Genvoya is comprised of three active ingredients previously approved by the TGA, and a fourth active ingredient, tenofovir alafenamide (as fumarate) (TAF), which is a new chemical entity.
The proposed tablet is closely related to the TGA approved Stribild fixed dose combination tablets (AUST R 194081), which is formulated with the same quantities of EVG (150mg) COBI (150 mg) and FTC (200 mg) together with TDF (300 mg) instead of the TAF (10 mg, as fumarate).
Tenofovir alafenamide (as fumarate) (TAF) has been developed as the next generation oral prodrug of tenofovir. Both TAF and TDF are converted to tenofovir (TVF), which is metabolised intercellularly to the active metabolite, tenofovir diphosphate (TFV-DP), a competitive inhibitor of HIV-1 reverse transcriptase (RT) and hepatitis B virus (HBV) RT, thereby effectively blocking the replication and spread of the HIV virus. TAF is claimed to have a unique metabolism that provides enhanced lymphatic delivery of TFV, resulting in higher intracellular levels of the active phosphorylated metabolite TFV-DP, and lower circulating levels of TFV when compared to TDF. Thus, the clinical dose of TAF is much lower than the clinical dose of TDF (10 mg versus 300 mg). These features have the potential to translate into less risk of nephrotoxicity and less decrease in bone mineral density, which are noted risks with TDF administration.
Details of the drug substance were previously evaluated by the TGA as part of the submissions, to register Vitekta (elvitegravir) 85 mg and 150 mg film coated tablets, and the fixed dose combination tablet Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate) tablets.
Figure 2. Structure of Cobicistat
Details of the drug substance were previously evaluated by the TGA as part of the submissions, to register Tybost (cobicistat) 150 mg film coated tablets, and the fixed dose combination tablet Stribild.
Cobicistat is an amorphous solid that cannot be readily isolated as the neat drug substance. Consequently it is isolated by adsorption onto silicon dioxide to provide a stable solid form, which facilitates handling and is suitable for further drug product processing. Hence cobicistat on silicon dioxide is defined as the drug substance and is used in this form in the manufacture of the combination tablets.
Figure 3. Structure of Emtricitabine
Details of the drug substance were previously evaluated by the TGA as part of the submissions, to register Emtriva emtricitabine 200 mg capsules, and the fixed dose combination tablet Stribild.
Assurance has been provided stating that all details relating to the drug substances, EVG, COBI and FTC, are identical to those previously evaluated for the above mentioned applications and any subsequent amendments.
The drug substance specifications applied to the drug substance are considered adequate to ensure the quality and consistency of manufacture of the finished product.
Tenofovir alafenamide fumarate
Figure 4. Structure of tenofovir alafenamide fumarate and tenofovir disoproxil fumarate
Tenofovir alafenamide fumarate is defined as the hemi-fumarate salt depicted above. It is a non-hygroscopic white to off-white or tan powder that is soluble to slightly soluble in aqueous media over a wide pH range, with the solubility decreasing with an increase in pH. The proposed drug substance specifications comply with TGA requirements and are considered adequate to ensure the quality and consistency of manufacture of the finished product.
The proposed fixed dose combination tablet is green, capsule shaped, and are film coated with ‘GSI’ debossed on one side and ‘510’ on the other side.
All excipients are conventional ingredients used in numerous registered oral dosage forms.
Dissolution performance of the proposed tablets during development and for quality control purposes was monitored by an adequately justified test method. Little or no change in dissolution was observed on storage.
The tablets are packaged in packs of 30 tabs 100 mL white HDPE bottles containing 30 tablets and 3 grams of silica gel desiccant. Each bottle is capped with a white continuous thread, child resistant polypropylene screw cap fitted with an induction sealed, aluminium faced liner.
Release and expiry limits are applied for individual unspecified degradants associated with each drug substance which are within the applicable International Conference on Harmonisation (ICH) qualification threshold.
Degradation pathways for each drug substance have been adequately investigated and limits are applied for specified impurities for each drug substance. These limits have been qualified by toxicological studies, which have been assessed as acceptable by the TGA toxicological section.
Batches of tablets typically have very low levels of total impurities associated with each drug substance at release. On long term storage (18 months) there were no significant increases in degradants associated with elvitegravir or emtricitabine with minor increases in some cobicistat related degradants. Moderate increases in TAF related degradants were observed but all results were well within specified limits.
