Healthy Volunteers, Pharmacokinetics
Conditions
Keywords
healthy volunteers, pharmacokinetics
Brief summary
Poor adherence to tenofovir (TDF) and emtricitabine (FTC) for Human Immunodeficiency Virus (HIV) pre-exposure prophylaxis (PrEP) is common and the leading cause of therapeutic failure. The investigators need better ways to measure adherence in patients on PrEP. This application will address the need to measure adherence by evaluating an integrated technology system, Proteus Discover, when combined with Truvada. The Proteus Sensor System (PSS) will confirm that Truvada was taken, monitor adherence in both recent and long term dosing, and provides feedback to encourage adherence. The goal of this study is to determine whether the use of the PSS with Truvada will vary the drug concentrations of FTC/TDF. Participants will have 2 study visits where they will be randomized to either start with the combined PSS with Truvada or just Truvada alone. Study participants will come to the Clinical & Translational Research Center (CTRC) in the morning and take the assigned dose and will then have blood drawn at about .25, 0.5, 1, 2, 4, 6, and 10 hours after medication is taken. Participants will then return to the CTRC for blood draws 24, 48, and 72 hours after they took the dose on the first day. The second visit will mimic the first except that the participant will take the other dose form.
Interventions
DRUGTENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA]
DEVICEProteus Sensor System
Sponsors
University of Colorado, Denver
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Ambulatory 18-45 year old adults. 2. Ability to comply with study procedures
Exclusion criteria
1. Inability to give informed consent 2. Pregnancy or planning to become pregnant within 3 months of study completion 3. Currently breastfeeding 4. High risk of HIV-1 infection (for example: sexually active with an HIV infected partner; men who have sex with men who may engage in condom-less intercourse with HIV-infected partners or partner of unknown status during the study; males or females who exchange sex for money, shelter, or gifts; active injection drug use or during the last 12 months; newly diagnosed sexually transmitted infections in last 6 months) 5. Positive HIV+ ELISA or suspected acute HIV infection in the opinion of the clinician. (example signs and symptoms of acute HIV infection include combinations of fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy cervical or inguinal) 6. Positive hepatitis B virus (HBV) surface antigen test. 7. Uncontrolled or symptomatic bone disease or history of non-traumatic bone fractures 8. Active psychiatric illness or alcohol/drug abuse that, in the opinion of the investigators, would interfere with study requirements 9. Creatinine clearance \< 60 ml/min, or history of serious renal disease 10. Urine dipstick protein ≥ 2+ 11. Total bilirubin and/or hepatic transaminases (ALT and AST) ≥ 2.5x upper limit of normal 12. Absolute neutrophil count ≤ 1,500/mm3, platelets count ≤ 100,000/mm3, or hemoglobin ≤ 10 g/dL. 13. Any laboratory value or uncontrolled medical conditions that, in the opinion of investigators, would interfere with the study conditions or increase risk to the participant 14. \> Grade I abnormalities in screening laboratory tests (Complete Blood Count, Comprehensive Metabolic Panel, Lipase, Phosphorus) per Division of AIDS (DAIDS) Grading Table 15. Contraindicated concomitant medications based upon product information or that, in the opinion of the investigators, would interact with the study medications or increase risk to participant such as: investigational agents (within 30 days of enrollment), aminoglycosides, ganciclovir/valganciclovir, chronic high-dose acyclovir/valacyclovir (\>800mg acyclovir or \> 500mg valacyclovir for \> 7 days), cyclosporine, amphotericin B, foscarnet, and cidofovir, and products with same or similar active ingredients as the study medications including TRUVADA®, ATRIPLA®, COMPLERA®, EMTRIVA®, VIREAD®; or drugs containing lamivudine or adefovir, which are close analogs of FTC and tenofovir. 16. Current participation in other interventional research studies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration (Cmax) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | Tenofovir and emtricitabine concentration max (Cmax) following FTC/TDF in the overencapsulated versus non-encapsulated form. Drug concentrations will be assayed with validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methodology. |
| Area Under the Concentration-time Curve (AUC) | 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose | Tenofovir and emtricitabine area under the concentration-time curve (AUC) following FTC/TDF in the overencapsulated versus non-encapsulated form. Drug concentrations will be assayed with validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methodology. |
Participant flow
Recruitment details
IRB approval was obtained for 48 subjects to allow for screen failures, withdrawals, lost to follow up, etc.
Participants by arm
| Arm | Count |
|---|---|
| All Participants Single dose of unencapsulated and coencapsulated TDF/FTC. A 14-day washout separated each dosing. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Pregnancy | 0 | 1 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Race/Ethnicity, Customized Race/Ethnicity African American | 3 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Caucasian | 19 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 3 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 14 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
Area Under the Concentration-time Curve (AUC)
Tenofovir and emtricitabine area under the concentration-time curve (AUC) following FTC/TDF in the overencapsulated versus non-encapsulated form. Drug concentrations will be assayed with validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methodology.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
Population: All subjects who completed the study: single dose of unencapsulated and coencapsulated TDF/FTC. A 14-day washout separated each dosing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Area Under the Concentration-time Curve (AUC) | TFV AUC-coencapsulated | 2042 ng*h/mL | Geometric Coefficient of Variation 26 |
| All Participants | Area Under the Concentration-time Curve (AUC) | TFV AUC-unencapsulated | 1978 ng*h/mL | Geometric Coefficient of Variation 27 |
| All Participants | Area Under the Concentration-time Curve (AUC) | FTC AUC-unencapsulated | 9342 ng*h/mL | Geometric Coefficient of Variation 23 |
| All Participants | Area Under the Concentration-time Curve (AUC) | FTC AUC-coencapsulated | 9512 ng*h/mL | Geometric Coefficient of Variation 20 |
Primary
Peak Plasma Concentration (Cmax)
Tenofovir and emtricitabine concentration max (Cmax) following FTC/TDF in the overencapsulated versus non-encapsulated form. Drug concentrations will be assayed with validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methodology.
Time frame: 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose
Population: All subjects who completed the study: single dose of unencapsulated and coencapsulated TDF/FTC. A 14-day washout separated each dosing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants | Peak Plasma Concentration (Cmax) | TFV Cmax-unencapsulated | 222 ng/mL | Geometric Coefficient of Variation 37 |
| All Participants | Peak Plasma Concentration (Cmax) | TFV Cmax-coencapsulated | 229 ng/mL | Geometric Coefficient of Variation 32 |
| All Participants | Peak Plasma Concentration (Cmax) | FTC Cmax-unencapsulated | 1567 ng/mL | Geometric Coefficient of Variation 33 |
| All Participants | Peak Plasma Concentration (Cmax) | FTC Cmax-coencapsulated | 1684 ng/mL | Geometric Coefficient of Variation 29 |