, Protease Inhibitor, Antiretrovirals, Cytochrome P450, Drug Transporters, Healthy Volunteer, HV
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 81 participants (actual)
- Lead sponsor
- National Institutes of Health Clinical Center (CC)US National Institutes of Health
- Study start
- 22 Nov 2002
- Primary completion
- 24 Aug 2007 (actual)
- Study completion
- 24 Aug 2007 (actual)
- First posted
- 26 Nov 2002 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
Key exclusion criteria (12 listed)
- Concomitant routine therapy with any prescription, over the counter, herbal, or holistic medications, including oral contraceptives for 30 days prior to study participation.
- Inability to obtain venous access for sample collection.
- Presence of Diabetes mellitus, Human immunodeficiency virus (HIV) infection, cardiac disease (hypertension; congestive heart failure etc.), renal disease (chronic or acute renal failure or insufficiency), respiratory disease (asthma requiring chronic treatment; chronic obstructive pulmonary disease) or any other condition that may interfere with the interpretation of the study results or not be in the best interest of the subject in the opinion of the investigator.
- Positive pregnancy test or breastfeeding female.
- The presence of persistent diarrhea or malabsorption that would interfere with the subject's ability to absorb drugs.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Midazolam | Drug | – |
| Indinavir | Drug | – |
| Saquinavir | Drug | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 9287227Hammer 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. doi: 10.1056/NEJM199709113371101.
- Background: PubMed 10391416Acosta EP, Henry K, Baken L, Page LM, Fletcher CV. Indinavir concentrations and antiviral effect. Pharmacotherapy. 1999 Jun;19(6):708-12. doi: 10.1592/phco.19.9.708.31544.
- Background: PubMed 11444575Matheny CJ, Lamb MW, Brouwer KR, Pollack GM. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy. 2001 Jul;21(7):778-96. doi: 10.1592/phco.21.9.778.34558.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nicolas Wentzensen, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Midazolam, Indinavir and Saquinavir in people with Healthy and HIV Infections, run by National Institutes of Health Clinical Center (CC) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00050180, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.