SECTION 2.7 CLINICAL SUMMARY Section 2.7.1 — Summary of ... · GMR geometric means ratio HIV-1 human immunodeficiency virus (type 1) HPLC high performance liquid chromatography

SECTION 2.7 CLINICAL SUMMARY

Section 2.7.1 — Summary of Biopharmaceutical Studies and Associated Analytical Methods

EMTRICITABINE/RILPIVIRINE/

TENOFOVIR DISOPROXIL FUMARATE FIXED-DOSE COMBINATION

Gilead Sciences International Limited

12 August 2010

CONFIDENTIAL AND PROPRIETARY INFORMATION

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Section 2.7.1 Summary of Biopharmaceutical Studies Final

CONFIDENTIAL Page 2 12AUG2010

TABLE OF CONTENTS

SECTION 2.7 CLINICAL SUMMARY ................................................................................................................1 TABLE OF CONTENTS .......................................................................................................................................2 GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS ..............................................................6 2.7. CLINICAL SUMMARY ...............................................................................................................................9

2.7.1. Summary of Biopharmaceutical Studies and Associated Analytical Methods .................................9 2.7.1.1. Background and Overview..............................................................................................9

2.7.1.1.1. Formulation Development .......................................................................10 2.7.1.1.2. Dissolution Profile ...................................................................................12 2.7.1.1.3. Analytical Methods..................................................................................12

2.7.1.2. Summary of Results of Individual Studies....................................................................20 2.7.1.2.1. Emtricitabine............................................................................................20 2.7.1.2.2. Rilpivirine ................................................................................................23 2.7.1.2.3. Tenofovir DF ...........................................................................................35 2.7.1.2.4. Emtricitabine/Tenofovir DF.....................................................................38 2.7.1.2.5. Emtricitabine/Rilpivirine/Tenofovir DF Fixed-Dose

Combination Tablet .................................................................................40 2.7.1.3. Comparison and Analyses of Results across Studies ....................................................47

2.7.1.3.1. Bioavailability of Emtricitabine...............................................................47 2.7.1.3.2. Bioavailability of Rilpivirine ...................................................................47 2.7.1.3.3. Bioavailability of Tenofovir ....................................................................48 2.7.1.3.4. Assessment of Bioequivalence of

Emtricitabine/Tenofovir DF Tablets ........................................................49 2.7.1.3.5. Assessment of Bioequivalence of

Emtricitabine/Rilpivirine/Tenofovir DF Tablets......................................54 2.7.1.3.6. Effect of Food ..........................................................................................66 2.7.1.3.7. Discussion and Conclusions ....................................................................73

2.7.1.4. Appendices....................................................................................................................74 2.7.1.4.1. Tabular Summary of Quantitative Composition of the

Proposed Commercial Formulation of Emtricitabine/Rilpivirine/Tenofovir DF Tablets......................................75

2.7.1.4.2. Quantitative Composition of Formulations 1, 2, 3, and 4 of Emtricitabine/Rilpivirine/Tenofovir DF Tablets .................................76

2.7.1.4.3. Summary of In Vitro Dissolution Profiles for the Formulations of Emtricitabine/Rilpivirine/Tenofovir DF Fixed-Dose Combination Tablets Used in Studies GS-US-264-0103 and GS-US-264-0101..................................................79

2.7.1.4.4. Emtricitabine: Tabular Summary of Biopharmaceutic Studies......................................................................................................81

2.7.1.4.5. Rilpivirine: Tabular Summary of Completed Biopharmaceutical Trials – Comparative Bioavailability Trials ........................................................................................................83

2.7.1.4.6. Rilpivirine: Summary of Analytical Methods for Individual Trials.......................................................................................89

2.7.1.4.7. Tenofovir DF: Tabular Summary of Biopharmaceutic Studies......................................................................................................95

2.7.1.4.8. Emtricitabine/Tenofovir DF: Tabular Summary of Biopharmaceutic Studies .........................................................................96

2.7.1.4.9. Emtricitabine/ Rilpivirine/Tenofovir DF: Tabular Summary of Biopharmaceutic Studies.....................................................98



LIST OF IN-TEXT TABLES Table 1. Biopharmaceutics Classification of Emtricitabine,

Rilpivirine HCl, and Tenofovir DF ...............................................................................12 Table 2. Bioanalytical Assay Validation Characteristics for

Determination of TMC278 in Plasma ...........................................................................14 Table 3. Study GS-US-104-0172: Bioanalytical Assay Validation for

Human Plasma ..............................................................................................................19 Table 4. Studies GS-US-264-0103 and GS-US-264-0101: Bioanalytical

Assay Validation for Emtricitabine, Rilpivirine, and Tenofovir in Human Plasma ..............................................................................................................19

Table 5. Trial C102: Pharmacokinetics of TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278, Compared to a Reference Oral Solution Formulation of TMC278, Under Fed Conditions...................................................................................26

Table 6. Trial C102: Pharmacokinetics of TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278 Given Under Fed or Fasted Conditions.........................................................................27

Table 7. Trial C117: Pharmacokinetics of TMC278 After Single-Dose Administration of 100- or 150-mg TMC278 Formulated as Phase III (Test) or Phase IIb (Reference) Tablet .....................................................................30

Table 8. Trial C137: Pharmacokinetics of TMC278 After Single-Dose Administration of 75 mg TMC278 Given Under Fed Conditions With Different Types of Meals or Under Fasted Conditions ........................................33

Table 9. Clinical Biopharmaceutic Trials, Including Information on TMC278 Dosage Form, Formulation Number, and Dose .............................................35

Table 10. Study GS-US-264-0103 (Development Formulations 3 and 4): Summary of Emtricitabine, Rilpivirine, and Tenofovir Pharmacokinetic Parameters .........................................................................................43

Table 11. Study GS-US-264-0101 (Development Formulations 1 and 2): Summary of Emtricitabine, Rilpivirine, and Tenofovir Pharmacokinetic Parameters .........................................................................................46

Table 12. Study GS-US-104-0172: Summary of Emtricitabine Pharmacokinetic Parameters .........................................................................................51

Table 13. Study GS-US-104-0172: Statistical Comparisons of Emtricitabine Pharmacokinetic Parameters for Treatment B Versus Treatment A ......................................................................................................51

Table 14. Study GS-US-104-0172: Summary of Tenofovir Pharmacokinetic Parameters .........................................................................................53

Table 15. Study GS-US-104-0172: Statistical Comparisons of Tenofovir Pharmacokinetic Parameters for Treatment B Versus Treatment A ..................................................................................................................53

Table 16. GS-US-264-0103: Summary of Emtricitabine Pharmacokinetic Parameters Following a Single Dose of Study Treatment.............................................57

Table 17. GS-US-264-0103: Statistical Comparisons of Emtricitabine Pharmacokinetic Parameters for Test Versus Reference Treatments.....................................................................................................................58

Table 18. GS-US-264-0103: Summary of Rilpivirine Pharmacokinetic Parameters Following a Single Dose of Study Treatment.............................................61

Table 19. GS-US-264-0103: Statistical Comparisons of Rilpivirine Pharmacokinetic Parameters for Test Versus Reference Treatments.....................................................................................................................62

Table 20. GS-US-264-0103: Summary of Tenofovir Pharmacokinetic Parameters Following a Single Dose of Study Treatment.............................................65



Table 21. GS-US-264-0103: Statistical Comparisons of Tenofovir Pharmacokinetic Parameters for Test Versus Reference Treatments.....................................................................................................................66

Table 22. Study GS-00-914: Pharmacokinetics of Tenofovir Following Oral Administration of the Original Commercial Formulation (1 300 mg) of Tenofovir DF in the Fed and Fasted State...........................................68

Table 23. Study GS-00-914: Pharmacokinetic Geometric Least Squares Mean Ratios (90% Confidence Intervals) for the Original Commercial Formulation (1 300 mg) of Tenofovir DF Administered in the Fasted and Fed States....................................................................69

Table 24. Study GS-00-909: Pharmacokinetics of Tenofovir Following Oral Administration of Tenofovir DF with a Light Meal (Study GS-01-932) and Historical Data Following Administration in the Fasted State ................................................................................69

Table 25. Study GS-US-104-0172: Tenofovir Pharmacokinetic Parameters After Administration of the Emtricitabine/Tenofovir DF Tablet to Fasted and Fed Subjects ............................................................................................70

Table 26. Study GS-US-104-0172: Food Effect on Pharmacokinetics of Tenofovir Administered as the Emtricitabine/Tenofovir DF Tablet ............................................................................................................................71

Table 27. Study GS-US-104-0172: Emtricitabine Pharmacokinetic Parameters After Administration of the Emtricitabine/ Tenofovir DF Tablet to Fasted and Fed Subjects..........................................................72

Table 28. Study GS-US-104-0172: Food Effect on Pharmacokinetics of Emtricitabine Administered as the Emtricitabine/Tenofovir DF Tablet ............................................................................................................................72

LIST OF IN-TEXT FIGURES

Figure 1. Trial C102: Mean Plasma Concentration-Time Profiles of

TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278 Compared to a Reference Oral Solution Formulation of TMC278 (Upper Panels) and of Capsule and Tablet Formulations Under Fed Compared to Fasted Conditions (Lower Panels)............................................................................................25

Figure 2. Trial C117: Mean Plasma Concentration-Time Profiles of TMC278 After Single-Dose Administration of TMC278 as Phase III and Phase IIb Tablets .....................................................................................29

Figure 3. Trial C137: Mean Plasma Concentration-Time Profiles of TMC278 Single-Dose Administration of 75 mg TMC278 Given Under Fed Conditions With Different Types of Meals or Under Fasted Conditions..........................................................................................................32

