Relative Bioavailability and Food Effect for Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Fixed Dose Combination

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the pharmacokinetics and relative bioavailability of Emtricitabine (FTC) and Tenofovir alafenamide (TAF) when administered as a fixed-dose combination (FDC) with darunavir (DRV) and cobicistat (COBI) (darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) relative to administration as an FDC with Elvitegravir (EVG) and COBI (Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide), under fed conditions in healthy subjects (Panel 1); evaluate the single-dose pharmacokinetics and relative bioavailability of DRV, COBI, FTC and TAF when administered as an FDC (D/C/F/TAF) or as separate agents (D+C+FTC/TAF), under fed conditions in healthy subjects (Panel 2) and to evaluate the impact of food (fasting or high-fat breakfast) on the single-dose pharmacokinetics of DRV, COBI, FTC, and TAF when administered as an FDC (D/C/F/TAF) in healthy subjects (Panel 3).

Detailed Description
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This is a Phase 1, 3-panel, open-label, randomized, 2-way crossover study in healthy subjects. Healthy subjects will be divided over 3 panels (Panel 1, 2 and 3). Subjects will be randomized within each panel. In each panel, during 2 subsequent sessions, each subject will receive 2 treatments (Treatments A and B in Panel 1, Treatments C and D in Panel 2, and Treatments E and F in Panel 3). Each treatment is defined as follows: Treatment A: single oral dose of D/C/F/TAF 800/150/200/10 milligram (mg) as FDC tablet under fed conditions (standardized regular breakfast); Treatment B: single oral dose of E/C/F/TAF 150/150/200/10 mg as FDC tablet under fed conditions; Treatment C: single oral dose of D/C/F/TAF 800/150/200/10 mg as FDC tablet under fed conditions; Treatment D: single oral dose of DRV as 800-mg tablet, FTC/TAF as 200/10 mg tablet and COBI 150 mg tablet under fed conditions. Treatment E: single oral dose of D/C/F/TAF 800/150/200/10 mg as FDC tablet, under fasted condition and Treatment F: single oral dose of D/C/F/TAF 800/150/200/10 mg tablet, with a standardized high-fat breakfast. Each treatment will be separated by a washout period of at least 7 days. Primarily pharmacokinetic parameters will be assessed. Subjects' safety will be assessed throughout.

Official Title
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A Single-dose, Open-label, Randomized, Crossover Study to Assess the Impact of Food on the Pharmacokinetics of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Administered as a Fixed-dose Combination Tablet, and the Relative Bioavailability

Conditions
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Healthy

Intervention / Treatment
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* Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC
* Drug: Elvitegravir /Cobicistat/Emtricitabine/Tenofovir alafenamide FDC
* Drug: Darunavir
* Drug: Emtricitabine/Tenofovir alafenamide (FTC/TAF)
* Drug: Cobicistat
* Other: High-fat Breakfast
* Other: Standardized Regular Breakfast


