Effect of Gender and HIV Infection on Zidovudine and Lamivudine Pharmacokinetics

Overview

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.

Full Title of Study: “Sex and Disease Dependent Nucleoside Analog Toxicity”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Non-Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Other
  • Masking: None (Open Label)
• Study Primary Completion Date: July 2008

Interventions

• 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

Arms, Groups and Cohorts

• 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.
• 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.

Clinical Trial Outcome Measures

Primary Measures

• ZDV-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject
  • Time Frame: Day 12 of dosing
  • To compare ZDV- triphosphate concentrations in HIV-negative versus HIV-infected subjects.
• 3TC-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject
  • Time Frame: Day 12 of dosing
  • To compare 3TC- triphosphate concentrations in HIV-negative versus HIV-infected subjects.

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 55 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

• Lead Sponsor
  • University of Colorado, Denver
• Collaborator
  • National Institute of Allergy and Infectious Diseases (NIAID)
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Peter L. Anderson, PharmD, Principal Investigator, University of Colorado Denver and Health Sciences Center

References

Anderson PL. Recent developments in the clinical pharmacology of anti-HIV nucleoside analogs. Curr Opin HIV AIDS. 2008 May;3(3):258-65. doi: 10.1097/COH.0b013e3282f85dc1.

Anderson PL, Rower JE. Zidovudine and Lamivudine for HIV Infection. Clin Med Rev Ther. 2010;2:a2004.

Ghodke Y, Anderson PL, Sangkuhl K, Lamba J, Altman RB, Klein TE. PharmGKB summary: zidovudine pathway. Pharmacogenet Genomics. 2012 Dec;22(12):891-4. doi: 10.1097/FPC.0b013e32835879a8.

Citations Reporting on Results

Rower JE, Klein B, Bushman LR, Anderson PL. Validation of a sensitive LC/MS/MS method for the determination of zidovudine and lamivudine in human plasma. Biomed Chromatogr. 2012 Jan;26(1):12-20. doi: 10.1002/bmc.1617. Epub 2011 Apr 4.

Anderson PL, Zheng JH, King T, Bushman LR, Predhomme J, Meditz A, Gerber J, Fletcher CV. Concentrations of zidovudine- and lamivudine-triphosphate according to cell type in HIV-seronegative adults. AIDS. 2007 Sep 12;21(14):1849-54.

Rower JE, Meditz A, Gardner EM, Lichtenstein K, Predhomme J, Bushman LR, Klein B, Zheng JH, Mawhinney S, Anderson PL. Effect of HIV-1 infection and sex on the cellular pharmacology of the antiretroviral drugs zidovudine and lamivudine. Antimicrob Agents Chemother. 2012 Jun;56(6):3011-9. doi: 10.1128/AAC.06337-11. Epub 2012 Mar 5.