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Effect of Gender and HIV Infection on Zidovudine and Lamivudine Pharmacokinetics

This study has been completed.
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
University of Hawaii
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01386970
First received: June 28, 2011
Last updated: May 1, 2017
Last verified: May 2017
  Purpose
This study evaluated the blood and blood cell concentrations of zidovudine and lamivudine in men versus women and in those with versus without HIV infection. Additionally, markers of side effects were correlated with blood levels of the drugs. The hypothesis was that women and those with HIV would have higher drug levels, as well as markers of side effects.

Condition Intervention Phase
HIV Drug: zidovudine 300mg and lamivudine 150mg as Combivir Phase 4

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Sex and Disease Dependent Nucleoside Analog Toxicity

Resource links provided by NLM:


Further study details as provided by University of Colorado, Denver:

Primary Outcome Measures:
  • To compare zidovudine (ZDV)- and lamivudine (3TC)-triphosphate concentrations in women versus men. [ Time Frame: 12 days ]
    1st dose and day 12 dose compared after 12 days


Secondary Outcome Measures:
  • Change in mitochondrial DNA before and after blood analysis [ Time Frame: day 12 (HIV negative) up to 2 years (HIV-infected) ]
    To investigate relationships between ZDV- and 3TC-triphosphate concentrations and changes in mitochondrial DNA

  • To investigate relationships between ZDV- and 3TC-triphosphate concentrations and the incidence of clinical side effects. [ Time Frame: day 12 (HIV-negative) various longer duration in times (HIV-infected) ]
    To investigate relationships between ZDV- and 3TC-triphosphate concentrations and changes in mitochondrial DNA

  • Drug levels compared between HIV negative and HIV infected subject [ Time Frame: 1st dose and day 12 dose ]
    To compare ZDV- and 3TC- triphosphate concentrations in HIV-negative versus HIV-infected subjects.


Other Outcome Measures:
  • genetic associations with ZDV and 3TC disposition [ Time Frame: study time frame ]
    Variability in genes encoding proteins influencing the disposition of ZDV and 3TC will be correlated with ZDV and 3TC disposition.


Enrollment: 51
Study Start Date: May 2005
Study Completion Date: July 2010
Primary Completion Date: July 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: HIV-negative
This group was used to compare intracellular ZDV- and 3TC-triphosphate concentrations to the HIV-infected group and in men versus women.
Drug: zidovudine 300mg and lamivudine 150mg as Combivir
twice daily for 12 days in the HIV-negative group and indefinitely for their care in the HIV-positive group
Active Comparator: HIV-infected
This group was started on ZDV-3TC based therapy. Intracellular ZDV- and 3TC-triphosphate concentrations were compared in men versus women and the HIV-negative group.
Drug: zidovudine 300mg and lamivudine 150mg as Combivir
twice daily for 12 days in the HIV-negative group and indefinitely for their care in the HIV-positive group

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Documented physician-diagnosed HIV-infection (HIV+ antibody or plasma HIV-RNA+); HIV-negative volunteers must have a negative HIV-ELISA.
  • Age 18 to 55 years;
  • Either antiretroviral naïve, or no HIV-therapy in the preceding 6 months;
  • Planned antiretroviral regimen includes standard doses of ZDV plus 3TC as part of the antiretroviral regimen. Once- or twice-daily 3TC will be allowed.

Exclusion Criteria:

  • Any medical condition that in the opinion of the investigators would jeopardize the intent of the study.
  • In the opinion of the investigator, any concomitant immunomodulatory medications, chemotherapeutic agents, investigational drugs, and alternative therapies, including, glucocorticoids, recombinant growth factors or cytokines (e.g. Granulocyte-macrophage colony-stimulating factor, Granulocyte colony-stimulating factor, interferon-alpha or gamma, human growth hormone, etc), ribavirin, birth-control pills, and sex hormones that could interfere with the cellular pharmacology of the study medications;
  • Concomitant medications that interfere with renal drug clearances including, tenofovir, adefovir, cidofovir, ganciclovir, probenecid, or any similarly problematic medication in the opinion of the investigators;
  • Concomitant warfarin or daily aspirin (to prevent excess bleeding from biopsy).
  • Pregnancy or a plan to become pregnant, or menopause;
  • Any > or = grade II abnormality in hemoglobin, absolute neutrophil count, routine liver function tests, serum creatinine, or other organ function abnormalities.
  • Any medical or personal condition that, in the judgment of the investigators, may influence the subject's ability to comply with study conditions, such as active mental illnesses, or plans to leave the geographical area.
  • Inability to give informed consent.
  • Triple nucleoside analog reverse transcriptase regimens.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01386970

Locations
United States, Colorado
University of Colorado Denver and Health Sciences Center
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
National Institute of Allergy and Infectious Diseases (NIAID)
University of Hawaii
Investigators
Principal Investigator: Peter L. Anderson, PharmD University of Colorado Denver and Health Sciences Center
  More Information

Publications:
Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01386970     History of Changes
Other Study ID Numbers: 04-1101
R01AI064029 ( U.S. NIH Grant/Contract )
Study First Received: June 28, 2011
Last Updated: May 1, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: No plan to share.

Keywords provided by University of Colorado, Denver:
Pharmacokinetics
antiretroviral therapy
nucleoside analogs
mitochondrial toxicity
clinical pharmacology
cellular pharmacology
pharmacogenetics

Additional relevant MeSH terms:
Lamivudine
Zidovudine
Lamivudine, zidovudine drug combination
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Anti-HIV Agents
Antimetabolites

ClinicalTrials.gov processed this record on August 21, 2017