Figure 4. Studies GS-US-264-0103 and GS-US-264-0101 Schema.............................................41 Figure 5. Study GS-US-104-0172: Plasma Concentration-Time Profile of

Emtricitabine After Administration of Treatment A or Treatment B...................................................................................................................50

Figure 6. Study GS-US-104-0172: Plasma Concentration-Time Profile of Tenofovir After Administration of Treatment A or Treatment B..................................52

Figure 7. GS-US-264-0103: Mean (SD) Plasma Emtricitabine Concentration-Time Profiles by Treatment Over 24 Hours ..........................................55

Figure 8. GS-US-264-0103: Mean (SD) Plasma Emtricitabine Concentration-Time Profiles by Treatment over 192 Hours .........................................56

Figure 9. GS-US-264-0103: Mean (SD) Plasma Rilpivirine Concentration-Time Profiles by Treatment over 24 Hours ...........................................59



Figure 10. GS-US-264-0103: Mean (SD) Plasma Rilpivirine Concentration-Time Profiles by Treatment over 192 Hours .........................................60

Figure 11. GS-US-264-0103: Mean (SD) Plasma Tenofovir Concentration-Time Profiles by Treatment Over 24 Hours ..................................................................63

Figure 12. GS-US-264-0103: Mean (SD) Plasma Tenofovir Concentration-Time Profiles by Treatment Over 192 Hours ................................................................64



GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS AE adverse event AUC area under the (time–plasma concentration) curve BLQ below the limit of quantitation BCS biopharmaceutics classification system CI confidence interval Cmax maximum plasma or serum concentration CRR, CSR clinical research or study report CV coefficient of variation EFV efavirenz EMA, EMEA European Medicines Evaluation Agency EU European Union FDC fixed-dose combination FTC emtricitabine FTC/RPV/TDF emtricitabine/rilpivirine/tenofovir disoproxil fumarate (fixed-dose

combination product) GLS geometric least squares GLSM geometric least-squares mean GMR geometric means ratio HIV-1 human immunodeficiency virus (type 1) HPLC high performance liquid chromatography LC/MS/MS, LC-MS/MS liquid chromatography/tandem mass spectrometry LC/MS (SIM) liquid chromatography/ mass spectrometry (selected ion monitoring) LLQ lower limit of quantitation LS least squares MAA Marketing Authorization Application NF National Formulary NRTI nucleoside reverse transcriptase inhibitor NtRTI nucleotide reverse transcriptase inhibitor PK pharmacokinetic Q1, Q3 quartile 1, quartile 3 QT interval of time from the beginning of the QRS complex to the end of

the T wave (on the electrocardiogram) QTc corrected QT interval RPV rilpivirine (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg

RPV), TMC278 SAE serious adverse event T½, t ½, term elimination half-life Tmax, tmax time to maximum plasma concentration TDF tenofovir disoproxil fumarate, tenofovir DF (300 mg TDF is equivalent

to 245 mg tenofovir disoproxil or 136 mg of tenofovir)



GLOSSARY OF ABBREVIATIONS AND DEFINITION OF TERMS (CONT)

TEAE treatment-emergent adverse event TFV tenofovir TMC278 rilpivirine (research name) UPLC ultra-high performance liquid chromatography US, USA United States of America USP United States Pharmacopeia w/w by weight or weight/weight



Rilpivirine Trial Naming Conventions

Throughout the development of TMC278, different naming conventions were used for the clinical trials, depending on when the trial was conducted. The first part of the trial identifier was one of the following:

R278474-CDE- (used for the earlier trials)

R278474-

TMC278-

TMC278-TiDP6- (used for the most recent trials in adults)

All but 3 of the clinical trials were given a suffix of a unique 3-digit number preceded by the letter C (for “clinical”), eg, C201 or C209. In this document, trials are given their full name where they are first mentioned (eg, TMC278-TiDP6-C209, R278474-CDE-101), but are subsequently referred to by a short name only (eg, C209, CDE-101).



2.7. CLINICAL SUMMARY

2.7.1. SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS

2.7.1.1. Background and Overview

This dossier is being submitted in support of a marketing authorization application (MAA) for a fixed-dose combination (FDC) film-coated tablet that contains the active substances emtricitabine (FTC), rilpivirine (RPV, which is also referred to as TMC278 throughout this document), and tenofovir disoproxil fumarate (tenofovir DF, TDF). Emtricitabine and TDF are antiretroviral agents developed by Gilead Sciences that have been approved for the treatment of human immunodeficiency virus type 1 (HIV-1) infection as the respective stand-alone agents Emtriva® (Commission Decision granted on 24 October 2003, [EU/1/03/261/001-003]) and Viread® (Commission Decision granted on 05 February 2002, [U/1/01/200/001-2]), and as the FDC product Truvada (emtricitabine/tenofovir DF [FTC/TDF]; Commission Decision granted on 21 February 2005 [EU/1/04/305/001]). Emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI), and TDF, a nucleotide reverse transcriptase inhibitor (NtRTI), are listed as preferred agents in United States (US) and international treatment guidelines {15207}, {12716}, {14065}. Emtricitabine and TDF are also approved for the treatment of HIV-1 infection in combination with efavirenz (EFV), a nonnucleoside reverse transcriptase inhibitor (NNRTI). This FDC product is Atripla (efavirenz/emtricitabine/tenofovir DF, [EFV/FTC/TDF]; Commission Decision granted on 13 December 2007, [EU/1/07/430/001-2]). These products are currently approved in the US, the European Community, and other countries worldwide for use in adults. In some regions, Emtriva and Viread are approved for use in adolescents; Emtriva, which is also available as an oral solution formulation, may be administered to children as young as 4 months of age. Rilpivirine, an NNRTI, is an investigational agent that is being submitted for approval by Tibotec BVBA.

Gilead Sciences has coformulated FTC and TDF, the standard of care NRTI backbone, with RPV into a FDC tablet. This FDC tablet is referred to as emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF; dose strength 200/25/300 mg, respectively) throughout this document. Each FTC/RPV/TDF FDC tablet contains FTC, RPV, and TDF at the same dosages as recommended for the individual components, ie, 200 mg of FTC, 25 mg RPV (27.5 mg rilpivirine hydrochloride is equivalent to 25 mg RPV), and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg tenofovir disoproxil or 136 mg tenofovir [TFV]). It is proposed that the FTC/RPV/TDF FDC tablet be indicated for the treatment of HIV-1 infection in adults and taken orally once daily with a meal.

In accordance with the advice received from the European Medicines Evaluation Agency (EMA) at the EMA meeting held on 20 (see meeting minutes provided in Module 1.2, Annex 5.14), the MAAs for RPV as a single agent and for the FTC/RPV/TDF FDC tablet are being submitted in parallel by Tibotec BVBA and Gilead Sciences, respectively.



As the RPV component is a new chemical entity, this FDC MAA dossier contains full data on this new component while providing the key data on the Truvada (ie, FTC, TDF, and FTC/TDF) components that support the efficacy and safety claims in the FTC/RPV/TDF FDC prescribing information. All Truvada studies considered to support the FDC are included to ensure that this is a ‘stand-alone dossier’. This is in agreement with the feedback received at the meeting with the EMA on 20 and with the meeting with the Rapporteur/Co-Rapporteur on 20 (see Module 1.2.5.14, final minutes). To assist the reviewer, a listing of all the FTC, TDF, FTC/TDF, and EFV/FTC/TDF nonclinical and clinical reports is provided in Section 2.5.8. Clinical data for FTC, RPV, TDF, Truvada, and Atripla are provided in Module 2.7; clinical study reports (CSRs), periodic safety update reports (PSURs), and other relevant data for these products are provided in Module 5.

This MAA for the FTC/RPV/TDF FDC tablet is primarily supported by two Phase 3 clinical studies conducted by Tibotec BVBA and one biopharmaceutic study, GS-US-264-0103, along with supporting chemistry, manufacturing, and controls information for the combination tablet. The Phase 3 studies, TMC278-C209 and TMC278-C215, are described in Module 2.7.3 and synopses are provided in Module 2.7.6. The biopharmaceutic study GS-US-264-0103, conducted with the proposed commercial formulation of the FDC tablet, demonstrated bioequivalence in the fed state of the FTC/RPV/TDF FDC tablet and the concurrently administered individual components FTC (hard capsule), TDF (tablet), and RPV (tablet). The principal bioequivalence data for Study GS-US-264-0103 are summarized in Sections 2.7.1.2.5.1 and 2.7.1.3.5, and a synopsis is provided in Module 2.7.6. Data from studies of FTC, TDF, and RPV that are relevant for the assessment of the FTC/RPV/TDF FDC tablet are also described in this summary.

The findings of an earlier bioequivalence study (GS-US-264-0101) that was conducted with 2 other development formulations of the FDC tablet are summarized in this submission. In this study, the 90% confidence intervals (CIs) for the geometric mean ratios (test/reference) were contained within the specified bounds of 80% to 125% for the primary pharmacokinetic (PK) parameters of FTC and TFV, but not for RPV (see Section 2.7.1.2.5.2). Thus, this study concluded that Formulations 1 and 2 were not bioequivalent to the reference treatment of the individual components FTC+RPV+TDF administered concurrently.

A relative bioavailability study comparing the FTC/RPV/TDF FDC tablet with concurrent administration of the individual components (200 mg FTC, 25 mg RPV, 300 mg TDF) under fasted conditions in healthy subjects is ongoing. The clinical study report (CSR) will be available October 2010.

2.7.1.1.1. Formulation Development



2.7.1.1.2. Dissolution Profile

Table 1.

