Effect of Gender and HIV Infection on Zidovudine and Lamivudine Pharmacokinetics

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01386970
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH), University of Hawaii (Other)
• Enrollment: 43
• Location: 1
• Arms: 2
• Duration (Months): 62
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV	Drug: zidovudine 300mg and lamivudine 150mg as Combivir	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Sex and Disease Dependent Nucleoside Analog Toxicity
• Study Start Date: May 1, 2005
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. ZDV-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject [Day 12 of dosing]

   To compare ZDV- triphosphate concentrations in HIV-negative versus HIV-infected subjects.

2. 3TC-TP Drug Levels Compared Between HIV Negative and HIV Infected Subject [Day 12 of dosing]

   To compare 3TC- triphosphate concentrations in HIV-negative versus HIV-infected subjects.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

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

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01386970
• Other Study ID Numbers: 04-1101; R01AI064029
• First Posted: Jul 1, 2011
• Last Update Posted: Mar 16, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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

Study Results

Participant Flow

Arm/Group Title	HIV-negative	HIV-infected
Arm/Group Description	This group was used to compare intracellular ZDV- and 3TC-triphosphate concentrations to the HIV-infected group and in men versus women. zidovudine 300mg and lamivudine 150mg as Combivir: twice daily for 12 days in the HIV-negative group	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. zidovudine 300mg and lamivudine 150mg as Combivir: indefinitely for their care in the HIV-positive group
Period Title: Overall Study
STARTED	20	23
COMPLETED	16	21
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	HIV-negative	HIV-infected	Total
Arm/Group Description	This group was used to compare intracellular ZDV- and 3TC-triphosphate concentrations to the HIV-infected group and in men versus women. zidovudine 300mg and lamivudine 150mg as Combivir: twice daily for 12 days in the HIV-negative group	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. zidovudine 300mg and lamivudine 150mg as Combivir: indefinitely for their care in the HIV-positive group	Total of all reporting groups
Overall Participants	20	23	43
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	20 100%	23 100%	43 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	8 40%	6 26.1%	14 32.6%
Male	12 60%	17 73.9%	29 67.4%
Race/Ethnicity, Customized (Count of Participants)
African American	4 20%	7 30.4%	11 25.6%
Non- African-American	16 80%	16 69.6%	32 74.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV-negative	HIV-infected
Arm/Group Description	This group was used to compare intracellular ZDV-triphosphate concentrations to the HIV-infected group zidovudine 300mg twice daily for 12 days in the HIV-negative group	This group was used to compare intracellular ZDV-triphosphate concentrations to the HIV-infected group zidovudine 300mg twice daily for 12 days in the HIV-negative group
Measure Participants	20	23
Median (Inter-Quartile Range) [pmol/10^6 cells]	33.89	29.7

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	HIV-negative	HIV-infected
Arm/Group Description	This group was used to measure intracellular 3TC-triphosphate concentrations in those who are HIV-negative lamivudine 150mg twice daily for 12 days in the HIV-negative group	This group was used to measure intracellular 3TC-triphosphate concentrations in those who are HIV-positive lamivudine 150mg twice daily indefinitely for their care in the HIV-positive group
Measure Participants	20	23
Median (Inter-Quartile Range) [pmol/10^6 cells]	7.25	5.3

Adverse Events

Time Frame	Time of consenting to study exit (Day 12 or earlier).
Adverse Event Reporting Description	AEs were graded per the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0 - December 2004 (Clarification dated August 2009) (US Dept HHS, NIH, NIAID) Available from: https://rsc.niaid.nih.gov/sites/default/files/table-for-grading-severity-of-adult-pediatric-adverse-events.pdf
Arm/Group Title	HIV-negative		HIV-infected
Arm/Group Description	This group was used to compare intracellular ZDV- and 3TC-triphosphate concentrations to the HIV-infected group and in men versus women. zidovudine 300mg and lamivudine 150mg as Combivir: twice daily for 12 days in the HIV-negative group		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. zidovudine 300mg and lamivudine 150mg as Combivir: indefinitely for their care in the HIV-positive group
All Cause Mortality
	HIV-negative		HIV-infected
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/23 (0%)
Serious Adverse Events
	HIV-negative		HIV-infected
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	HIV-negative		HIV-infected
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/20 (35%)		8/23 (34.8%)
Endocrine disorders
Abnormal Lab- Amylase	0/20 (0%)		7/23 (30.4%)
Gastrointestinal disorders
Nausea, Vomiting, and/or Diarrhea	4/20 (20%)		1/23 (4.3%)
Hepatobiliary disorders
Abnormal lab- Bilirubin	7/20 (35%)		8/23 (34.8%)
Abnormal Lab- albumin	0/20 (0%)		6/23 (26.1%)
Abnormal Lab- Alanine Aminotransferase (ALT)	0/20 (0%)		7/23 (30.4%)
Abnormal Lab- Aspartate transaminase (AST)	0/20 (0%)		7/23 (30.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.