Dose Proportionality of TFV-DP After a Single Dose of GS-7340 in Women

NCT02357602 | Completed Phase 1 DMC

• 1 other identifier: 14-2797
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Purpose: The purpose of this study is to characterize the dose-proportionality in the distribution of tenofovir alafenamide (TAF) and tenofovir (TFV) in plasma and mucosal tissues, and TFV-diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs) and mucosal tissues of healthy female subjects following a single oral dose of GS-7430 at 5mg, 10mg, and 25mg.

Conditions

Healthy

Keywords

Participants; HIV-1 negative

Outcome Measures

Primary Outcomes (3)

• Plasma Dose-Proportionality

  To characterize the dose-proportionality in the distribution of TAF and TFV in the plasma of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.

  Pre-dose and 1, 3, 6, 12, 24 hours, and 3, 7, 10, and 14 days following single dose

• Tissue Dose-Proportionality

  To characterize the dose-proportionality in the distribution of TAF and TFV in mucosal tissues, and TFV-DP in mucosal tissues of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.

  At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose

• PBMC Dose-Proportionality

  To characterize the dose-proportionality in the distribution of TFV-DP in PBMCs of healthy female subjects following a single oral dose of GS-7340 at 5mg, 10mg, and 25mg. This will be used to develop a predictive pharmacokinetic model for TAF which will allow for TFVdp exposure predictions given a specific dose and dosing interval.

  Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose

Secondary Outcomes (4)

• Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood

  Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose

• Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in peripheral blood

  Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose

• Intra-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues

  At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose

• Inter-subject variability in intracellular deoxyadenosine triphosphate (dATP) in mucosal tissues

  At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose

Other Outcomes (1)

• Cervicovaginal Fluid (CVF) Concentration

  At 1, 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose.

Study Arms (3)

1. GS-7340 25mg

EXPERIMENTAL

The first 8 women on study will be assigned to take a single dose of 25mg TAF (1 tablet) orally.

Drug: GS-7340

2. GS-7340 10mg

EXPERIMENTAL

The 2nd group of 8 women will be sequentially assigned to take a single dose of 10mg TAF (1 tablet) orally.

Drug: GS-7340

3. GS-7340 5mg

EXPERIMENTAL

The final 8 women on study will be sequentially assigned to take a single dose of 5mg TAF (1/2 tablet) orally.

Drug: GS-7340

Interventions

GS-7340 DRUG

Medication is supplied in 10 or 25mg tablets, so subjects will receive either 1/2 or one tablet in a single dose.

Also known as: TAF, Tenofovir Alafenamide

1. GS-7340 25mg; 2. GS-7340 10mg; 3. GS-7340 5mg

Eligibility Criteria

• Age: 18 Years - 49 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy pre-menopausal female subjects between the ages of 18 and 49 years, inclusive on the date of screening, with an intact gastrointestinal tract, uterus, and cervix.
• All subjects must have an estimated calculated creatinine clearance (eCcr) of at least 80 mL/min
• All subjects must have negative pregnancy tests, and be using an acceptable form of birth control
• Body Mass Index (BMI) of approximately 18 to 34 kg/m²; and a total body weight \> 45 kg (99 lbs).
• Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the trial.
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.
• Subject must have documentation of a normal pap smear within 36 months of the screening visit, no procedures for abnormal cervical/vaginal pathology in the last six months, at least one prior gynecological visit as part of subject's routine medical history.
• Subject must be willing to abstain from sexual intercourse, douching, and all intravaginal and intrarectal objects and products for at least 72 hours prior to Day 1 until study completion.
• Subject must be HIV-1 and Hepatitis B surface antigen negative
• Subject must not be actively involved in the conception process.
• Subject must be able to swallow pills and have no allergies to any component of the study products

You may not qualify if:

• Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease (including documented drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing).
• Subjects with a history of hysterectomy
• Subjects who are pregnant, possibly pregnant or lactating
• Subjects with a presence of vaginal discharge or genital bleeding at screening
• History of febrile illness within five days prior to first dose.
• Any condition possibly affecting drug absorption (eg, gastrectomy).
• A positive urine drug screen.
• A positive result for HIV, Hepatitis B or C
• An untreated-positive test for syphilis, gonorrhea, Chlamydia, or trichomonas at screening, or symptomatic bacterial vaginosis.
• Any laboratory chemistry or hematology result Grade 2 or greater according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Laboratory Grading Tables
• Treatment with an investigational drug within 4 months preceding the first dose of trial medication.
• History of regular alcohol consumption exceeding study limits
• Participation in a clinical trial involving vaginal or rectal biopsies within 6 months preceding the first dose of trial medication.
• Use of prescription or nonprescription drugs, vitamins, and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of trial medication and unable to avoid use during the study period until after the last sample is collected.
• Blood donation of approximately 1 pint (500 mL) within 56 days prior to dosing.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• Gilead Sciences: collaborator

Study Sites (1)

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (1)

• Cottrell ML, Garrett KL, Prince HMA, Sykes C, Schauer A, Emerson CW, Peery A, Rooney JF, McCallister S, Gay C, Kashuba ADM. Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother. 2017 Jun 1;72(6):1731-1740. doi: 10.1093/jac/dkx064.

  PMID: 28369415 DERIVED

MeSH Terms

Interventions

tenofovir alafenamide

Study Officials

• Angela DM Kashuba, PharmD

  UNC Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2015
• First Posted: February 6, 2015
• Study Start: March 1, 2015
• Primary Completion: October 1, 2015
• Study Completion: November 1, 2016
• Last Updated: November 30, 2016

Record last verified: 2016-11

Locations

US (1)