2.7.1.1.3. Analytical Methods

Detailed descriptions and reports of the bioanalytical methods, validation results, quality control data, and assay performance results for each method are included within the appendices of the CSRs for FTC, TDF, and FTC/TDF studies and/or in Module 5.3.1.4. The analytical methods used to determine RPV in plasma and validation data are described in Section 2.7.1.1.3.2 and in Module 5.3.1.4.



2.7.1.1.3.1. Emtricitabine

The bioanalytical methods used for the determination of FTC concentrations were solid-phase extraction followed by liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis for plasma samples and solid-phase extraction followed by LC/MS (selected ion monitoring [SIM]) analysis for urine samples or dilution of the urine followed by direct injection onto LC/MS/MS. Although the validated concentration range of the methods for measuring FTC plasma concentrations varied slightly from study to study, this was typically from 2.5 to 10 ng/mL up to 5000 to 10,000 ng/mL.

2.7.1.1.3.2. Rilpivirine

The following sections give an overview of the information presented in this summary based upon the completed biopharmaceutic trials. References to drug exposure refer to area under the plasma concentration-time curve (AUC), unless stated otherwise.

2.7.1.1.3.2.1. Determination of TMC278 in Plasma

During the clinical development of TMC278, small changes were made to the original bioanalytical assay used for the determination of TMC278 in plasma, so that a total of 4 assays were developed and validated to support the TMC278 pharmacokinetic program. These changes included improvements in the chromatographic conditions, implementation of a stable isotope-labeled internal standard, and a switch to other instrumentation.

The assays were developed at 2 different laboratories and were all based on the same detection technique (liquid chromatography with tandem mass-spectrometry [LC-MS/MS]). The performance of these assays was characterized by means of a validation process, in line with internal procedures and international bioanalytical guidelines. The validation data for all TMC278 bioanalytical methods are summarized in Table 2. The analytical methods are summarized below, and further details are available in the individual method validation reports in Module 5.3.1.4. All concentrations of TMC278 reference and internal standards are expressed as free base-equivalents/volume.

When TMC278 is exposed to light, the drug is transformed to another isomeric form (Z isomer), which could have an impact on the data obtained. Therefore, all pharmacokinetic samples in each of the trials were protected from light during processing and storage.

In-trial validation was conducted for the individual trials, and validation data are included in the respective bioanalytical study summaries. An overview of the analytical methods employed for each trial is provided in Appendix 2.7.1.4.6.



Table 2. Bioanalytical Assay Validation Characteristics for Determination of TMC278 in Plasma

Compliance with Pre-specified Criteria Report No. (Location)

Method (Internal

Standard)

Range of Quantification

(ng/mL) Recovery

(%) Accuracya Precisionb

Permitted Dilution Ratio and

Concentration

Specificityc (Interfering

Peaks)

BA28 (Module 5.3.1.4/TMC278-PRD BA28-AVR-Compl; -AVRA-1; -AVRA-2)

LC-MS/MS ( )

1.00 to 2000 5.00 ng/mL: 98.4

100 ng/mL: 94.8

2000 ng/mL: 94.2

1.00 ng/mL: |20|% 2.50 ng/mL: |15|% 62.6 ng/mL: |15|%

1525 ng/mL: |15|%

1.00 ng/mL: 20% 2.50 ng/mL: 15% 62.6 ng/mL: 15%

1525 ng/mL: 15%

Ratio: up to 1:100 Concentration: up to

200000 ng/mL

Interference 20%

BA218 (Module 5.3.1.4/TMC278-BA218 -AVR-Compl [incl. -AVRA-1]; -AVRA-2; -AVRA-3)

LC-MS/MS ( ,

)

1.00 to 2000 5.00 ng/mL: 90.6

50.0 ng/mL: 89.6

2000 ng/mL: 88.8

1.00 ng/mL: |20|% 2.50 ng/mL: |15|% 50.1 ng/mL: |15|%

1500 ng/mL: |15|%

1.00 ng/mL: 20% 2.50 ng/mL: 15% 50.1 ng/mL: 15%

1500 ng/mL: 15%

Ratio up to 1:100 Concentration: up to

200000 ng/mL

Interference 20%

BA1071 (Module 5.3.1.4/TMC278-PRD-BA1071-AVR)

UPLC-MS/MS

( )

1.00 to 2000 ND 1.00 ng/mL: |20|% 2.77 ng/mL: |15|% 55.3 ng/mL: |15|%

1570 ng/mL: |15|%

1.00 ng/mL: 20% 2.77 ng/mL: 15% 55.3 ng/mL: 15%

1570 ng/mL: 15%


200000 ng/mL

Interference 20%

ABL6187 (Module 5.3.1.4/TMC278-ABL6187-AVR)

LC-MS/MS (

)

1.00 to 2000 5.00 ng/mL: 98.9

50.0 ng/mL: 94.7

500 ng/mL: 93.2

1.00 ng/mL: |20|% 3.00 ng/mL: |15|% 50.0 ng/mL: |15|%

1600 ng/mL: |15|% 16000 ng/mL: |15|%

1.00 ng/mL: 20% 3.00 ng/mL: 15% 50.0 ng/mL: 15%

1600 ng/mL: 15% 16000 ng/mL: 15%


16000 ng/mL

No interfering

peaks

ND = not determined; UPLC-MS/MS = ultra high-performance liquid chromatography with tandem mass-spectrometry a % deviation from nominal concentration b % variability of replicates c Calculated as [(amount found – amount added) / amount added] × 100.



LC-MS/MS Assay for Human Heparin plasma, Developed at Johnson & Johnson Pharmaceutical Research and Development

For the initial analytical method (R278474/BA28, refer to Module 5.3.1.4, TMC278-PRD BA28-AVR-Compl; -AVRA-1; -AVRA-2), the trial samples were diluted with blank human heparin plasma (up to 100-fold dilution was validated). Aliquots (100 μL) of the diluted or undiluted samples, or quality control samples in human heparin plasma, were diluted with 1 M acetic acid (3 mL) and spiked with methanol (100 L) and an internal standard solution ( , 5 ng/100 L methanol; 100 L). Solid-phase extraction columns were rinsed with methanol (3 mL), Milli-Q water (3 mL), and 1 M acetic acid (1 mL). The samples were then added to the solid-phase extraction columns, which were subsequently washed with Milli-Q water (3 mL), 1 M acetic acid (1 mL), and methanol (3 mL). Columns were eluted with 3 mL methanol-ammonium hydroxide 25% (98:2, v/v). The organic layer was evaporated to dryness under nitrogen at 65°C. The extraction residue was reconstituted in 250 L of injection mixture (50% 0.01 M ammonium formate adjusted to pH 4.0, and 50% methanol) for analysis by HPLC.

The HPLC consisted of an HP-100 liquid chromatograph (pump and degasser), a CTC-PAL autosampler, and a 5 cm × 4.6 mm I.D. column packed with 3 m Hypersil-BDS C18, which was operated at ambient temperature. A mixture of 35% 0.01 M ammonium formate adjusted to pH 4.0 and 65% methanol was used as the elution mixture. Isocratic chromatographic separation was achieved after injecting 10 μL of the sample at a flow rate of 0.8 mL/min.

An MS/MS system (Triple Quadrupole Mass Spectrometer API-4000, Turbo-Ionspray™ Interface) in the positive ion-mode was used for detection. The following multiple-reaction monitoring transitions were monitored for TMC278 and the internal standard : Q1 Mass m/z 367.1 to Q3 Mass m/z 224.0 for TMC278 and Q1 Mass m/z 341.1 to Q3 Mass m/z 198.0 for with a dwell time of 500 ms for both compounds. The effective linear range was 1.00 to 2000 ng/mL (undiluted). All procedures were conducted while samples were protected from light.

Subsequently, the application of the method was extended to all departmental instruments of the same brand and type, and the Q1 m/z of TMC278 was changed slightly to 367.2 (refer to Module 5.3.1.4, TMC278-BA28-AVRA-1).

The initial solid phase extraction LC-MS/MS method to quantify TMC278 in plasma was adapted to increase sample throughput (ie, protein precipitation and use of calibrator samples) (R278474/BA218, refer to Module 5.3.1.4, TMC278-BA218-AVR-Compl [include -AVRA-1]). Acetonitrile (300 L) was added to aliquots (100 μL) of trial samples, in addition to spiking with methanol and internal standard solution. Samples were then centrifuged for 10 minutes at a minimum of 4000 g before injection onto the LC-MS/MS system. A 3 m Polaris C18-A (Varian, 5 cm × 4.6 mm I.D.) column was used with stepwise gradient elution. After injection of 10 μL of sample, the initial elution mixture composition of 35% 0.01 M ammonium formate (pH 4.0 with formic acid) and 65% methanol at a flow rate of 1 mL/min was changed stepwise to 5% 0.01 M ammonium formate and 95%



methanol at a flow rate of 2 mL/min, before returning to the initial conditions at the end of the analysis. The MS/MS system was as described above.

Subsequently, the plasma aliquot needed for analysis was reduced to 0.05 mL (refer to Module 5.3.1.4, TMC278-BA218-AVR-Compl [include -AVRA-1]), and the internal standard was replaced by the stable isotope-labeled internal standard (m/z 372.2 to 225.0) to improve the assay (refer to Module 5.3.1.4, TMC278-BA218-AVRA-2).

