Differences in Blood Levels of Nevirapine in HIV-infected Patients in Uganda and the United States
| Status: | Completed |
|---|---|
| Conditions: | HIV / AIDS |
| Therapuetic Areas: | Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | February 2003 |
| End Date: | April 2011 |
Global Initiative to Characterize Differences in Antiretroviral Pharmacokinetics in HIV-Infected Populations
This study will determine whether blood levels of the anti-HIV medicine nevirapine are
different in HIV-infected patients in the United States from patients in Uganda. People from
all over the world take medications to treat HIV infection. These medicines work well in
some people but not in others, and they cause harmful side effects in some people and not in
others. These differences may be related to variations in how much of the drug reaches the
blood. Differences in drug blood levels among people in various areas of the world may be
attributed to differences in diet, state of health, ability to absorb the medicines from the
stomach, ability to eliminate the drugs from the body, and the brand of medicine taken. This
study will help scientists learn whether differences in blood levels of HIV medicines are
important in determining how well the drugs work in different patient populations.
HIV-infected patients 18 years of age and older in the United States and in Kampala, Uganda
who have been on an antiretroviral treatment regimen that includes at least 28 consecutive
days of nevirapine may be eligible for this study. Candidates will be screened with a
medical history, physical examination, and blood tests.
Participants will have a total of approximately about 5 ounces of blood drawn during this 6-
to 8-hour study. They will come to the NIH clinic in the morning, and a catheter (plastic
tube) will be inserted into an arm vein for collecting blood. (Alternatively, blood can be
collected by a needle inserted into an arm vein.) Blood will be withdrawn according to the
following schedule:
- About 5 tablespoons will be collected upon arrival at the clinic after an overnight
fast. Within 30 minutes of this blood draw, the patient will have breakfast and take
his or her morning dose of nevirapine, along with any other medications that need to be
taken at that time.
- 1 tablespoon of blood will be drawn 2 hours after the nevirapine dose.
- 1 tablespoon of blood will be drawn 4 hours later (6 hours after the nevirapine dose).
The blood will be analyzed for levels of nevirapine and possibly other HIV medicines. Some
of the blood will be stored for later analysis of genes (cytochrome P450 and MDR1) that are
involved in eliminating medicines from the body.
different in HIV-infected patients in the United States from patients in Uganda. People from
all over the world take medications to treat HIV infection. These medicines work well in
some people but not in others, and they cause harmful side effects in some people and not in
others. These differences may be related to variations in how much of the drug reaches the
blood. Differences in drug blood levels among people in various areas of the world may be
attributed to differences in diet, state of health, ability to absorb the medicines from the
stomach, ability to eliminate the drugs from the body, and the brand of medicine taken. This
study will help scientists learn whether differences in blood levels of HIV medicines are
important in determining how well the drugs work in different patient populations.
HIV-infected patients 18 years of age and older in the United States and in Kampala, Uganda
who have been on an antiretroviral treatment regimen that includes at least 28 consecutive
days of nevirapine may be eligible for this study. Candidates will be screened with a
medical history, physical examination, and blood tests.
Participants will have a total of approximately about 5 ounces of blood drawn during this 6-
to 8-hour study. They will come to the NIH clinic in the morning, and a catheter (plastic
tube) will be inserted into an arm vein for collecting blood. (Alternatively, blood can be
collected by a needle inserted into an arm vein.) Blood will be withdrawn according to the
following schedule:
- About 5 tablespoons will be collected upon arrival at the clinic after an overnight
fast. Within 30 minutes of this blood draw, the patient will have breakfast and take
his or her morning dose of nevirapine, along with any other medications that need to be
taken at that time.
- 1 tablespoon of blood will be drawn 2 hours after the nevirapine dose.
- 1 tablespoon of blood will be drawn 4 hours later (6 hours after the nevirapine dose).
The blood will be analyzed for levels of nevirapine and possibly other HIV medicines. Some
of the blood will be stored for later analysis of genes (cytochrome P450 and MDR1) that are
involved in eliminating medicines from the body.
The overwhelming majority of HIV-infected persons reside in the developing world. As such,
recent efforts have focused on providing antiretroviral pharmacotherapy to this population.
