Cobicistat

The standard adult dosage for Cobicistat (Tybost) is 150 mg taken orally once daily. It is crucial to understand that this dose is not flexible; it is specifically calibrated to provide the optimal level of CYP3A inhibition to boost co-administered drugs.

• When used with Atazanavir: 150 mg of Cobicistat is taken with 300 mg of Atazanavir once daily.
• When used with Darunavir: 150 mg of Cobicistat is taken with 800 mg of Darunavir once daily.

In both scenarios, the medications must be part of a larger antiretroviral regimen that usually includes two other 'backbone' medications (typically nucleoside reverse transcriptase inhibitors).

Cobicistat is approved for use in pediatric patients weighing at least 35 kg (approximately 77 lbs). The dosage for these pediatric patients is the same as the adult dose: 150 mg once daily. It is generally administered as part of a fixed-dose combination tablet (like Genvoya or Symtuza) or alongside standalone atazanavir or darunavir. Cobicistat has not been established as safe or effective in children weighing less than 35 kg, as the pharmacokinetics in smaller children may differ significantly, potentially leading to sub-therapeutic levels of the boosted drug or increased toxicity.

Renal Impairment

Cobicistat is known to cause a modest increase in serum creatinine levels. This is not due to a decrease in the glomerular filtration rate (GFR), which is the actual filtering capacity of the kidney. Instead, Cobicistat inhibits the tubular secretion of creatinine.

• Initiation: Cobicistat should not be started in patients with an estimated creatinine clearance (CrCl) of less than 70 mL/min if it is being used as part of a regimen containing tenofovir disoproxil fumarate (TDF), such as Stribild.
• Monitoring: If CrCl drops below 50 mL/min during treatment with a TDF-containing regimen, the medication should generally be discontinued. However, when Cobicistat is used as a standalone booster (Tybost) with atazanavir or darunavir, it can often be used in patients with mild-to-moderate renal impairment, though close monitoring is required.

Hepatic Impairment

• Mild to Moderate (Child-Pugh Class A or B): No dosage adjustment of Cobicistat is typically required.
• Severe (Child-Pugh Class C): Cobicistat has not been studied in patients with severe hepatic impairment. Therefore, its use is generally not recommended in this population.

Elderly Patients

Clinical trials of Cobicistat did not include sufficient numbers of patients aged 65 and over to determine if they respond differently than younger patients. In general, caution should be exercised when prescribing for elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and concomitant diseases or other drug therapies.

For Cobicistat to work effectively, it must be taken exactly as prescribed.

1. 1With Food: Cobicistat must be taken with food. A meal or a snack significantly improves the absorption of the drug. Taking it on an empty stomach may lead to lower blood levels, which could cause the HIV treatment to fail.
2. 2Consistency: Take the dose at the same time every day to maintain steady levels in your blood.
3. 3Swallow Whole: Tablets should be swallowed whole. Do not crush, chew, or split the tablets, as this can interfere with the controlled release and absorption of the medication.
4. 4Storage: Store the medication at room temperature (20°C to 25°C or 68°F to 77°F) in its original container. Keep the container tightly closed to protect it from moisture.

If you miss a dose of Cobicistat, take it as soon as you remember, provided it is within 12 hours of the scheduled time. You must take it with food. If more than 12 hours have passed since the scheduled time, skip the missed dose and return to your regular dosing schedule. Do not 'double up' or take two doses at once to make up for a missed one.

In the event of an overdose, contact your local poison control center or seek emergency medical attention immediately. While there is no specific antidote for Cobicistat, treatment typically involves supportive care, including monitoring of vital signs and observation of the clinical status of the patient. Because Cobicistat is highly protein-bound, it is unlikely to be significantly removed by hemodialysis or peritoneal dialysis.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or stop taking the medication without medical guidance, as this can lead to drug resistance.

Because Cobicistat is almost always administered with other medications, it can be difficult to distinguish its side effects from those of the co-administered drugs. However, the following are frequently reported by patients taking Cobicistat-boosted regimens:

• Nausea and Diarrhea: These are the most common gastrointestinal complaints. They typically occur during the first few weeks of treatment as the body adjusts to the medication. Taking the drug with a substantial meal can often mitigate these effects.
• Increased Serum Creatinine: Almost all patients will see a slight rise in their creatinine levels (usually by about 0.1 to 0.15 mg/dL) within the first few weeks. This is a known pharmacological effect of Cobicistat and does not usually indicate actual kidney damage, though it must be monitored to ensure it doesn't mask other renal issues.
• Fatigue and Headache: General feelings of tiredness or mild-to-moderate headaches are common but usually transient.
• Jaundice (Yellowing of the eyes/skin): This is specifically common when Cobicistat is used to boost atazanavir. Atazanavir can increase bilirubin levels, and Cobicistat can further enhance this effect. While often harmless (cosmetic jaundice), it should always be reported to a doctor.