For higher throughput, an ultra-high performance liquid chromatography (UPLC) LC-MS/MS method was developed (TMC278/BA1071, refer to Module 5.3.1.4, TMC278-PRD-BA1071-AVR). Aliquots of the trial sample and human heparin plasma (100 L) were transferred to a black 96 round deep-well microplate. Methanol (50 L), internal standard solution ( , 20.0 ng/100 L methanol; 50 L), and acetonitrile (350 L) were added, the microplate was heat-sealed, mixed for 3 minutes, and centrifuged for 10 minutes at 5000 to 6000 g. Gradient elution chromatographic separation (using an Acquity™ UPLC) was performed at 55°C on columns (5 cm × 2.1 mm I.D.) packed with 1.7 m Acquity BEH C18 (Waters). After injection of 2 μL of sample, the initial elution mixture composition of 48% 0.01 M ammonium formate (pH 4.0 with formic acid) and 52% methanol at a flow rate of 0.75 mL/min was changed stepwise to 2% 0.01 M ammonium formate and 98% methanol at a flow rate of 0.75 mL/min, before returning to the initial conditions at the end of the analysis. The MS/MS system was as described above. All stability experiments were performed under yellow light conditions.

LC-MS/MS Assay for Human Heparin Plasma, Developed at

Based upon analytical method BA218 (see above section), the LC-MS/MS assay for determination of TMC278 in human heparin plasma was partially validated for use at

The Netherlands (analytical method ABL6187, refer to Module 5.3.1.4, TMC278-ABL6187-AVR).

In this validation assay, an aliquot of the trial sample (100 μL) was diluted with 200 μL Elix-10 water before addition of methanol (50 L) and the internal standard work solution (50 μL of 1000 ng/mL in methanol). The samples were incubated for 10 minutes, then 0.5 mL acetonitrile was added and the samples were again incubated for 10 minutes. After centrifugation for 10 minutes at 4700 rpm and 5°C, 0.4 mL of the clear supernatant was taken and 0.4 mL of 10 mM ammonium formate/0.05% formic acid buffer solution was added. The samples were then centrifuged for 5 minutes at 4700 rpm and 5°C. The supernatant was used for LC-MS/MS analysis.

The LC system consisted of an Alliance 2795 HPLC system with a 5 cm × 4.6 mm I.D. column packed with 3 m Hypersil-BDS C18 maintained at 40°C. After injection of 10 μL of sample, the initial elution mixture composition of 45% 0.01 M ammonium formate (pH 4.0 with formic acid) and 55% methanol at a flow rate of 1.0 mL/min was changed stepwise to 5% 0.01 M ammonium formate and 95% methanol at a flow rate of 2.0 mL/min, before returning to the initial conditions at the end of the analysis.



An MS/MS system (API-4000) in the positive ion-mode was used for detection. The following multiple-reaction monitoring transitions were monitored for TMC278 and the internal standard: Q1 Mass m/z 367 to Q3 Mass m/z 224.0 with a dwell time of 500 ms for TMC278 and Q1 Mass m/z 372 to Q3 Mass m/z 225 with a dwell time of 200 ms for the internal standard. All procedures were performed under yellow light conditions.

For each individual trial, small adaptations to the instrument settings were allowed to optimize the assay performance for the analysis of trial samples.

2.7.1.1.3.2.2. Stability of TMC278 in Human Heparin Blood and Human Heparin Plasma

The stability of TMC278 (5.00 and 938 ng/mL) was evaluated in human heparin blood stored under the following conditions:

4ºC for 2 and 24 hours

Room temperature for 2 and 24 hours

37ºC for up to 2 hours

The stability of TMC278 (5.00 and 1525 ng/mL) was evaluated in human heparin plasma stored under the following conditions:

Room temperature for up to 72 hours

4 freeze/thaw cycles

–18ºC for long-term storage

Stability was considered proven if the concentration of TMC278 remained between 90.0% and 110.0% of the concentration in the reference samples (refer to Module 5.3.1.4, TMC278-PRD BA28-AVR-Compl). Samples were stored protected from light and all stability experiments were performed under yellow light conditions.

The stability of TMC278 in human heparin blood was demonstrated at both concentrations for all conditions mentioned above. The stability of TMC278 in human heparin plasma was demonstrated at both concentrations after 4 freeze/thaw cycles (compared to reference samples that underwent 1 freeze/thaw cycle). TMC278 was also stable in human heparin plasma for up to 72 hours at room temperature. The long-term stability of TMC278 in human heparin plasma at –18°C has been demonstrated for at least 1528 days.

2.7.1.1.3.2.3. Determination of Coadministered Drugs in Plasma

In-trial confirmation of the assay validation for coadministered drugs was conducted for the individual trials, and validation data are included in the respective bioanalytical study



summaries. An overview of the analytical methods employed for each trial is provided in Appendix 2.7.1.4.6.

The method validation reports for the methods used for quantitative determination of coadministered drugs in the clinical trials are available in Module 5.3.1.4.

2.7.1.1.3.3. Tenofovir DF

Concentrations of TFV in human serum and urine samples obtained for human pharmacokinetic studies were determined using validated fluorescence derivatization, reverse-phase, ion-pair HPLC methods that were developed according to ICH guidelines.

Blood samples collected during the trials were tested for TFV concentrations in serum using a validated LC/MS/MS method. Results were linear over the range of 24 to 1000 ng/mL when the HPLC method was used and were linear over the range of 3.01 to 602.84 ng/mL when the LC/MS/MS method was used. The LC/MS/MS method allowed for detection of the terminal elimination phase of drug for 48 hours postdosing, which was nearly 3 times the in vivo elimination half-life of the compound.

The serum and urine assay methods were highly sensitive and specific for TFV with interday accuracy of 6.8% for serum and 6.5% for urine. The interday precision was 3.3% for serum and 5.9% for urine.

2.7.1.1.3.4. Truvada (Emtricitabine/Tenofovir DF) Tablet

Concentrations of TFV and FTC in human plasma samples collected during Study GS-US-104-0172, a Phase 1 pharmacokinetic study in healthy subjects, were determined using a LC/MS/MS bioanalytical method (Module 5.3.1.2, Study GS-US-104-0172 CSR). Study GS-US-104-0172 is further described in Section 2.7.1.2.4 and Section 2.7.1.3.4.

The analytical method used in this study is different than those used in the individual component studies (ie, for TFV, serum [rather than plasma] was analyzed by an HPLC method; for FTC, plasma was analyzed using solid-phase extraction followed by LC/MS/MS analysis).

The methods were validated and were linear over a range of 5 to 2000 g/mL with a lower limit of quantitation (LLQ) of 5 g/mL for FTC, and over a range of 10 to 1000 ng/mL with an LLQ of 10 ng/mL for TFV. The methods were highly sensitive and specific for FTC and TFV. In quality control samples, interday accuracy deviations ranged from 0.3% to 6.2% and 2.6% to 4.4% for TFV and FTC, respectively, and interday precision deviations ranged from 5.35% to 16.55% and 4.92% to 7.20% for TFV and FTC, respectively. Assay validation parameters for Study GS-US-104-0172 are summarized in Table 3.



Table 3. Study GS-US-104-0172: Bioanalytical Assay Validation for Human Plasma

Emtricitabine Tenofovir

Linear Range 5 to 2000 μg/mL 10 to 1000 ng/mL

Lower Limit of Quantitation 5 μg/mL 10 ng/mL

Inter-Assay Precision Rangea 4.0% to 9.5% 4.4% to 7.9%

Inter-Assay Accuracy Rangeb 1.7% to 8.0% 5.2% to 4.0%

Stability (days) 522 at 80°C 66 at 22°Cc

a Relative standard deviation b Difference from nominal concentrations c Long-term stability testing was ongoing at the time the report was prepared. Source: Module 5.3.1.2, Study GS-US-104-0172 CSR, Section 16.3

2.7.1.1.3.5. FTC/RPV/TDF Fixed-Dose Combination Tablet

Concentrations of FTC, RPV, and TFV in plasma samples collected during the bioequivalence studies (GS-US-264-0103 and GS-US-264-0101) were determined using fully validated, high-performance LC/MS/MS bioanalytical methods. All samples were analyzed in the timeframe supported by frozen stability storage data. The assays for FTC and TFV were performed and validated by ( USA). The RPV assay was performed and validated by ( The Netherlands) for samples from Study GS-US-264-0103, and by Johnson & Johnson PRD (Beerse, Belgium) for samples from Study GS-US-264-0101. The assay validation parameters for Studies GS-US-264-0103 and GS-US-264-0101 are summarized in Table 4, below. The bioanalytical sample analysis and validation reports are provided in Appendix 16.1.10 of the respective CSR (Module 5.3.1.2, Study GS-US-264-0103 CSR, and GS-US-264-0101 CSR).

Table 4. Studies GS-US-264-0103 and GS-US-264-0101: Bioanalytical Assay Validation for Emtricitabine, Rilpivirine, and Tenofovir in Human Plasma

Parameter Emtricitabine Rilpivirine Tenofovir

Linear range (ng/mL) 5 to 3000 1 to 2000 5 to 3000

Lower limit of quantitation (ng/mL) 5 1 5

Interassay precision range (%CV) 1.4 to 5.7 2.3 to 5.8 2.4 to 6.5

Interassay accuracy range (%) –7.8 to 2.4 –0.5 to 4.0 –4.7 to 2.0

Stability in Frozen Matrix (days at –70ºC) 190 1528 190

Source: Module 5.3.1.2, Study GS-US-264-0103 CSR and Study GS-US-264-0101 CSR, Section 7.5.2.8.1, Table 7-4, Appendix 16.1.10



2.7.1.2. Summary of Results of Individual Studies

2.7.1.2.1. Emtricitabine

A number of single-agent biopharmaceutical studies are described in this section. These studies formally assessed the bioequivalence of the clinical and commercial formulations (FTC-109 and FTC-111), and food effect on the commercial formulation (FTC-111), using pharmacokinetic equivalence testing in healthy subjects. Another study (FTC-110) assessed the absolute bioavailability of the compound using an intravenous formulation and the relative bioavailability (namely, in comparison to the absolute bioavailability) of the commercial capsule formulation and of an oral solution formulation.

