darunavir and cobicistat

Action and Spectrum

Actions and Spectrum: 

darunavir and cobicistat are both antiretroviral drugs used in the treatment of HIV infection. 

Darunavir is a protease inhibitor that works by blocking the activity of the HIV protease enzyme, which is essential for the virus to replicate and spread. By inhibiting this enzyme, darunavir helps to prevent the virus from multiplying and spreading in the body. 

Cobicistat, on the other hand, is a pharmacokinetic enhancer that works by inhibiting an enzyme called cytochrome P450 3A4 (CYP3A4). Metabolism is through CYP3A4 like many drugs, including darunavir. By inhibiting this enzyme, cobicistat can increase the blood levels of darunavir and improve its effectiveness. 

The spectrum of activity of darunavir and cobicistat is limited to HIV-1, the most common strain of the virus that causes HIV infection. They are typically used in combination with other antiretroviral drugs as part of highly active antiretroviral therapy (HAART) to suppress viral replication and improve immune function in people living with HIV. 

Drug Interaction

Adverse Reaction

Frequency defined 

darunavir 

>10% 

Increased total cholesterol (10-25%) 

1-10% 

Diarrhea (9%) 

Abdominal pain (6%) 

Rash (6%) 

Headache (7%) 

Increased triglycerides (3-10%) 

Nausea (4%) 

Vomiting (2%) 

Anorexia (2%) 

cobicistat 

>10% 

Nausea, all grades (12%) 

Jaundice, all grades (13%) 

Ocular icterus, all grades (15%) 

Total bilirubin, >2.5 x ULN (65%) 

1-10%  

Rash, grades 2-4 (5%) 

Jaundice, grades 2-4 (5%) 

Glycosuria, >1000 mg/dL (3%) 

Creatine kinase, >10 x ULN (5%) 

ALT or AST, >5 x ULN (3%) 

Urine RBC, >75 RBC/HPF (3%) 

Ocular icterus, grades 2-4 (3%) 

Nausea, grades 2-4 (2%) 

Serum amylase, >2 x ULN (4%) 

GGT, >5 x ULN (2%) 

Black Box Warning

Black Box Warning: 

The combination medication containing darunavir and cobicistat has risk of drug interactions and serious or life-threatening adverse reactions. 

Specifically, the warning highlights the potential for darunavir and cobicistat to cause liver problems, including liver failure and death, especially in people with underlying liver disease or hepatitis B or C virus co-infection.

The warning also notes the risk of severe skin reactions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis, which can be fatal. 

Contraindication / Caution

Contraindication/Caution: 

Contraindications of Darunavir include: 

• Hypersensitivity to darunavir or any of its components 
• Concomitant use with medications that are highly dependent on CYP3A for metabolism and have a narrow therapeutic window (such as dihydroergotamine, ergotamine, pimozide, cisapride, lovastatin, simvastatin, and St. John’s Wort) 
• Severe hepatic impairment (Child-Pugh Class C) 

Contraindications of cobicistat include: 

• Hypersensitivity to cobicistat or any of its components 
• Concomitant use with medications that are contraindicated with cobicistat’s partner medication (such as drugs metabolized by CYP3A that have a narrow therapeutic window) 
• Severe hepatic impairment (Child-Pugh Class C) 
• Concurrent use with drugs that are strong or moderate CYP3A inhibitors, inducers, or substrates, unless dosage adjustments are made. 

Caution 

• Allergic reactions: Some people might experience an allergic reaction to darunavir or cobicistat. If you experience symptoms such as difficulty breathing, hives, or swelling of the face, tongue, lips or throat seek medical attention immediately. 
• Liver problems: darunavir and cobicistat can cause liver problems, especially in people with pre-existing liver disease. If you experience symptoms such as yellowing of the skin or eyes, dark urine, or abdominal pain, contact your doctor immediately. 
• Kidney problems: Cobicistat can cause kidney problems, especially in people with pre-existing kidney disease. If you experience symptoms such as decreased urine output, swelling of the feet or ankles, or fatigue, contact your doctor immediately. 
• Drug interactions: darunavir and cobicistat can interact with other medications, including over-the-counter drugs and herbal supplements. Before taking these medications, make sure your physicianis aware of medications you are currently taking. 
• Resistance: Over time, HIV can become resistant to darunavir and cobicistat. It is key to take medications exactly as prescribed and to not miss any doses. 
• Pregnancy and breastfeeding: darunavir and cobicistat may not be safe for pregnant or breastfeeding women. Talk to your physician if you are pregnant or planning to become pregnant, or if you are breastfeeding. 