The proposed finished product specifications have been adequately justified and comply with TGA requirements, except for the assay limit at expiry for TAF. The proposed expiry does not comply with the official Therapeutic Goods Order 78 ‘General Requirements for Tablets and Capsules’ which requires that all registered tablets which do not have an individual BP monograph must have a content of active of at least 92.5 to 107.5%5. Since compliance with TGO 78 is a legislative requirement, the product cannot be registered unless this limit is appropriately tightened. Negotiations with the sponsor regarding this issue are ongoing.6
They are considered adequate to ensure the quality of the finished product at release and throughout the shelf-life.
The tablets show good stability and a shelf life of 24 months when stored below 30°C, is considered justified, pending acceptable resolution of the issue of the assay limit at expiry for TAF.
Rate and extent of absorption
Following oral administration of the proposed drug product in HIV-1 infected patients, peak plasma concentrations were observed approximately 4 hours post dose for EVG, 3 hours post dose for COBI, 3 hours post dose for FTC, and 1 hour for TAF.
Metabolism and distribution
Elvitegravir (EVG) is 98 to 99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng/mL to 1.6 µg/mL. The mean plasma to blood drug concentration ratio was 1.37. Elvitegravir undergoes primarily oxidative metabolism via cytochrome P 450(CYP); CYP3A, and is secondarily glucuronidated via uridine diphosphate glucuronosyltransferase (UGT) UGT1A1/3 enzymes. Following oral administration of boosted 14C-elvitegravir, EVG was the predominant species in plasma, representing approximately 94% of the circulating radioactivity.
Cobicistat (COBI) is 97 to 98% bound to human plasma proteins and the mean plasma to blood drug concentration ratio was 2. Cobicistat is metabolised via CYP3A (major) and CYP2D6 (minor) mediated oxidation and does not undergo glucuronidation. Following oral administration of 14C-cobicistat, 99% of circulating radioactivity in plasma was unchanged COBI. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of COBI.
In vitro binding of emtricitabine (FTC) to human plasma proteins is < 4% and is independent of concentration over the range of 0.02 to 200 µg/mL. The metabolites of FTC include 3’-sulfoxide diastereomers and their glucuronic acid conjugate.
Metabolism is a major elimination pathway for TAF in humans, accounting for > 80% of an oral dose. In vitro, TAF is hydrolysed within cells to form to TFV (major metabolite), which is phosphorylated to the active metabolite, tenofovir diphosphate (TFV-DP). In vitro binding of TFV to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01 to 25 µg per mL. Ex-vivo binding of TAF to human plasma proteins in samples collected during clinical studies was approximately 80%.
Notably, results from the Phase I study showed that exposure to TAF when administered as a component of the combination tablet was approximately 2.2 to 2.6 fold that when administered alone. The greater exposure to TAF when administered as a component of the combination tablet is presumed to result from the inhibition of TAF intestinal secretory transport by COBI.
Mode, route and rate of elimination
94.8% of the dose of EVG was recovered in faeces, consistent with the hepatobiliary excretion of EVG; 6.7% of the administered dose was recovered in urine as unchanged EVG. The median terminal plasma half-life of EVG following administration of the drug product is approximately 12.9 hours.
Eighty six percent and 8.2% of the dose of COBI were recovered in faeces and urine, respectively. The median terminal plasma half-life of COBI following administration of the drug product is approximately 3.5 hours.
Following administration of radiolabelled FTC approximately 86% is recovered in the urine and 13% is recovered as metabolites. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Emtriva, the plasma FTC half-life is approximately 10 hours.
Tenofovir alafenamide is eliminated following metabolism to TFV. TAF and TFV have a median plasma half-life of 0.51 and 32.37 hours, respectively. Tenofovir is eliminated from the body by the kidneys by both glomerular filtration and active tubular secretion. Renal excretion of intact TAF is a minor pathway with less than 1% of the dose eliminated in urine. The pharmacologically active metabolite, TFV-DP, has a half-life of 150 to 180 hours within peripheral blood mononuclear cells (PBMCs).
