Symtuza PDF: Drug Combination for Treating HIV

Okay, here is the markdown conversion of the document provided: # Symtuza®: Fixed-Dose Combination Symtuza® is a fixed-combination prescription drug, also known as a **fixed-dose combination (FDC)**. ## FDA's Policy for Fixed Dose Two or more drugs may be combined in a single dosage form to: *...

Okay, here is the markdown conversion of the document provided: # Symtuza®: Fixed-Dose Combination Symtuza® is a fixed-combination prescription drug, also known as a **fixed-dose combination (FDC)**. ## FDA's Policy for Fixed Dose Two or more drugs may be combined in a single dosage form to: * Enhance the safety or effectiveness of the principal active component. * Minimize the potential for abuse of the principal active component. Considered in compliance based on evaluations of the NAS-NRC report on the combination. ## Solid Carrier Particles Improve the processability of a pharmaceutical agent. **Colloidal silicon dioxide** is hygroscopic but when combined with the API's: * The resulting combination (a free-flowing powder with high loading values for the compound of formula) exhibits acceptable physical and chemical stability, rapid drug release properties, and excellent compressibility. * Can be processed into a solid dosage form such as a tablet with good drug release properties, low tablet friability, good chemical and physical stability, and a low amount of residual solvents. ## Treating HIV After a single unit dosage form of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide, subject exhibits a viral load of less than or equal to 50 copies, preferably less than 50 copies, or HIV-1 virus particles per mL of blood plasma, after at least 24 weeks of the once-daily administration of the single unit dosage form. ## Problems Solved by Symtuza ® Symtuza ® immediate-release tablet combines four active ingredients into a once daily oral tablet form (darunavir, cobicistat, emtricitabine, and tenofovir). Multiple antivirals with different activity profiles lead to a large reduction in HIV, greater compliance, reducing pill burden, and increasing HIV suppression in infected individuals. ## FDA Approved Product Indications ( Cite Your Basis) Symtuza is a 4 drug combination of darunavir, human immunodeficiency virus protease inhibitor, cobicistat, CYP3A inhibitor, and emtricitabine and tenofovir alafenamide, both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg who have no prior antiretroviral treatment history or who are virologically suppressed on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. * **Dosage Form/Product:** Tablet for oral administration. * **Active Drugs:** * 800mg of darunavir * 150mg of cobicistat * 200mg of emtricitabine * 10mg of tenofovir alafenamide * **Inactive Excipients:** Colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. ## Preformulation Studies: Physicochemical Properties The table below summarizes the physicochemical properties of the drug substance to aid in designing a stable, effective, and safe dosage form: | Physicochemical Properties | Darunavir ethanolate | Cobicistat | Emtricitabine | Tenofovir alafenamide hemifumarate | | :------------------------- | :------------------ | :-------- | :----------- | :------------------------------------- | | M.W. | 593.73 | 776.02 | 247.24 | 534.50 | | M.P | 91-100°C | No crystalline form found | 136-140°C | 104-107°C | | Solubility | 0.13 mg/mL at 20°C (slightly soluble in water) | 0.1 mg/mL | 112 mg/mL | 4.86 mg/ml at 20°C | | LogP | 3.9 | 4.3 | -0.4 | No evidence | | BCS | 2 | 2 | 1 | 3 | | Morphology | Crystalline | Amorphous | Crystalline | Crystalline | | Prodrug | No evidence | No evidence | No evidence | yes | ## Solubility The table below summarizes the Solubility properties of the API: | Drug substance | USP Solubility Description for 1) Water and 2) 0.1N HCI | pH dependent OR pH independent? | | :-------------------- | :-------------------------------------------------------- | :----------------------------- | | Darunavir | 1. Very slightly soluble <br> 2. Very slightly soluble | Independent | | Cobicistat | 1. Practically insoluble <br> 2. Soluble | Dependent | | Emtricitabine | 1. Freely soluble <br> 2. Freely soluble | Independent | | Tenofovir alafenamide | 1. Sparingly Soluble <br> 2. Soluble | Dependent | ## pH Degradation Characteristics and Drug Stability * Darunavir: carbamate completely hydrolyzed in basic conditions. * Darunavir is significantly insatiable. * In acidic conditions and in oxidative media under heating new products were produced * Cobicistat: * Cobicistat undergoes degradation in acidic environments * Considered to be relatively stable in alkaline conditions. * Emtricitabine: * Emtricitabine was found to be stable in all of the stress conditions which include acid hydrolysis, alkali hydrolysis, oxidative degradation, and thermal degradation. * Tenofovir alafenamide: * TAF degradation is heavily dependent on pH as the most important influence. * Degradation can occur in hydrolysis. * The most ideal pH to minimize TAF degradation is 5.3. ## Manufacturing Symtuza ® Tablets (Example 5 of US '518) There are two parts to manufacture Symtuza ® Tablets according to Example 5 of US '518. ### Part 1: Cobicistat on Silicon Dioxide The solid-state properties of Cobicistat make it difficult to handle and process on a large scale ((US ‘718, col 1, lines 44-51): 1. Has a low glass transition temperature. 