Module 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods
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CONFIDENTIAL 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods Module 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods Copyright 2012 ViiV Healthcare and the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited. 1 CONFIDENTIAL 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods TABLE OF CONTENTS PAGE ABBREVIATIONS ...........................................................................................................3 1. BACKGROUND AND OVERVIEW ...........................................................................4 1.1. Conclusions ..................................................................................................4 1.2. Formulation Development.............................................................................5 1.3. In Vitro Dissolution Data .............................................................................10 1.3.1. Comparative of 2 x 25 mg Clinical Tablets and 1 x 50 mg Clinical Tablets, Phase III Formulation.........................................10 1.3.2. Comparison of Phase III Clinical Image and Commercial Image Tablets..............................................................................13 1.4. Analytical Methods......................................................................................17 1.4.1. Validation.....................................................................................17 1.4.2. Summary of Within Study Quality Control Sample Analysis .........18 2. SUMMARY OF RESULTS OF INDIVIDUAL STUDIES...........................................19 2.1. Relative Bioavailability ................................................................................19 2.1.1. ING111322 Relative bioavailability of DTG 10 mg oral tablet formulation vs oral suspension...........................................19 2.1.2. ING113068 Effect of particle size on bioavailability.....................20 2.2. Bioequivalence ...........................................................................................22 2.2.1. ING113674 Relative bioavailbility of three DTG tablet formulations and effect of food.....................................................22 2.3. Effect of Food on Bioavailability ..................................................................23 2.3.1. ING111322 Effect of food on the DTG 10 mg oral tablet formulation...................................................................................23 2.3.2. ING112941 Effect of food on the DTG 25 mg tablet used in Phase II studies .......................................................................24 2.3.3. ING113674 Effect of food on the 25 mg tablet formulation selected for Phase III studies.......................................................25 2.4. Absolute Bioavailability ...............................................................................26 3. COMPARISON AND ANALYSES OF RESULTS ACROSS STUDIES ...................27 3.1. In vitro Dissolution and in vivo Bioavailability ..............................................27 3.2. Recommendation for Dosing Dolutegravir Relative to Food........................28 4. REFERENCES.......................................................................................................30 2 CONFIDENTIAL 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods ABBREVIATIONS API Active Pharmaceutical Ingredient AUC Area under concentration-time curve AUC(0-) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time AUC(0-) Area under the concentration-time curve over the dosing interval BCS Biopharmaceutics Classification System CI Confidence Interval Cmax Maximum observed concentration Cτ Pre-dose (trough) concentration at the end of the dosing interval CV Coefficient of variance DCS Developability Classification System DTG Dolutegravir FaSSIF Fasted state simulated intestinal fluid GLS Geometric Least-Squares h or hr Hour(s) IC50 50% inhibitory concentration IV Intravenous HIV Human immunodeficiency virus LLQ Lower limit of quantification MICRP Independent (multivariate) confidence region procedure mL milliliter PK Pharmacokinetic t½ Terminal phase half-life τ Dosing interval tmax Time of occurrence of Cmax Trademark Information Trademarks of ViiV Healthcare Trademarks not owned by ViiV Healthcare NONE SAS TurboIonSpray 3 CONFIDENTIAL 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods 1. BACKGROUND AND OVERVIEW Dolutegravir (DTG) is an HIV integrase inhibitor (INI) which has been developed for treatment-naïve and treatment-experienced HIV-infected adults. Limited data on DTG in HIV-infected children ages 12 to < 18 are also included in the initial submission. This document summarizes the pertinent biopharmaceutical characteristics of DTG immediate release formulations and supports the approval of Dolutegravir Tablets, 50mg, by describing: Various formulations developed and used in clinical studies (Section 1.2); In vitro dissolution profiles for various formulations (Section 1.3) The relative bioavailability studies completed for the various DTG formulations used throughout the clinical development of the compound (Section 2) The impact of food on the bioavailability of DTG tablet formulations (Section 2.3) Bioanalytical methods used to determine DTG concentration in the biological samples collected in clinical studies are summarized in this module as well (Section 1.4). Tablets manufactured at the commercial site were administered in the Phase III studies that demonstrated the safety and efficacy of DTG in HIV-infected subjects. Data from clinical biopharmaceutics studies ING111322, ING112941, ING113068, and ING113674, along with chemistry, manufacturing and controls (CMC) and bioanalytical methods data, form the basis of the biopharmaceutical evaluation of DTG in this submission. 1.1. Conclusions The conclusions from the biopharmaceutic evaluations are as follows: All strengths and batches of DTG tablets (50 mg and 25 mg) used in clinical studies had consistent in vitro dissolution. The bioanalytical methods used to measure concentrations of DTG in human plasma were sensitive, selective, accurate and reproducible. Stability of the analyte was demonstrated during sample processing and long-term storage. The oral bioavailability of the tablet was less than that of a suspension with mean AUC(0-) decreased by 30% following administration of the tablet compared to the suspension formulation under the fasted condition. The rate of absorption of the drug from tablet was slower than suspension. Changes in particle size did not have a significant impact on exposure. A formulation of un-micronized particles demonstrated similar exposure to the current tablet formulation (of micronized particles). These data support the particle size specification for the micronized API. 4 CONFIDENTIAL 2.7.1 Summary of Biopharmaceutic Studies and Associated Analytical Methods For DTG tablets, a 25 mg tablet with the Phase III formulation composition met the bioequivalence criteria with the 25 mg tablet used in the Phase II studies. A higher strength tablet of this formulation (50 mg tablet) was manufactured at the commercial site for use in Phase III clinical trials. This 50 mg tablet has the same % weight/weight composition but made at double the tablet weight of the 25 mg tablets used to establish bioequivalence to the Phase II product. The in-vitro dissolution profiles (3 media used) of the 50 mg tablets (Phase III formulation) compare closely to the profiles of two 25 mg tablets (Phase III composition) tested per dissolution vessel (i.e. total dose level = 50 mg). Administration with food increases the exposure of DTG. Plasma DTG AUC(0-) increased by 33%, 41%, and 66% when DTG was administered with low fat, moderate fat and high fat food, respectively. DTG can be taken with or without food based on the accumulated safety data in Phase IIb and III studies which permitted DTG dosing without restriction to food or food content. DTG 50 mg tablets manufactured at the commercial site were administered in the Phase III studies that demonstrated the safety and efficacy of DTG in HIV-infected patients. No pivotal bioequivalence study was required because the commercial formulation is identical to the Phase III clinical trial tablet formulation, differing only in the film coat color/level, and the degree of concavity of the tooling used to produce the tablets. 1.2. Formulation Development DTG sodium, Form 1, is a non-hygroscopic, crystalline solid with suitable solid state stability and oral bioavailability. DTG sodium has a solubility of 3.2 mg/ml in water at 25C. In buffered solutions, across the physiological pH range 1-7, the solubility is significantly lower at, or below, 50 g/ml. The measured permeability is approximately 3 x 10-4 cm/sec. The combination of low solubility with high predicted permeability puts dolutegravir in BCS class II. Particle size reduction of the DTG sodium (by micronisation) was selected at the start of its development based upon early data pharmacokinetic generated in dogs. Dosage formulations and strengths administered in each of the clinical studies are provided in Appendix Table 1. A summary of drug substance and drug product is provided in Appendix Table 2. Initial Phase I studies for DTG sodium utilised a powder for reconstitution consisting of DTG sodium, hypromellose and sodium lauryl sulphate. Doses of up to 250