2.7.1.2.1.1. Study FTC-109

Title A Pilot Study to Evaluate the Bioequivalence/Bioavailability between the 100 mg and 200 mg Capsule Formulations of Emtricitabine in Healthy Volunteers

Objectives The objective of this pilot study was to compare the bioavailability of a 200-mg capsule dosage form of FTC intended for commercialization with a 100-mg capsule dosage form that was used in the Phase 2 and Phase 3 clinical trials of FTC.

Study Design This was an open-label, randomized, 2-way crossover study. Each subject received 2 single, oral doses of 200 mg FTC separated by a 1-week washout interval. Treatment A consisted of two 100-mg FTC capsules (Formulation C) and Treatment B consisted of one 200-mg FTC capsule (Formulation B). Both treatments were administered under fasting conditions. Serial blood (plasma) samples were collected for 24 hours after each dose for determination of plasma FTC concentrations.

Study Population 12 healthy volunteers, 7 male and 5 female, aged 19 to 55 years (mean: 30 years).

Pharmacokinetic Results The geometric mean ratio (B/A) for Cmax was 98% (with the 90% CIs of 83% and 115%) and that for AUCinf was 97% (with the 90% CIs of 89% and 106%). The 90% CIs were therefore within 80% to 125% for each of these parameters.

Safety Results Single 200-mg doses of FTC in either capsule formulation were well tolerated, based on evaluation of reported adverse events (AEs), physical examination findings, including vital signs measurements, and clinical laboratory test results. There were no serious adverse events (SAEs) reported and there were no discontinuations due to AEs. Five subjects reported a total of 11 AEs. Headache and nausea, reported by 4 (33%) and 2 (17%) of the 12 subjects, respectively, were the most common AEs. All AEs reported were mild in severity.



Conclusions The intended commercial formulation (200-mg capsule) of FTC was bioequivalent to the clinical trial formulation (two 100-mg capsules) with regard to AUCinf and Cmax estimates.

2.7.1.2.1.2. Study FTC-111

Title An Open-Label Study to Compare the Bioavailability/Bioequivalence of Two Dosage Forms of Emtricitabine (100 mg Capsules and 200 mg Capsules) and the Effect of Food on the Bioavailability of Emtricitabine Administered as a 200 mg Capsule in Healthy Volunteers

Objectives The objectives of this study were as follows:

To compare the bioavailability of the final (ie, intended for marketing) dosage formulation of FTC (200-mg capsule) with a previous dosage formulation of FTC (100-mg capsule) that had been administered to subjects in pivotal clinical trials

To determine the effect of a high-fat meal on the bioavailability of the 200-mg capsule formulation of FTC

Study Design This was an open-label, randomized, 3-way crossover study. Each subject received 3 single 200-mg FTC treatments:

Treatment A: two 100-mg capsules (Formulation C)

Treatment B: one 200-mg capsule (Formulation B)

Treatment C: one 200-mg capsule, administered within 20 minutes of starting and 5 minutes after completing a high-fat meal (Formulation B)

All treatments were administered after an overnight fast and there was a 1-week washout interval between treatments. Serial blood (plasma) samples were collected for 24 hours after each dose for determination of plasma FTC concentrations. Safety was assessed based on reported AEs, physical examination findings, including vital signs measurements, and clinical laboratory test results.


Pharmacokinetic Results For the 200-mg capsule in relation to the two 100-mg capsules, the geometric mean ratio (B/A) for Cmax was 107% (with 90% CIs of 99% and 116%) and that for AUCinf was 102% (with 90% CIs of 97% and 106%). The 90% CIs were therefore within 80% to 125% for each of these parameters.



For the 200-mg capsule, fed in relation to fasted, the geometric mean ratio (C/B) for Cmax was 72% (with 90% CIs of 67% and 78%) and that for AUCinf was 91% (with 90% CIs of 87% and 95%).

Safety Results Single oral 200-mg doses of FTC, administered under fasting and fed conditions, were well tolerated, based on reported AEs, physical examination findings, including vital signs measurements, and clinical laboratory test results. There were no SAEs reported.

Conclusions The commercial formulation (200-mg capsule) of FTC was bioequivalent to the clinical trial formulation (two 100-mg capsules) with regard to AUCinf and Cmax estimates.

The high-fat meal caused mean Cmax to decrease by approximately 29% and mean time to maximum plasma concentration (Tmax) to increase by approximately 1.5 hours, but had no effect on the extent (AUC0-t, AUCinf) of systemic bioavailability of the 200-mg FTC capsule formulation. The food effect observed is not expected to be clinically significant for FTC.

2.7.1.2.1.3. Study FTC-110

Title A Study to Evaluate the Relative and Absolute Bioavailability of Emtricitabine in Healthy Volunteers


To determine the relative bioavailability of FTC administered as the 200-mg capsule formulation in comparison to an oral solution formulation containing 10 mg/mL of FTC

To determine the absolute bioavailability of FTC, when administered as the 200-mg capsule formulation or the oral solution, compared to an intravenous dose of FTC

Study Design This was an open-label, randomized, 3-way crossover study. Subjects each received 3 single 200-mg FTC treatments:

Treatment A: one 200-mg FTC oral capsule

Treatment B: 20 mL of the 10-mg/mL FTC oral solution

Treatment C: 20 mL of a 10-mg/mL FTC intravenous solution (administered intravenously by continuous slow infusion over a period of 1 hour)

There was a 1-week washout between successive doses and all 3 treatments were administered under fasting conditions. Serial blood (plasma) and cumulative urine samples



were collected for 48 hours after each dose for determination of plasma and urine concentrations of FTC.


Pharmacokinetic Results Geometric mean ratios between the various formulations were as follows:

For the 200-mg capsule in relation to the intravenous solution, the ratio (A/C) for Cmax was 56% (with 90% CIs of 52% and 61%) and that for AUC0- was 93% (with 90% CIs of 87% and 99%).

For the oral solution in relation to the intravenous solution, the ratio (B/C) for Cmax was 37% (with 90% CIs of 34% and 40%) and that for AUC0- was 75% (with 90% CIs of 70% and 80%).

For the 200-mg capsule in relation to the oral solution, the ratio (A/B) for Cmax was 153% (with 90% CIs of 142% and 166%) and that for AUC0- was 124% (with 90% CIs of 117% and 133%).

Safety Results Single 200-mg doses of FTC, administered as the oral capsule and solution formulations intended for commercialization or administered intravenously by continuous slow infusion over a period of 1 hour, were well tolerated, based on reported AEs, physical examination findings, including vital signs measurements and clinical laboratory test results. There were no SAEs reported. A total of 45 AEs were reported by 9 of the 12 subjects (75%). All of the AEs were mild (39/45) or moderate (6/45) in severity and all events resolved without requiring treatment. Adverse events of moderate severity were headache, rhinitis, and nausea.

Conclusions Based on the AUC0- estimate, the absolute bioavailability of the 200-mg FTC capsule formulation is 93%. Based on the AUC0- estimate, the absolute bioavailability of 20 mL of the 10-mg/mL FTC oral solution formulation is 75%.

The relative bioavailability of the capsule formulation compared to oral solution was 124%. The finding of a lower bioavailability of the solution compared to the capsule was unexpected and difficult to explain. Nevertheless, the magnitude (~ 24%) of the difference between the 2 oral formulations is considered unlikely to be of any clinical importance.

2.7.1.2.2. Rilpivirine

Four single-agent studies are described in this section. Two trials (R278474-C102 and TMC278-C117) were conducted to formally investigate the relative oral bioavailability of TMC278 administered as solution, capsule, and tablet formulations in the search for an appropriate oral formulation. A third trial, TMC278-TiDP6-C137, was conducted to formally investigate the effect of different types of meals on the oral bioavailability of TMC278 given



as the 75-mg Phase III tablet. The fourth trial (TMC278-TiDP38-C145) investigated the bioavailability of TMC278 when administered as 3 oral pediatric concept formulations.

2.7.1.2.2.1. Trial C102

Title Relative Oral Bioavailability of TMC278 Administered as Capsule and Tablet Formulations Compared to a Solution Formulation of TMC278, and Effect of Food on Oral Bioavailability of TMC278

Objectives To investigate the oral bioavailability of TMC278 administered as 2 solid formulations compared to a reference solution formulation of TMC278

To investigate the effect of food on the bioavailability of TMC278 administered as the solid formulations

Study Design This was a Phase I, open-label, randomized, 3-period crossover trial with 2 parallel panels. The trial population consisted of 24 healthy subjects in 2 parallel panels. In each panel, 12 subjects received a single, oral dose of 100 mg TMC278 in each of 3 sessions (reference [Treatment A] under fed conditions and test [Treatment B in Panel 1 and Treatment C in Panel 2] once under fed and once under fasted conditions). The treatments were as follows:

Treatment A (reference): 4 mL of 25-mg/mL solution

Treatment B (test): 2 capsules, each containing 50 mg of TMC278

Treatment C (test): 1 TMC278 100-mg tablet (Phase IIb tablet)

The reference formulation was given under fed conditions (ie, within 10 minutes after a standardized breakfast) and the test formulations were each given once under fed and fasted conditions. Treatments were separated by a washout period of at least 2 weeks.

Further details on the design and results of this trial are available in the clinical research report (CRR) (refer to Module 5.3.1.1, Trial R278474-C102-CRR).

Study Population 24 healthy subjects

Pharmacokinetics Results The plasma concentration-time profiles of TMC278 showed that, under fed conditions, the mean plasma concentrations obtained with the capsule formulation were similar to the mean concentrations obtained with the oral solution, whereas the mean plasma concentrations obtained with the tablet were slightly lower (Figure 1). The pattern of decline following Cmax was similar for all 3 formulations of TMC278. While the mean plasma concentrations under fasted conditions were lower than those under fed conditions for the capsule and tablet



formulations, the pattern of decline following Cmax was not affected by food with either formulation. Cmax values were reached slightly later under fed conditions.