2. Is hygroscopic. 3. Is amorphous (“lacks crystallinity). 4. Is non-free-flowing making it difficult to process as a tablet. Therefore, the following process of combining cobicistat and silicon dioxide carrier to form a free-flowing powder with high cobicistat loading, acceptable physical and chemical stability, rapid drug release, and excellent compressibility. ### Manufacturing Process The Step-by-step manufacturing process for Cobicistat on Silicon Dioxide powder is: 1. **Solution Preparation:** Dissolve 60 g of cobicistat in 300 mL of dichloromethane. 2. **Adsorption:** Add 60 g of Aeroperl (silicon dioxide) to the solution and agitate for at least 30 minutes. 3. **Precipitation:** Slowly add 1.8 L of heptane over 1 hour while agitating. 4. **Filtration:** Continue agitation for 1 hour, then filter to isolate the solids. 5. **Washing:** Wash the solids with 500 mL of heptane. 6. **Drying:** Dry the product under vacuum at room temperature for 24 hours. 7. **Final Product:** Obtain a white powder (50% cobicistat on Aeroperl). The first mixture is mixed with a first lubricant, such as magnesium stearate, to form a second mixture. The second mixture is compacted to form a compacted mixture. The compaction method is preferably a dry technique, meaning no liquids are needed for processing. Roller compaction is a particularly preferred method for use in tenofovir alafenamide fumarate, which is moisture sensitive. The compacted mixture is milled to form granules. An oscillating mill method is preferred. The granules are mixed with a second lubricant, such as magnesium stearate, to produce a granule mixture. The granule mixture is compressed into one or more tablets. Then, the one or more tablets can be coated with a coating layer. ## B. Question: Explain the drug release mechanism of the Symtuza ® tablet. **Answer:** The mechanism Symtuza uses for drug release heavily relies on the inactive ingredients: * Croscarmellose Sodium superdisintegrant using the method of wicking and swelling. Croscarmellose Sodium is known for use in fast dissolving formulations, allowing the mechanism it uses to be applied to Symtuza. Symtuza also has other inactive ingredients such as * Microcrystalline cellulose (another disintegrant) and * Colloidal silicon dioxide and magnesium stearate (both being lubricants). Immediate release is achieved because of Croscarmellose Sodium. ## Is there a concern of dose content uniformity for any of the four drugs? **Answer:** Tenofovir alafenamide hemifumarate for example, has a low dosage form of 0.7% w/w which could cause dose content uniformity problems. A way to combat that would be through methods such as geometric dilutions in which a drug is thoroughly mixed by adding diluents, otherwise known as pharmaceutically acceptable excipients. The excipients used in the Symtyuza Tablet formulation include Microcrystalline cellulose, Magnesium stearate, Colloidal silicon dioxide and Croscarmellose sodium. ## Question: (Explain to the healthcare team how the drug product is formulated and manufactured into its dosage form? Assume that the Symtuza Tablet is given as Example 5 in US ‘518 Patent, incorporating teachings from Example 4 of US ‘718. Cite your basis. (25 points) **Answer:** For Patent US ‘518, the mixture is first mixed with a lubricant, magnesium stearate. The second mixture is compacted. The compaction method is preferably a dry technique. Tenofovir alafenamide fumarate is moisture sensitive. The compacted mixture is milled to form granules. The granules are mixed with a second lubricant, magnesium stearate, to produce a granule mixture. The granule mixture is compressed into one or more tablets. Then, tablets can be coated. The amount of each drug used is: * Darunavir (DRV) 800 milligram * Cobicistat (COBI) 150 mg * Emtricitabine (FTC) 200 mg * Tenofovir alafenamide (TAF) 10 mg. For Patent US ‘718, a 60 g solution of the compound in dichloromethane (300mL) was added with silicon dioxide and mixed by agitation for 30 minutes. Heptane (1.8L) was slowly added for 1 hour and then agitated for another hour. The solids were