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Pharmacokinetics of Intracellular TFV-DP and FTC-TP in HIV-infected Adolescents

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ClinicalTrials.gov Identifier: NCT03800394
Recruitment Status : Recruiting
First Posted : January 11, 2019
Last Update Posted : February 2, 2021
Sponsor:
Collaborator:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Information provided by (Responsible Party):
University of Florida

Study Description
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Brief Summary:
Tenofovir (TFV) disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) is the preferred nucleoside backbone of first-line antiretroviral therapy (ART) for adolescents in sub-Saharan Africa. In addition, TDF/FTC is recommended for preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection in adolescents at substantial risk of acquisition of HIV infection, as well as for hepatitis B virus (HBV) treatment in those with HBV/HIV coinfection. The efficacy TDF and FTC are dependent on intracellular concentrations of the active phosphate anabolites, called TFV diphosphate (TFV-DP) and FTC triphosphate (FTC-TP). However, the intracellular pharmacokinetics of TFV-DP and FTC-TP to examine the adequacy of current dosages in African adolescents has not been previously studied. Thus, examining the pharmacokinetics (PK) of these widely used antiretrovirals in African adolescents is important as ART outcomes remain poor and the recommended dosages of these drugs for children and adolescent were extrapolated from drug approval clinical trials in adult in the United States and Europe.

Condition or disease Intervention/treatment
Human Immunodeficiency Virus (HIV) Tuberculosis Coinfection Other: Observational PK study

Detailed Description:
This study will evaluate the intracellular PK of TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents with and without TB coinfection. As the clinical effects of TDF and FTC are related to the intracellular concentrations of the phosphate anabolites, called TFV-DP and FTC-TP, there is a need to understand the cellular pharmacology of TDF interactions in African HIV-infected adolescents with and without TB, as the study team cannot extrapolate from US patients not on antituberculosis (anti-TB) drugs. This study will enroll HIV-infected adolescents aged 10 to 18 years old with and without TB coinfection who are already established on ART. The study team hypothesize that younger age, adenosine triphosphate (ATP)-binding cassette subfamily C (ABCC) single nucleotide polymorphisms (SNPs) and anti-TB therapy may influence the intracellular TFV-DP and FTC-TP concentrations in adolescents.
Study Design
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Study Type : Observational
Estimated Enrollment : 54 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children
Actual Study Start Date : January 28, 2019
Estimated Primary Completion Date : August 31, 2022
Estimated Study Completion Date : August 31, 2023

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Group/Cohort Intervention/treatment
HIV only
Adolescents aged 10-19 years with HIV infection
 Other: Observational PK study
Effect of antituberculosis treatment, age and genetic factors on intracellular TFV-DP and FTC-TP concentrations
HIV/TB
Adolescents aged 10-19 years with HIV and TB coinfection
 Other: Observational PK study
Effect of antituberculosis treatment, age and genetic factors on intracellular TFV-DP and FTC-TP concentrations


Outcome Measures
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Primary Outcome Measures :
  1. Average concentration (Cav) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Mean and median Cav of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.

  2. Area under the time-concentration curve 0-24 hours (AUC0-24h) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Mean and median AUC0-24h of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.

  3. Cav of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean intracellular TFV-DP and FTC-TP Cav in adolescents with TB/HIV coinfection compared to those only HIV infection.

  4. AUC0-24h of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents with TB/HIV coinfection compared to those with only HIV infection.


Secondary Outcome Measures :
  1. Effect of age on TFV-DP and FTC-TP Cav. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean of intracellular TFV-DP and FTC-TP Cav in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.

  2. Effect of age on TFV-DP and FTC-TP AUC0-24h . [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.

  3. Intracellular TFV-DP and FTC-TP Cav in adolescents compared to that in historical adult controls. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean of intracellular TFV-DP and FTC-TP Cav in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.

  4. Intracellular TFV-DP and FTC-TP AUC0-24h in adolescents compared to that in historical adult controls. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.

  5. Relationship between Adenosine triphosphate (ATP)-binding cassette subfamily C, member 2 (ABCC2), member 4 (ABCC4) and member 10 (ABCC10) SNPs and TFV-DP and FTC-TP AUC0-24h. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Relationship between ABCC2, ABCC4 and ABCC10 SNPs and intracellular TFV-DP and FTC-TP AUC0-24h.

  6. Prevalence and covariates of intracellular TFV-DP Cav < 95 fmol/106 cells in adolescents. [ Time Frame: After at least 8 weeks of HIV therapy. ]
    Proportion of Ghanaian adolescents and factors associated with intracellular TFV-DP average concentration < 95 fmol/106 cells.


Biospecimen Retention:   Samples With DNA
Peripheral mononuclear cells (PBMCs) and deoxyribonucleic acid (DNA)

Eligibility Criteria
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Ages Eligible for Study:   10 Years to 19 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Adolescents aged 10-19 years with HIV with or without TB co-infection.
Criteria

Inclusion Criteria:

  • HIV-infected adolescents aged 10 to 19 years old who are stable on antiretroviral regimen containing TDF/FTC (300/200 mg daily) for at least 8 weeks.

Exclusion Criteria:

  • Unable to obtain informed signed consent from parent(s) or legal guardian.
  • Pregnant or breast feeding.
  • Require therapy for other opportunistic infections other than tuberculosis (TB).
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03800394


Contacts
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Contact: Awewura Kwara, MD 352-273-9501 awewura.kwara@medicine.ufl.edu
Contact: Oluwayemisi Ojewale, MBChB, MPH 3522739446 oawoyemi@ufl.edu

Locations
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Ghana
Kwame Nkrumah University of Science and Technology Recruiting
Kumasi, Ghana
Contact: Sampson Antwi, MBChB    +233265812061    Kantwi@gmail.com   
Contact: Anthony Enimil, MBChB    +233208164433    Tenimil@live.com   
Principal Investigator: Sampson Antwi, MBChB         
Sub-Investigator: Anthony Enimil, MBChB         
Sponsors and Collaborators
University of Florida
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Investigators
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Principal Investigator: Awewura Kwara, MD University of Florida
More Information
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Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03800394    
Other Study ID Numbers: IRB201801820 - PKAdol
2R01HD071779 ( U.S. NIH Grant/Contract )
First Posted: January 11, 2019    Key Record Dates
Last Update Posted: February 2, 2021
Last Verified: February 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by University of Florida:
Pharmacokinetic
Pharmacogenomic
Tenofovir diphosphate
Emtricitabine triphosphate
Adolescents
Additional relevant MeSH terms:
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Tuberculosis
Acquired Immunodeficiency Syndrome
HIV Infections
Coinfection
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Immunologic Deficiency Syndromes
 Immune System Diseases
Blood-Borne Infections
Communicable Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Slow Virus Diseases