Effect of Gender and HIV Infection on Zidovudine and Lamivudine Pharmacokinetics

This study has been completed.
Sponsor:
Collaborators:
University of Hawaii
Information provided by (Responsible Party):
University of Colorado, Denver
ClinicalTrials.gov Identifier:
NCT01386970
First received: June 28, 2011
Last updated: December 11, 2012
Last verified: December 2012
  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
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
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 ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: Yes ]
    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) ] [ Designated as safety issue: Yes ]
  • Drug levels compared between HIV negative and HIV infected subject [ Time Frame: 1st dose and day 12 dose ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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
Genders Eligible for Study:   Both
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
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
Study First Received: June 28, 2011
Last Updated: December 11, 2012
Health Authority: United States: Federal Government
United States: Institutional Review Board

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

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

ClinicalTrials.gov processed this record on August 20, 2014