Pregnancy / Lactation

Pregnancy consideration:  

AU TGA pregnancy category: B2
US FDA pregnancy category: Not assigned. 

Lactation:   

Excreted into human milk is Not known.  

Pregnancy category: 

• Category A: well-controlled and Satisfactory studies do not show risk to the fetus in the first/later trimester.        
• Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women.        
• Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.       
• Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.        
• Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.        
• Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

darunavir is a type of medication called a protease inhibitor. It works by blocking the action of the HIV protease enzyme, which is essential for the virus to replicate and spread. This helps to reduce the amount of HIV in the body, which can slow down the progression of the disease and improve the immune system’s ability to fight off infections. Darunavir is typically taken with other HIV medications to create a combination therapy that is more effective at suppressing the virus. 

Cobicistat is a medication that is often used in combination with other HIV medications to boost their effectiveness. It works by inhibiting an enzyme called CYP3A, which is responsible for breaking down certain HIV medications in the liver. By inhibiting this enzyme, cobicistat can increase the concentration of other HIV medications in the blood, making them more effective at fighting the virus. Cobicistat does not have any direct antiviral activity against HIV.  

Pharmacodynamics: 

Mechanism of action:darunavir is a protease inhibitor that works by selectively inhibiting the cleavage of Gag-Pol polyprotein precursors, which in turn prevents the formation of mature virus particles. 

cobicistat, on the other hand, is a CYP3A4 inhibitor that functions as a mechanism-based pharmacokinetic enhancer. Its role is to increase the systemic exposure of darunavir, which is a CYP3A4 substrate. 

Pharmacokinetics: 

Absorption 

The peak plasma time for darunavir is 4-4.5 hours, while for cobicistat it is 4-5 hours. The trough concentration of darunavir is 1875 ng/mL, and its AUC is 100,152 ng⋅hr/mL. It’s worth noting that absorption is increased when taken with a high-fat meal, which is why darunavir/cobicistat should be consumed with food. 

Distribution 

darunavir is 95% protein bound, whereas cobicistat is 97-98% protein bound. 

Metabolism 

Darunavir primarily undergoes oxidative metabolism and is extensively metabolized by CYP enzymes, especially by CYP3A. Cobicistat, on the other hand, is metabolized by both CYP3A and CYP2D6 enzymes, and it does not undergo glucuronidation. 

Elimination and Excretion 

The half-life of darunavir is 7 hours, while the half-life of cobicistat is 4 hours. 

darunavir is primarily excreted through feces (79.5%), with 41.2% of the drug being unchanged. In urine, only 13.9% of the drug is excreted, with 7.7% being unchanged. 

cobicistat is mainly excreted through feces (86.2%), with only 8.2% of the drug being excreted in urine. 

Adminstartion

Administration: 

Oral administration 

darunavir is a medication used in the treatment of HIV infection. It belongs to protease inhibitors and is often used in combination with other antiretroviral medications to suppress the virus and improve immune function. 

cobicistat is a medication that is sometimes used in combination with darunavir to enhance its effectiveness. cobicistat belongs to a class of drugs called pharmacokinetic enhancers, which work by inhibiting an enzyme that breaks down darunavir in the liver. This allows for higher levels of darunavir to be maintained in the blood, which can improve its antiviral activity. 

The recommended dose of darunavir and cobicistat depends on the patient’s age, weight, and other medical conditions. It is key to follow the prescribing instructions provided by your healthcare provider and to take the medications exactly as directed. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: darunavir and cobicistat 

Pronounced:[ koe-BIK-i-stat-and-dar-UE-na-vir] 

Why do we use darunavir and cobicistat? 

darunavir and cobicistat are used in the treatment of HIV infection. 

darunavir is a protease inhibitor that works by blocking an enzyme needed for the replication of the HIV virus. It is used as mixture of drugs with other antiretroviral medications to suppress the virus and improve immune function in people with HIV. 

cobicistat is a pharmacokinetic enhancer that works by inhibiting an enzyme that breaks down darunavir in the liver. This allows for higher levels of darunavir to be maintained in the blood, which can improve its antiviral activity. 

Together, darunavir and cobicistat are used as a fixed-dose combination medication to treat HIV infection in adults. The combination is usually used in combination with other antiretroviral drugs and is typically prescribed for patients who have not previously received antiretroviral treatment, as well as those who have developed resistance to other antiretroviral medications. 

It is important to note that darunavir and cobicistat are not a cure for HIV infection, but can help to control the virus and increase quality of life for people living with the disease. It is also important to take the medications exactly as directed by a healthcare provider in order to achieve the best possible outcomes.