Figure 1. Trial C102: Mean Plasma Concentration-Time Profiles of TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278 Compared to a Reference Oral Solution Formulation of TMC278 (Upper Panels) and of Capsule and Tablet Formulations Under Fed Compared to Fasted Conditions (Lower Panels)

0

50

100

150

200

250

300

350

400

0 6 12 18 24 30 36 42 48

TMC2

78 p

lasm

a co

nc. (

ng/m

L)

Planned time (h)

Capsule (fed)

Capsule (fasted)

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100

150

200

250

300

350

400

0 6 12 18 24 30 36 42 48

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nc. (

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Planned time (h)

Solution (fed)

Tablet (fed)

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100

150

200

250

300

350

400

0 6 12 18 24 30 36 42 48

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78 p

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nc. (

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Planned time (h)

Tablet (fed)

Tablet (fasted)

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200

250

300

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0 6 12 18 24 30 36 42 48

TMC2

78 p

lasm

a co

nc. (

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L)

Planned time (h)

Solution (fed)

Capsule (fed)

A B

C D

N = 12 subjects. Source: Module 5.3.1.1, Trail R278474-C102-CRR, Supporting Data Display 12

Under fed conditions, the mean exposure to TMC278 with the capsule formulation (Treatment B) was comparable to the mean exposure with the reference solution (Treatment A); the 90% CIs of the least squares (LS) means ratios for Cmax and AUC were within the 0.80 to 1.25 interval (Table 5). The mean exposure to TMC278 with the tablet (Treatment C) was up to 17% lower than the mean exposure with the reference solution (Treatment A), and the lower limits of the 90% CIs of the LS means ratios for Cmax and AUC values were below the lower boundary of the 0.80 to 1.25 interval. No relevant differences were observed between the reference solution and the capsule or tablet formulations for the time to reach tmax, and terminal elimination half-life (t1/2, term) of TMC278.



Table 5. Trial C102: Pharmacokinetics of TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278, Compared to a Reference Oral Solution Formulation of TMC278, Under Fed Conditions

Mean SD; tmax: Median (Range)

Parameter

Treatment A: TMC278 100 mg (Oral Solution)

(Reference)

Treatment B or C: TMC278 100 mg

(Capsule or Tablet) (Test)

Ratioa (Test:Reference) 90% CI

Panel 1: Treatment A (Oral Solution) versus Treatment B (Capsule)

N 12 12

tmax, h 4.0 (3.0 - 6.0) 3.5 (2.0 - 6.0) - -

Cmax, ng/mL 395 86 419 137 1.03 0.94 - 1.14

AUClast, ng h/mL 15304 3637 13567 2725 0.89 0.82 - 0.98

AUC , ng h/mL 15976 3958 14200 3070 0.90 0.82 - 0.98

t1/2, term, h 43.4 11.5 46.3 10.1 - -

Panel 2: Treatment A (Oral Solution) versus Treatment C (Phase IIb Tablet)

N 12 12

tmax, h 4.0 (3.0 - 6.0) 4.0 (3.0 - 6.0) - -

Cmax, ng/mL 372 37 316 59 0.84 0.74 - 0.95

AUClast, ng h/mL 12448 2688 10455 2525 0.83 0.73 - 0.95

AUC , ng h/mL 12944 2988 10906 2754 0.83 0.73 - 0.95

t1/2, term, h 42.6 11.1 43.6 12.2 - -

N = maximum number of subjects with data a Ratio based on LS means Source: Module 5.3.1.1, Trial R278474-C102-CRR, Section 4.2.5 and Section 4.2.6

The mean exposure to TMC278 was higher under fed conditions than under fasted conditions for both the capsule and tablet formulations. In terms of Cmax and area under the plasma concentration-time curve to last measurable or measured concentration (AUClast), the mean exposure was 1.6- and 1.5-fold higher, respectively, for the capsule, and 1.7- and 1.5-fold higher, respectively, for the tablet (Table 6). The median tmax of TMC278 was delayed slightly under fed conditions, compared to fasted conditions, with both the capsule and tablet formulations. Food had no relevant effect on the t1/2, term of TMC278. The inter-individual variability in the exposure to TMC278 (%CV for AUClast and area under the plasma concentration-time curve extrapolated to infinity [AUC ]) after intake of the solid formulations was reduced from approximately 40% under fasted conditions to approximately 20% to 25% under fed conditions (refer to Module 5.3.1.1, R278474-C102-CRR, Section 4.2).



Table 6. Trial C102: Pharmacokinetics of TMC278 After Single-Dose Administration of Capsule and Tablet Formulations of TMC278 Given Under Fed or Fasted Conditions


Parameter

Treatment B or C: TMC278 100 mg

(Fasted Conditions) (Reference)

Treatment B or C: TMC278 100 mg (Fed Conditions)

(Test) Ratioa

(Test:Reference) 90% CI

Panel 1: Treatment B (Capsule)

N 12 12

tmax, h 3.0 (2.0 - 32.0) 3.5 (2.0 - 6.0) - -

Cmax, ng/mL 295 141 419 137 1.61 1.13 - 2.29

AUClast, ng h/mL 9733 3795 13567 2725 1.52 1.18 - 1.95

AUC , ng h/mL 10144 3890 14200 3070 1.52 1.18 - 1.95

t1/2, term, h 45.2 11.0 46.3 10.1 - -

Panel 2: Treatment C (Phase IIb Tablet)

N 12 12

tmax, h 3.0 (3.0 - 6.0) 4.0 (3.0 - 6.0) - -

Cmax, ng/mL 210 119 316 59 1.71 1.29 - 2.27

AUClast, ng h/mL 7421 2939 10455 2525 1.46 1.25 - 1.71

AUC , ng h/mL 7804 3101 10906 2754 1.45 1.24 - 1.68

t1/2, term, h 44.9 12.4 43.6 12.2 - -

N = maximum number of subjects with data a Ratio based on LS means Source: Module 5.3.1.1, Trial R278474-C102-CRR, Section 4.2.5 and Section 4.2.6

Safety Results For safety results of this trial, refer to the TMC278-C102-CRR in Module 5.3.1.1.

Conclusions The capsule and tablet formulations of TMC278 both provide adequate exposure to TMC278, which is either comparable (capsule) or slightly lower (tablet) than the exposure obtained with the solution of TMC278. When administered as the capsule or tablet, the oral bioavailability of TMC278 is improved and the inter-individual variability in pharmacokinetic parameters is lower when TMC278 is given under fed conditions compared to fasted conditions.



2.7.1.2.2.2. Trial C117

Title Relative Oral Bioavailability of TMC278 Given as the Phase III Tablet Formulation Compared to the Reference Phase IIb Tablet Formulation

Objective To investigate the relative oral bioavailability of TMC278 when administered as the Phase III tablet compared to the Phase IIb tablet.

Study Design This was a Phase I, open-label, randomized, 2-period crossover trial. The trial population consisted of 32 healthy subjects in 2 parallel panels. A third planned panel (Panel 1 with Treatments A and B, related to comparison of the 25-mg dose) was removed from the trial design by protocol amendment 1 because, after review of the 24-week interim results of the dose-ranging trial C204, the 25-mg dose of TMC278 was considered a less likely candidate for further development. Later on, based on the beneficial benefit/risk assessment, the 25-mg dose was selected for further development (refer to Module 2.7.3, Section 2.7.3.2.2 for further details).

In Panels 2 and 3, 16 subjects each received a single, oral dose of TMC278 on each of 2 occasions, as follows:

Panel 2:

Treatment C (test): 4 TMC278 25-mg tablets (Phase III tablet);

Treatment D (reference): 1 TMC278 100-mg tablet (Phase IIb tablet);

Panel 3:

Treatment E (test): 1 TMC278 150-mg tablet (Phase III tablet);

Treatment F (reference): 3 TMC278 50-mg tablets (Phase IIb tablet). All treatments were taken under fed conditions within 10 minutes after completion of a standardized breakfast. Treatments were separated by a 13-day washout period.

Further details on the design and results of this trial are available in the CRR (refer to Module 5.3.1.2, TMC278-C117-CRR).


Pharmacokinetic Results There was a substantial overlap between the mean plasma concentration-time profiles of the Phase IIb and Phase III tablets for the 100- and 150-mg dose groups (Figure 2). The Cmax of the mean curves occurred at approximately 4 hours after dosing for all treatments.



Figure 2. Trial C117: Mean Plasma Concentration-Time Profiles of TMC278 After Single-Dose Administration of TMC278 as Phase III and Phase IIb Tablets

0

100

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300

400

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600

0 4 8 12 16 20 24

Time (h)

Pla

sma

conc

. of T

MC

278

(ng/

mL)

four 25 mg TMC278 Phase IIItablets (n=16)

one 100 mg TMC278 Phase IIbtablet (n=16)

one 150 mg TMC278 Phase IIItablet (n=16)

three 50 mg TMC278 Phase IIbtablets (n=16)

Source: Module 5.3.1.2, Trial TMC278-C117-CRR, Section 4.2.4

The mean Cmax and AUC values were comparable between the Phase III and Phase IIb tablets for the 100-mg (Treatment C versus Treatment D) and 150-mg (Treatment E versus Treatment F) dose groups (Table 7). In the 100-mg dose group, the 90% CIs of the LS means ratio were just outside the 0.80 to 1.25 interval for Cmax and AUC , and were within this interval for AUClast. In the 150-mg dose group, the 90% CIs of the LS means ratio were within the 0.80 to 1.25 interval for all pharmacokinetic parameters evaluated. No relevant differences were observed between the Phase III and Phase IIb tablets for the tmax, and t1/2, term of TMC278. The inter-individual variability within each of the test formulations was comparable to the variability within each of the reference formulations (refer to Module 5.3.1.2, TMC278-C117-CRR, Section 4.2.5).