The pharmacological activity is caused by the active entities TFV, FTC and EVG. Cobicistat is a CYP3A inhibitor, present to boost plasma levels of the therapeutically active agents, particularly EVG. It is described as a pharmacokinetic enhancer.
Dose response proportionality
Elvitegravir plasma exposures are non-linear and less than dose proportional, likely due to solubility limited absorption.
Cobicistat exposures are nonlinear and greater than dose proportional over the range of 50 mg to 400 mg, consistent with a mechanism based CYP3A inhibitor.
Effects of food
Relative to fasting conditions, the administration with a light meal (approximately 373 kcal, 20% fat) increased the mean systemic exposure of EVG by 34%. The alterations in mean systemic exposures of COBI and FTC were not clinically significant.
Relative to fasting conditions, the administration with a high fat meal (approximately 800 kcal, 50% fat) increased the mean systemic exposure of EVG by 87%. The alterations in mean systemic exposures of COBI and FTC were not clinically significant.
Relative to fasting conditions, the administration of Genvoya with a light meal (approximately400 kcal, 20% fat) or high fat meal (approximately 800 kcal, 50% fat) increased the mean systemic exposures of TAF by approximately 15% and 18%, respectively. The alterations in mean systemic exposures of TAF were not clinically significant. Genvoya should be taken with food.
The sponsor provided a justification for not providing any biopharmaceutic and/or absolute bioavailability data and this is considered acceptable, in part because of the similarity of the proposed product to the previously approved Stribild tablet.
A single comparative bioavailability study was submitted (Study GS-US-292-0103) comparing the bioavailability of EVG, COBI, FTC, TAF, and the active metabolite TFV following the administration of a single tablet regimen containing the proposed fixed dose combination tablet, and following administration of the components separately, in healthy subjects. The study was a single centre, randomised, open label, multiple dose, multiple cohort, 2 period, crossover study in healthy adult subjects.
Treatment A: one proposed combination tablet of EVG, COBI, FTC, TAF (150 / 150 / 200 / 10 mg)
Treatment B: EVG 150 mg tablet + COBI 150 mg tab
Treatment A: one proposed combination tablet of EVG, COBI, FTC, TAF (150 / 150 / 200 / 10 mg)
Treatment C: FTC 200 mg + TAF 25 mg
It is noted that the single tablet dose of TAF of 25 mg (versus the TAF content of the combination tablet of 10 mg) was chosen based on results from the Phase I study GS-US-292-0101 which showed that exposure to TAF when administered as a component of the combination tablet was approximately 2.2 to 2.6 fold that when administered alone. The greater exposure to TAF when administered as a component of the combination tablet is presumed to result from the inhibition of TAF intestinal secretory transport by COBI. The single tablets of COBI and TAF are not co-administered in either of the cohorts.
The sponsor submitted a rationalisation for applying wider than normal limits (70% to 143%) for the 90% confidence interval (CI) for all of the calculated parameters (that is AUCtau7, Cmax8 and Ctau9) and this has been submitted for clinical comment.
Notwithstanding this, more usual, tighter limits of 80 to 125% were met for AUC0-tau and Cmax for plasma levels of all four of the drug substances. The tighter limits were also met for the parameter Ctau for the drug substances EVG and TAF. However for COBI and FTC, the parameter Ctau was just outside the normal range on the upper side (133% and 128%, respectively). For the active metabolite TFV, all 3 measured parameters (AUCtau, Cmax and Ctau) were just outside the normal range on the upper side (130%, 134 and 134%, respectively). Comment of the clinical significance of these results has been sought.
Quality summary and conclusions
All pharmaceutical chemistry issues raised during the initial evaluation of this application have now been satisfactorily resolved apart from:
the expiry limit for assay of tenofovir alafenamide (TAF) in the finished product specifications does not comply with TGO 78 and consequently registration cannot be recommended. This is a critical issue and for registration approval to be considered, this limit must be tightened to at least 92.5 to 107.5.
It is anticipated that the sponsor will take steps to resolve the above issue prior to the Delegate’s decision.
Pending resolution of the above issue, the proposed Genvoya elvitegravir (150 mg), cobicistat (150 mg), emtricitabine (200 mg) and tenofovir alafenamide fumarate (10 mg) fixed dose combination tablets is recommended for registration with respect to pharmaceutical chemistry aspects.