However, there are a number of factors indigenous to non-Western HIV-infected patients that
may alter their virologic, immunologic, and/or toxicologic response to antiretroviral
therapy. Absorption, distribution, and clearance of antiretroviral medications may differ
among patients residing in non-Western countries secondary to dietary influences, parasitic
infection, and malabsorption. Genetic polymorphisms of drug metabolizing enzymes (cytochrome
P450; CYP) and drug transporters (i.e. P-glycoprotein) may also contribute to altered
pharmacokinetics among these patients. The purpose of this pilot, hypothesis-generating
study is (1) to characterize the pharmacokinetics of the non-nucleoside reverse
transcriptase inhibitor nevirapine in a non-Western HIV-infected population (Kampala,
Uganda) and in a similar cohort of HIV-infected individuals in the United States and (2) to
compare pharmacokinetic parameter values between the groups. Twenty-five subjects from each
site will participate. Subjects from the Ugandan site may participate regardless of their
CD4+ lymphocyte count and viral load; they will be studied prior to the U.S. cohort. The
U.S. group will be selected to include subjects that are matched by gender to their Ugandan
counterparts. Subjects will have one pre-dose and two post-dose blood samples collected for
the determination of nevirapine plasma concentrations. Samples will be analyzed using
LC/MS-MS. Population pharmacokinetics parameter values (Cmax, Cmin, AUC, CL/F, Vd) will be
determined using NONMEM(Trademark) and compared between groups. Blood samples collected
during the study will also be used to determine CYP and MDR1 genotypes of study subjects in
an effort to explain any observed differences in pharmacokinetics parameter values between
the study populations.
recent efforts have focused on providing antiretroviral pharmacotherapy to this population.
However, there are a number of factors indigenous to non-Western HIV-infected patients that
may alter their virologic, immunologic, and/or toxicologic response to antiretroviral
therapy. Absorption, distribution, and clearance of antiretroviral medications may differ
among patients residing in non-Western countries secondary to dietary influences, parasitic
infection, and malabsorption. Genetic polymorphisms of drug metabolizing enzymes (cytochrome
P450; CYP) and drug transporters (i.e. P-glycoprotein) may also contribute to altered
pharmacokinetics among these patients. The purpose of this pilot, hypothesis-generating
study is (1) to characterize the pharmacokinetics of the non-nucleoside reverse
transcriptase inhibitor nevirapine in a non-Western HIV-infected population (Kampala,
Uganda) and in a similar cohort of HIV-infected individuals in the United States and (2) to
compare pharmacokinetic parameter values between the groups. Twenty-five subjects from each
site will participate. Subjects from the Ugandan site may participate regardless of their
CD4+ lymphocyte count and viral load; they will be studied prior to the U.S. cohort. The
U.S. group will be selected to include subjects that are matched by gender to their Ugandan
counterparts. Subjects will have one pre-dose and two post-dose blood samples collected for
the determination of nevirapine plasma concentrations. Samples will be analyzed using
LC/MS-MS. Population pharmacokinetics parameter values (Cmax, Cmin, AUC, CL/F, Vd) will be
determined using NONMEM(Trademark) and compared between groups. Blood samples collected
during the study will also be used to determine CYP and MDR1 genotypes of study subjects in
an effort to explain any observed differences in pharmacokinetics parameter values between
the study populations.
- INCLUSION CRITERIA:
1. Documentation in the patient's medical record of HIV-1 infection using double
ELISA or a second confirmatory test (e.g., Western Blot) or any one of the
following: detectable p24 antigen, quantifiable plasma HIV RNA, or detectable
proviral DNA.
2. Males and females greater than or equal to 18 years of age
3. Laboratory values within acceptable limits
AST/SGOT less than or equal to 5 times the upper limit of normal (ULN)
Serum creatinine less than or equal to 2 times the ULN
Hemoglobin greater than or equal to 9.0 g/dL
4. Receipt of a stable nevirapine-containing antiretroviral regimen for at least 28
days.
5. Informed consent signed and subject declares that they have been adherent to
their nevirapine-containing antiretroviral regimen.
EXCLUSION CRITERIA:
1. Presence of life-threatening or unstable renal, hepatic, cardiovascular, hematologic,
neurologic, psychiatric, or respiratory disease, as determined by medical records, 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.
2. Laboratory values outside acceptable limits
AST/SGOT less than 5 times the upper limit of normal (ULN)
Serum creatinine greater than 2 times the ULN
Hemoglobin less than 9.0 g/dL
3. Positive pregnancy test.
4. Receipt of IL-2 within 3 months of study participation.
5. Drug or alcohol use that may impair safety or adherence.
6. Poor venous access.
7. Documented or reported fever (greater than 38.5 degrees C) within 7 days of
screening.
8. Active opportunistic infection requiring therapy.
9. Refusal to agree to allow for specimens to be stored for future research.
10. Greater than 4 loose/soft stools per day.
11. Subject is non-adherent with their nevirapine-containing antiretroviral regimen
and/or they have not provided informed consent.
We found this trial at
2
sites
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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