Table 7. Trial C117: Pharmacokinetics of TMC278 After Single-Dose Administration of 100- or 150-mg TMC278 Formulated as Phase III (Test) or Phase IIb (Reference) Tablet


Parameter

Treatments D or F: 100 or 150 mg TMC278

(Phase IIb Tablet) (Reference)

Treatment C or E: 100 or 150 mg TMC278

(Phase III Tablet) (Test)

Ratio a (Test:Reference) 90% CI

Panel 2: Treatment D (100 mg as 4 × 25-mg Phase IIb Tablet) versus Treatment C (100 mg as Phase III Tablet)

N 16 16

tmax, h 4.0 (2.0 - 12.0) 4.5 (3.0 - 9.0) - -

Cmax, ng/mL 400.7 149.6 339.2 125.7 0.85 0.72 - 1.02

AUClast, ng h/mL 12160 3952 12270 5123 0.99 0.80 - 1.22

AUC , ng h/mL 14010 5539 14070 6678 0.98 0.79 - 1.22

t1/2, term, h 56.46 27.17 52.82 17.62 - -

Panel 3: Treatment F (150 mg as Phase IIb Tablet) versus Treatment E (150 mg as 3 × 50-mg Phase III Tablet)

N 16 16

tmax, h 4.0 (2.0 - 6.0) 4.0 (3.0 - 6.0) - -

Cmax, ng/mL 630.4 165.5 597.6 116.9 0.96 0.86 - 1.08

AUClast, ng h/mL 19400 6414 19640 6467 0.98 0.88 - 1.10

AUC , ng h/mL 20740 7389 20910 8067 1.00 0.90 - 1.12

t1/2, term, h 39.88 11.80 40.02 12.12 - -

N = maximum number of subjects with data Ratio based on LS means ratio Source: Module 5.3.1.2, Trial TMC278-C117-CRR, Section 4.2.5 and Section 4.2.6


Conclusions The oral bioavailability of TMC278 using the Phase III tablet is comparable to the bioavailability of TMC278 administered as the Phase IIb tablet.

2.7.1.2.2.3. Trial C137

Title Effect of Food on Oral Bioavailability of TMC278 Administered as the Phase III Tablet



Study Design This was a Phase I, open-label, randomized, 4-period crossover trial to investigate the effect of different types of meals on the oral bioavailability of TMC278 given as the 75-mg Phase III tablet.

The trial population consisted of 20 healthy subjects. In each of 4 sessions, subjects received a single, oral dose of 75 mg TMC278 within 10 minutes after completing one of the following types of breakfast, or under fasted conditions:

Treatment A (reference): Normal-fat breakfast (533 kcal, 21 g fat, 189 kcal from fat, 268 kcal from carbohydrates, and 76 kcal from proteins)

Treatment B (test): Fasted conditions (subjects had to have fasted overnight for at least 10 hours)

Treatment C (test): High-fat breakfast (928 kcal, 56 g fat, 504 kcal from fat, 260 kcal from carbohydrates, and 164 kcal from proteins)

Treatment D (test): Protein-rich nutritional drink (Ensure® HP, 240 mL; 300 kcal, 7.9 g fat, 72 kcal from fat, 153 kcal from carbohydrates, and 75 kcal from proteins)

Treatments were separated by a washout period of at least 13 days. Additional details on the design and results of the trial are available in the CRR (refer to Module 5.3.1.1, TMC278-TiDP6-C137-CRR).


Pharmacokinetics Results The mean plasma concentration-time profiles of TMC278 were lower when TMC278 was administered under fasted conditions and after a protein-rich nutritional drink, compared to TMC278 administered after a normal-fat breakfast (Figure 3). The mean plasma concentrations of TMC278 were comparable when TMC278 was taken after a high-fat breakfast or after a normal-fat breakfast. A lag time of approximately 1 to 2 hours was observed when TMC278 was taken after the protein-rich nutritional drink compared to lag times of up to 0.5 hours for the other treatments.



Figure 3. Trial C137: Mean Plasma Concentration-Time Profiles of TMC278 Single-Dose Administration of 75 mg TMC278 Given Under Fed Conditions With Different Types of Meals or Under Fasted Conditions

0

50

100

150

200

250

300

350

400

450

0 4 8 12 16 20 24

Time (h)

Plas

ma c

onc.

of T

MC

278

(ng/

mL)

Standard breakfast (n=19)Fasting conditions (n=19)High-fat breakfast (n=19)Protein-rich nutritional drink (n=18)

Mean and standard deviation data are shown. The standard breakfast is referred to as normal-fat breakfast in the text. Source: Module 5.3.1.1, Trial TMC278-TiDP6-C137-CRR, Section 4.2.4

The mean exposure to TMC278 (in terms of Cmax and AUC parameters) was comparable when administered after a normal-fat breakfast (Treatment A) and after a high-fat breakfast (Treatment C) (Table 8). The 90% CIs of the LS means ratios were within the 0.80 to 1.25 interval for Cmax and AUClast, and the lower limit of the 90% CI for AUC was just below 0.80. Administration of TMC278 under fasted conditions (Treatment B) and after a protein-rich nutritional drink (Treatment D) decreased the bioavailability of TMC278 by approximately 40% to 50% compared to administration after a normal-fat breakfast. The median tmax was 5 hours when TMC278 was administered under fed conditions, irrespective of the type of meal, compared to 4 hours under fasted conditions. The mean t1/2, term was comparable for all treatments. The inter-individual variability was similar within each of the treatment groups.



Table 8. Trial C137: Pharmacokinetics of TMC278 After Single-Dose Administration of 75 mg TMC278 Given Under Fed Conditions With Different Types of Meals or Under Fasted Conditions


Parameter

Treatment A: TMC278 75 mg

Normal-Fat Breakfast (Reference)

Treatment B, C, or D: TMC278 75 mg

Fasted or Other Meal Types (Test)

Ratioa (Test:Reference) 90% CI

Treatment A (Normal-Fat Breakfast) versus Treatment B (Fasted Conditions)

N 19 19

tmax, h 5.0 (2.0 - 9.0) 4.0 (2.0 - 24.0) - -

Cmax, ng/mL 296.4 117.6 170.2 65.61 0.54 0.43 - 0.69

AUClast, ng h/mL 10340 3894 6230 2339 0.57 0.46 - 0.72

AUC , ng h/mL 11450 4431 7202 3024 0.59 0.47 - 0.74

t1/2, term, h 47.98 22.08 54.84 28.25 - -

Treatment A (Normal-Fat Breakfast) versus Treatment C (High-Fat Breakfast)

N 19 19

tmax, h 5.0 (2.0 - 9.0) 5.0 (3.0 - 9.0) - -

Cmax, ng/mL 296.4 117.6 279.8 102.6 0.92 0.81 - 1.05

AUClast, ng h/mL 10340 3894 9717 3535 0.92 0.80 - 1.07

AUC , ng h/mL 11450 4431 10670 4331 0.91 0.79 - 1.05

t1/2, term, h 47.98 22.08 43.05 17.28 - -

Treatment A (Normal-Fat Breakfast) versus Treatment D (Protein-Rich Nutritional Drink)

N 19 18

tmax, h 5.0 (2.0 - 9.0) 5.0 (4.0 - 9.0) - -

Cmax, ng/mL 296.4 117.6 156.0 59.66 0.50 0.40 - 0.63

AUClast, ng h/mL 10340 3894 5437 2421 0.50 0.41 - 0.61

AUC , ng h/mL 11450 4431 6094 3047 0.51 0.42 - 0.62

t1/2, term, h 47.98 22.08 47.29 22.89 - -

N = maximum number of subjects with data a Ratio based on LS means ratio Source: Module 5.3.1.1, Trial TMC278-TiDP6-C137-CRR, Section 4.2.5 and Section 4.2.6




Conclusions The oral bioavailability of TMC278 was 40% to 50% lower when TMC278 was administered under fasted conditions or after a protein-rich nutritional drink, compared to when TMC278 was administered after a normal-fat breakfast. Administration of TMC278 after a high-fat breakfast or after a normal-fat breakfast resulted in similar exposures. TMC278 should therefore be administered with a meal to enhance the oral bioavailability.

2.7.1.2.2.4. Trial C145

Trial C145 was conducted to investigate the bioavailability of TMC278 when administered as 3 oral pediatric concept formulations in the context of potential use in pediatric development. (Although this is an evaluation of pediatric formulations and is not the proposed patient population of the FDC tablet MAA, this trial has been included for completeness and consistency with the TMC278 MAA.)

This trail was a Phase I, open-label, randomized, 3-period crossover trial to compare the bioavailability of TMC278 after administration as 1 of 3 oral concept pediatric formulations (a solution, a suspension, or granules) to the bioavailability when administered as the 25-mg Phase III tablet used in adults, and to assess the food effect for each concept formulation. The trial population consisted of 36 healthy adults, divided over 3 panels of 12 subjects each, one panel for each concept pediatric formulation. In each of the 3 panels, subjects received 3 different TMC278 treatments in a randomized fashion, in 3 subsequent sessions, separated by a washout period of at least 14 days.

