Clinical trial NCT01386970: Effect of Gender and HIV Infection on Zidovudine and Lamivudine Pharmacokinetics
Official title: Sex and Disease Dependent Nucleoside Analog Toxicity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: HIV
Keywords: Pharmacokinetics
antiretroviral therapy
nucleoside analogs
mitochondrial toxicity
clinical pharmacology
cellular pharmacology
pharmacogenetics
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: University of Hawaii
First posted: 2011-07-01
Enrollment: 43
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

Brief summary: 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.


Eligibility 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.

Primary outcomes:
measure: ZDV-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject
timeFrame: Day 12 of dosing
measure: 3TC-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject
timeFrame: Day 12 of dosing
Secondary outcomes:
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver and Health Sciences Center
state: Colorado
Study officials:
affiliation: University of Colorado Denver and Health Sciences Center
name: Peter L. Anderson, PharmD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Anderson PL, Rower JE. Zidovudine and Lamivudine for HIV Infection. Clin Med Rev Ther. 2010;2:a2004.
citation: 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. No abstract available.
citation: 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.
citation: 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. doi: 10.1097/QAD.0b013e3282741feb.
citation: 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.