isolated by filtration, and washed with 500mL of heptane. The resulting product was dried under vacuum at room temperature over a course of 24 hours. The silicone dioxide (Aeroperl) ~50 wt% was isolated with the result of 112g of product with 92.5% yield. According to US 518, to formulate the drug, use a bin blender at 12 rpm to combine and mix darunavir ethanolate, cobicistat on silicon dioxide, tenofovir alafenamide hemifumarate (TAF), emtricitabine (F), for 5-20 minutes then and Magnesium stearate for 2-4 minutes. The next step is to compact the blend with a roller compactor to get ribbons which will then be milled with an oscillating mill and a 1.5 mm screen. Then compress the blend with a rotary tablet press. You will also need to make a film-coating suspension by adding film-coating powder and water mixed into an appropriate vessel until suspended properly. Preheat the tablets in a pan coater rotating to be sprayed with the film-coating suspension with exhaust air at a temperature approximately 44-52 degrees celsius. Finally, these tablets are packaged into their dosage form. ## Question: Explain to the healthcare team how a patient who is unable to swallow the whole tablet should be administered the required dose split into two and taken one after another immediately. Symtuza should be taken once daily with or without food for patients weighing at least 40kg. It was shown that splitting the tablet did not alter the bioavailability compared to taking the tablet whole. ## Question: Explain to a group of healthcare professionals why cobicistat was included in the Symtuza ® Tablet. Consider both the specific role of cobicistat and its preferred inclusion over ritonavir. Consider the following paper in your answer **Answer:** Cobicistat is a potent and selective inhibitor of Human CYP3A. It is included in the formulation of Symtuza compared to Ritonavir to "boost” anti-HIV drugs without risking drug-resistant HIV variants. HIV Protease inhibitors are metabolized primarily by the enzyme Cytochrome P-450, specifically CYP3A in the liver and intestine. By utilizing cobicistat as a CYP3A inhibitor, the systemic concentration of antiretroviral drugs increases. Cobicistat is preferred over ritonavir due to the decreased potential cobicistat has for causing undesired drug-drug interactions and lipid disorder compared to ritonavir. * Darunavir ethanolate - inhibitor of the HIV-1 protease. * Cobicistat on silicon dioxide - Cobistat is absorbed onto silicone dioxide * Emtricitabine - An HIV nucleoside analog reverse transcriptase inhibitor (HIV NRI). * Tenofovir alafenamide hemifumarate - HIV NRTI, is converted in vivo to Tenofovir. * Microcrystalline cellulose - It is an adsorbent, direct compression excipient, suspending agent, as well as a tablet and capsule diluent. * Croscarmellose sodium - It is a tablet and capsule disintegrant. * Magnesium stearate - It is a tablet and capsule lubricant ## Explain the dosing regimen and timing of doses required to achieve therapeutic blood levels to treat the approved clinical indication(s). Explain challenges that patients experience taking/administering/having administered the drug product relating to compliance and adherence. Consider the Wilkins et al paper, the Cohen et al paper and the FDA approved product label for Symtuza ® in your answer. Cite your basis. (25 points) * Fixed dose design limits dose variation. The tablet is large. * The recommended dosage of Symtuza is 1 Tablet by mouth once a day with food. The patient population for this dose is adults and pediatric patients weighing at least 40kg. Symtuza is indicated for patients infected with HIV-1 who have no prior antiretroviral treatment history or who are virologically suppressed (HIV-1 RNA less than 50 copies per ml) on a stable antiretroviral regimen for at least 6 months and have no known substitutions associated with resistance to darunavir or tenofovir. Fixed dose combination formulations have been developed to combine active pharmaceutical ingredients (APIs) with different mechanisms of action into 1 dosage form. Compliance when faced with taking 3 or more medications is low in patient populations that exhibit homelessness, and marginally house patients are more at risk of antiretroviral therapy adherence. In utilizing combination therapy the introduction of HAART (Highly Active Antiretroviral Therapy) results in greater compliance, reducing pill burden, and increasing HIV suppression in infected individuals. In formulating antiretrovirals this way, advantages include increased patient adherence, simplifying dosing schedule (1 tablet opposed to many), prevents dose dividing, and increases drug resistance prevention. Synergism is also observed specifically for Symtuza increasing the efficacy.