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

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: GS-7340

• Registration Number: NCT02357602
• Lead Sponsor: University of North Carolina, Chapel Hill

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.

Detailed Description

Participants:

This study will consist of approximately 24 premenopausal healthy volunteer women between 18-49 years of age with an intact cervix, uterus, and gastrointestinal tract. Women will be enrolled in the study within 42 days of screening depending on the timing of their menstrual cycle in comparison to the screening visit, and then will be on study for 14 days, with follow-up 1-14 days after the end of study sampling. All study visits will be conducted in the North Carolina Translational and Clinical Sciences (NCTraCS) Clinical Translational Research Center (CTRC) at the University of North Carolina at Chapel Hill.

Procedures (methods):This is a Phase 1, single center, open-label, dose-ranging pharmacokinetic study of TFV and TFV-DP mucosal tissue concentrations measured after a single dose of GS-7340. Each arm is divided into three dosing groups: 5, 10, or 25mg. Participants will take a single dose of study drug within 7-14 days following the end of the subjects' menstrual period. Participants will be sequentially assigned to one of the three TAF doses and four biopsy schedules. Two women from each of the dosing groups will be assigned to one of four biopsy schedules for a total of 8 women per dosing group. Samples of blood plasma, cervicovaginal fluid (CVF), cervical tissue, vaginal tissue, and rectal tissue will be collected from participants at varying time points over the 14 days post-dose. Subjects will return to clinic within 14 days after the last sampling to complete a follow-up safety visit.

Study Timeline

• Study First Submitted: 2015-01-14
• Study First Submitted QC: 2015-02-02
• Study First Posted: 2015-02-06
• Study Start: 2015-03
• Primary Completion: 2015-10
• Status Verified: 2016-11
• Study Completion: 2016-11
• Last Update Submitted: 2016-11-29
• Last Update Posted: 2016-11-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 24

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
3. GS-7340 5mg	GS-7340	The final 8 women on study will be sequentially assigned to take a single dose of 5mg TAF (1/2 tablet) orally.
1. GS-7340 25mg	GS-7340	The first 8 women on study will be assigned to take a single dose of 25mg TAF (1 tablet) orally.
2. GS-7340 10mg	GS-7340	The 2nd group of 8 women will be sequentially assigned to take a single dose of 10mg TAF (1 tablet) orally.

Primary Outcome Measures

Name	Time	Method
Plasma Dose-Proportionality	Pre-dose and 1, 3, 6, 12, 24 hours, and 3, 7, 10, and 14 days following single dose	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.
PBMC Dose-Proportionality	Pre-dose and 3, 6, 12, 24 hours and 3, 7, 10, and 14 days following single dose	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.
Tissue Dose-Proportionality	At 3, 6, 12 and 24 hours and 3, 7, 10 and 14 days following single dose	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.

Secondary Outcome Measures

Name	Time	Method
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	To determine intra-subject variability in intracellular dATP in PBMCs and ratios of TFVdp:dATP.
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	To determine intra-subject variability in intracellular dATP in cervical, vaginal, and rectal tissues and ratios of TFVdp:dATP.
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	To determine inter-subject variability in intracellular dATP in cervical, vaginal, and rectal tissues and ratios of TFVdp:dATP.
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	To determine inter-subject variability in intracellular dATP in PBMCs and ratios of TFVdp:dATP.

Trial Locations

Locations (1)

University of North Carolina at Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States