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be a non-smoker for at least 3 months prior to selection Subject must have a body mass index (BMI, weight in kg divided by the square of height in meters) of 18.5 to 30.0 kg/m^2, extremes included Subject must be healthy on the basis of physical examination, medical history, vital signs, and 12-lead ECG performed at screening. If the results are outside the normal reference ranges, the subject may be included only if they are not listed under the exclusion criteria and if the Investigator judges the abnormalities or deviations from normal to be not clinically significant. This determination must be recorded in the subject's source documents and initialed by the Investigator Subject must be healthy on the basis of clinical laboratory tests performed at screening. If the results of the biochemistry panel, hematology, or urinalysis are outside the normal reference ranges, the subject may be included only if the abnormalities or deviations from normal are not listed in the exclusion criteria, and the Investigator judges they are not clinically significant. This determination must be recorded in the subject's source documents and initialed by the Investigator Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol Exclusion Criteria: Subject has a positive human immunodeficiency virus-1 (HIV-1) or HIV-2 test at screening Subject has hepatitis A, B, or C infection (confirmed by a positive hepatitis A antibody immunoglobulin M (IgM), hepatitis B surface antigen, and/or hepatitis C virus antibody, respectively) at screening Subject has currently significant and active diarrhea, nausea, or constipation that in the Investigator's opinion could influence drug absorption or bioavailability Subject has any history of renal insufficiency Subject has known allergies, hypersensitivity, or intolerance to DRV, COBI (GS-9350), EVG (Panel 1 only), FTC, TAF or their excipients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel 1: Group 1<br>Subject will receive a single oral tablet of fixed dose combination (FDC) containing darunavir (DRV)/ cobicistat (COBI)/emtricitabine (FTC) /tenofovir alafenamide (TAF) (D/C/F/TAF) under fed conditions (standardized regular breakfast, test Panel 1) on Day 1 of treatment period 1 and by FDC of elvitegravir (EVG)/cobicistat (COBI)/emtricitabine (FTC)/ tenofovir alafenamide (TAF) (E/C/F/TAF) under fed conditions (standardized regular breakfast, reference Panel 1) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Drug: Elvitegravir /Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing EVG 150 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Other: Standardized Regular Breakfast<br>* Standardized regular breakfast will administered.<br>|
| Experimental: Panel 1: Group 2<br>Subject will receive a single oral tablet of FDC containing E/C/F/TAF under fed conditions (standardized regular breakfast, reference Panel 1) on Day 1 of treatment period 1 and a single oral tablet of FDC containing D/C/F/TAF under fed conditions (standardized regular breakfast, test Panel 1) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Drug: Elvitegravir /Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing EVG 150 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Other: Standardized Regular Breakfast<br>* Standardized regular breakfast will administered.<br>|
| Experimental: Panel 2: Group 1<br>Subject will receive a single oral tablet of D/C/F/TAF under fed conditions (standardized regular breakfast, test Panel 2) on Day 1 of treatment period 1 and a single oral tablet of DRV, a tablet of emtricitabine/ tenofovir alafenamide (FTC/TAF) and a tablet of COBI under fed conditions (standardized regular breakfast, reference Panel 2) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Drug: Darunavir<br>* A tablet containing Darunavir (DRV) 800 mg will be administered.<br>Drug: Emtricitabine/Tenofovir alafenamide (FTC/TAF)<br>* A tablet containing Emtricitabine (FTC) 200 mg and Tenofovir alafenamide (TAF) 10 mg will be administered.<br>Drug: Cobicistat<br>* A tablet containing cobicistat (COBI) 150 mg will be administered.<br>Other: Standardized Regular Breakfast<br>* Standardized regular breakfast will administered.<br>|
| Experimental: Panel 2: Group 2<br>Subject will receive a single oral tablet of DRV, a tablet of FTC/TAF and a tablet of COBI under fed conditions (standardized regular breakfast, reference Panel 2) on Day 1 of treatment period 2 and a single oral tablet of D/C/F/TAF under fed conditions (standardized regular breakfast, test Panel 2) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Drug: Darunavir<br>* A tablet containing Darunavir (DRV) 800 mg will be administered.<br>Drug: Emtricitabine/Tenofovir alafenamide (FTC/TAF)<br>* A tablet containing Emtricitabine (FTC) 200 mg and Tenofovir alafenamide (TAF) 10 mg will be administered.<br>Drug: Cobicistat<br>* A tablet containing cobicistat (COBI) 150 mg will be administered.<br>Other: Standardized Regular Breakfast<br>* Standardized regular breakfast will administered.<br>|
| Experimental: Panel 3: Group 1<br>Subject will receive a single oral tablet of D/C/F/TAF under fasted conditions (test Panel 3) on Day 1 of treatment period 1 and a single oral tablet of D/C/F/TAF with a standardized high-fat breakfast (reference Panel 3) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>|
| Experimental: Panel 3: Group 2<br>Subject will receive a single oral tablet of D/C/F/TAF with a standardized high-fat breakfast (reference Panel 3) on Day 1 of treatment period 1 followed by a single oral tablet of D/C/F/TAF under fasted conditions (test Panel 3) on Day 1 of treatment period 2. | Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir alafenamide FDC<br>* A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF 10 mg as FDC will be administered.<br>Other: High-fat Breakfast<br>* High-fat breakfast will be administered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Plasma Concentration (Cmax) of Darunavir (DRV), cobicistat (COBI), Emtricitabine (FTC) and Tenofovir Alafenamide (TAF) | The Cmax is the maximum observed plasma concentration. | Up to 72 Hours after study drug administration | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Quantifiable Time (AUC [0-last]) of Darunavir (DRV), cobicistat (COBI), Emtricitabine (FTC) and Tenofovir Alafenamide (TAF) | The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time. | Up to 72 Hours after study drug administration | 
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinite Time (AUC[0-infinity]) of Darunavir (DRV), cobicistat (COBI), Emtricitabine (FTC) and Tenofovir Alafenamide (TAF) | The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant. | Up to 72 Hours after study drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with Adverse Events | An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. | From signing the Informed Consent Form (ICF) up to 10 days after last study drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunodeficiency Virus Type 1, Human, Immunodeficiency Virus Type 2, Human, Cobicistat, Tenofovir Alafenamide, Emtricitabine, Elvitegravir, Darunavir