The different treatments were:

Panel 1: single 25-mg TMC278 dose (2.5 mL) of oral solution (10 mg/mL) given under fed (Treatment A1) and fasted (Treatment B1) conditions

Panel 2: single 25-mg TMC278 dose (5 mL) of oral suspension (5 mg/mL) given under fed (Treatment A2) and fasted (Treatment B2) conditions

Panel 3: single 25-mg TMC278 dose (10 g) of oral granules (2.5 mg/g) given under fed (Treatment A3) and fasted (Treatment B3) conditions

Panels 1, 2, and 3: single 25-mg TMC278 dose as the 25 mg Phase III tablet under fed conditions (Treatments C1, C2, C3)

For further details on the formulations used, see Table 9.

In each treatment session, full pharmacokinetic profiles of TMC278 were measured up to 168 hours after intake. A taste questionnaire was used to evaluate the palatability of each concept pediatric formulation. Further details on the design and results of this trial are available in the study report (refer to Module 5.3.1.2, TMC278-TiDP38-C145-CRR).



Table 9. Clinical Biopharmaceutic Trials, Including Information on TMC278 Dosage Form, Formulation Number, and Dose

TMC278

Clinical Trial Number (Abbreviated Number) Dosage Form

Formulation Number Dose

Relative Bioavailability Trials - Optimization of Oral Formulation

25 mg/mL solution R278474 F002 100 mg

50 mg capsule R278474 F003 100 mg

R278474-C102 (C102) (Section 2.7.1.3.2)

100 mg tablet (Phase IIb tablet) R314585 F002 100 mg



25 mg tablet (Phase III tablet) R314585 F006 100 mg

TMC278-C117 (C117) (Section 2.7.1.3.2))


Relative Bioavailability Trial - Concept Formulations for Potential Use in Pediatric Development

10 mg/mL solution R278474 F008 25 mg

5 mg/mL suspension R314585 F014 25 mg

2.5 mg/g granules R314585 F015 25 mg

TMC278-TiDP38-C145 (C145)


Food Effect Trial

TMC278-TiDP6-C137 (C137) (Section 2.7.1.3.6.2)


Source: clinical research reports (CRRs)

2.7.1.2.3. Tenofovir DF

One single-agent biopharmaceutical study (GS-00-914, (Module 5.3.1.2, Study GS-00-914 CSR) is described in this section. This study formally assessed the bioequivalence of the clinical and commercial formulations and food effect on the commercial formulation using pharmacokinetic equivalence testing in healthy subjects. Four other relevant studies, which are described in Section 2.7.2, are cited at the end of this section. These studies provide data in relation to bioavailability and food effects with TDF.

2.7.1.2.3.1. Study GS-00-914

Title A Phase 1, Randomized, Open-Label, Pharmacokinetic Study in Healthy Volunteers to Assess the 1) Bioequivalence of the Clinical and Intended Commercial Formulations of Tenofovir Disoproxil Fumarate and the 2) Effect of Food on the Bioavailability and Pharmacokinetics of the Intended Commercial Formulation of Tenofovir Disoproxil Fumarate 300 mg Tablets




To determine the pharmacokinetic profile of a single dose of the clinical formulation of TDF 300 mg (4 75 mg tablets) when administered under fasted conditions

To determine the pharmacokinetic profile of a single dose of the intended commercial formulation of TDF 300-mg tablets when administered under fasted conditions

To evaluate the bioequivalence of the 300-mg clinical dose and intended commercial formulations of TDF 300-mg tablets when administered under fasted conditions

To determine the pharmacokinetic profile of a single dose of the intended commercial formulation of TDF 300-mg tablets when administered under fed conditions

To evaluate whether food affects the pharmacokinetic profile of the intended commercial formulation of TDF 300-mg tablets.

Study Design An integrated, 3-period, randomized, open-label, bioequivalence, and food-effect study. Each subject received each of the following as a single dose interspersed by a 7- to 14-day washout period:

Treatment A: 4 75-mg tenofovir DF tablets (Formulation #1: clinical formulation) in the fasted state

Treatment B: One 300-mg tenofovir DF tablet (Formulation #5: commercial formulation) in the fasted state

Treatment C: One 300-mg tenofovir DF tablet (Formulation #5: commercial formulation) in the fed state

Study Population A total of 40 subjects were enrolled in the study, and 36 subjects (90%) completed the study.

Pharmacokinetic Results For fasted-state comparisons, the geometric mean ratio (B/A) for Cmax was 96% (with the 90% CIs of 88% and 106%) and that for AUCinf was 101% (with the 90% CIs of 96% and 106%). The 90% CIs were, therefore, within 80% to 125% for each of these parameters.

The administration of the commercial formulation following a high-fat meal resulted in delayed Tmax. The geometric mean ratio (C/B) for Cmax was 114% (with the 90% CIs of 104% and 125%) and that for AUCinf was 138% (with the 90% CIs of 132% and 145%). Geometric mean Cmax was approximately 14% higher for the fed treatment; however, the 90% CIs were within 80% to 125%. The 90% CIs for AUCinf were outside 80% to 125%, indicating a food effect.



Renal clearance of TFV exceeds creatinine clearance indicating elimination via both active secretion and glomerular filtration. The terminal elimination half-life of approximately 18 hours supports the once daily-dosing schedule of TDF.

Safety Results A total of 68 treatment-emergent adverse events (TEAEs) were reported by 19 (48%) of the 40 subjects dosed with study treatment. Relative to Treatments A and C, more subjects reported AEs following dosing with Treatment B. Headache was the most frequently reported event across all treatments. All events reported during the study were mild or moderate in severity, except one episode of ear pain considered severe in nature. There were no SAEs reported, and no subject discontinued the study due to an AE. No significant treatment-related differences were observed for any safety parameter that was assessed.

Conclusions The commercial formulation of TDF is bioequivalent to the formulation used in clinical trials. Administration of TDF with food (high-fat meal) results in enhanced bioavailability of TFV. The 3 treatments (ie, the clinical formulation in the fasted state and the commercial formulation in the fed and fasted states) were safe and well tolerated in this group of healthy subjects.

2.7.1.2.3.2. Additional Relevant Studies

Pertinent data in relation to bioavailability and food effects are available from 4 additional studies, which are listed below. Narratives for these studies are to be found in the Summary of Clinical Pharmacology (Section 2.7.2).

Study GS-97-901: In this Phase 1/2 placebo-controlled study, the pharmacokinetics and bioavailability of oral TDF (75-, 150-, 300-, or 600-mg tablets) were assessed in HIV-1 infected adults (Module 5.3.4, Study GS-97-901 CSR).

Study GS-01-932: This Phase 1, steady-state pharmacokinetic drug-interaction study provides data on the effect of food on the bioavailability of TFV following multiple oral administrations of 300-mg TDF tablets to healthy subjects (Module 5.3.3.4, Study GS-01-932 CSR).

Study GS-00-909: This Phase 1, randomized, open-label, multiple-dose, drug interaction study provides comparative data on the steady-state pharmacokinetics of TFV following multiple oral administration of 300-mg TDF tablets to healthy subjects in the fasted state (Module 5.3.3.4, Study GS-00-909 CSR).

Study GS-96-701: The oral bioavailability of TFV from TDF was estimated by reference to historical data obtained in the evaluation of the 1-mg/kg intravenous dose administered in this study to HIV-1 infected adults (Module 5.3.4, Study GS-96-701 CSR).



2.7.1.2.4. Emtricitabine/Tenofovir DF

One biopharmaceutical study, GS-US-104-0172 (Module 5.3.1.2, Study GS-US-104-0172 CSR), is described in this section. This study formally assessed the bioequivalence between the FTC/TDF tablet and concurrent administration of a TDF tablet and an FTC capsule, and also the food effect on the FTC/TDF tablet using pharmacokinetic equivalence testing in healthy subjects.

2.7.1.2.4.1. Study GS-US-104-0172

Title A Phase 1 Pharmacokinetic Study in Healthy Volunteers to Evaluate the Bioequivalence of the Combined Formulated Tablet of Tenofovir Disoproxil Fumarate and Emtricitabine Compared to Tenofovir Disoproxil Fumarate and Emtricitabine Administered Concurrently and the Effect of Food on Pharmacokinetics

Objectives The primary objectives of this study were:

To establish bioequivalence between the combination tablet (containing 300 mg TDF and 200 mg FTC) and concurrent administration of the 300-mg tablet of TDF and the 200-mg capsule of FTC by evaluation of Cmax and AUC of TFV and FTC

To investigate the effect of food (high-fat meal and light meal) on the pharmacokinetics of the FTC/TDF tablet

To assess the safety of TDF and FTC when administered together either as the FTC/TDF tablet or as separate formulations

Study Design This was an open-label, randomized, 4-way crossover, pharmacokinetic study designed to evaluate the bioequivalence of an FTC/TDF tablet compared with FTC and TDF administered concurrently and to also evaluate the effect of food on absorption. Each subject received each of the following as a single dose interspersed by a 7-day washout period:

Treatment Description

Treatment A A single tablet of tenofovir disoproxil fumarate (tenofovir DF) 300 mg coadministered with a single capsule of emtricitabine 200 mg, under fasted conditions.

Treatment B A tablet consisting of tenofovir DF 300 mg/emtricitabine 200 mg, administered under fasted conditions.

Treatment C A tablet consisting of tenofovir DF 300 mg/emtricitabine 200 mg, administered under fed (high-fat meal) conditions.

Treatment D A tablet consisting of tenofovir DF 300 mg/emtricitabine 200 mg, administered under fed (light meal) conditions.



Whole blood samples were collected over a 48-hour period after administration for pharmacokinetic assessments. Safety was evaluated by assessment of clinical laboratory tests at base

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SECTION 2.7 CLINICAL SUMMARY Section 2.7.1 — Summary of ... · GMR geometric means ratio HIV-1 human immunodeficiency virus (type 1) HPLC high performance liquid chromatography