• Dizziness and Insomnia: Some patients report difficulty sleeping or a sensation of lightheadedness.
• Vomiting and Abdominal Pain: More significant GI distress may occur in a subset of patients.
• Rash: Mild skin rashes may develop. If a rash is accompanied by fever or blistering, it requires immediate medical evaluation.
• Dyspepsia (Indigestion): A feeling of fullness or burning in the upper abdomen.

• Severe Hypersensitivity: Rare but serious allergic reactions including angioedema (swelling of the face, lips, or tongue).
• Depression or Anxiety: While more common with certain other HIV drugs (like efavirenz), mood changes have been rarely reported with Cobicistat-containing regimens.
• Pancreatitis: Inflammation of the pancreas, characterized by severe upper abdominal pain radiating to the back.

> Warning: Stop taking Cobicistat and call your doctor immediately if you experience any of these serious symptoms.

• Signs of Kidney Failure: While Cobicistat causes a benign rise in creatinine, actual kidney damage (nephrotoxicity) can occur, especially if used with tenofovir. Symptoms include significantly decreased urination, swelling in the legs or ankles, and shortness of breath.
• Liver Toxicity (Hepatotoxicity): Symptoms include dark-colored urine, pale stools, severe nausea, and intense yellowing of the skin or eyes. This is more common in patients with pre-existing Hepatitis B or C.
• Lactic Acidosis: This is a rare but life-threatening buildup of acid in the blood. Symptoms include unusual muscle pain, stomach pain with nausea/vomiting, cold arms and legs, feeling dizzy or lightheaded, and a fast or irregular heartbeat.
• Immune Reconstitution Inflammatory Syndrome (IRIS): After starting HIV treatment, the immune system may get stronger and begin to fight infections that were hidden in the body. This can cause a sudden onset of inflammatory symptoms.

• Bone Density Changes: Long-term use of antiretroviral therapy, particularly those containing tenofovir disoproxil fumarate (often used with Cobicistat), has been associated with a decrease in bone mineral density and an increased risk of fractures.
• Fat Redistribution (Lipodystrophy): Changes in body fat, including increased fat in the upper back and neck ('buffalo hump'), breast, and around the trunk, and loss of fat from the legs, arms, and face, can occur with long-term HIV therapy.
• Metabolic Changes: Increases in blood sugar (hyperglycemia) and blood fats (cholesterol and triglycerides) may occur, potentially increasing the risk of cardiovascular disease over time.

No FDA black box warnings exist for Cobicistat (Tybost) as a standalone agent. However, many of the fixed-dose combination tablets that contain Cobicistat (such as Stribild and Genvoya) carry Black Box Warnings regarding the risk of post-treatment acute exacerbation of Hepatitis B. If a patient has both HIV and HBV and stops taking their Cobicistat-containing combination pill, their Hepatitis B may suddenly become much worse. Always check the specific label of the combination product you are taking.

Report any unusual symptoms to your healthcare provider immediately. Regular blood tests are necessary to monitor for these side effects.

Cobicistat is a powerful 'booster' that significantly alters how your body processes other medications. The most critical safety concern with Cobicistat is the high potential for drug-drug interactions. Because it shuts down the CYP3A4 enzyme, taking it with certain other drugs can cause those drugs to build up to toxic, potentially fatal levels. Conversely, taking Cobicistat with drugs that 'induce' or speed up these enzymes can make Cobicistat ineffective, leading to the failure of your HIV treatment and the development of drug resistance.

As noted, while Tybost (standalone Cobicistat) does not have a Black Box Warning, the combination products it is part of often do. Specifically, products like Stribild, Genvoya, and Symtuza carry warnings regarding:

• Exacerbation of Hepatitis B: Severe acute exacerbations of Hepatitis B have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing emtricitabine or tenofovir. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected and discontinue Cobicistat-containing combinations.

• Renal Toxicity: Cobicistat should be used with extreme caution in patients with pre-existing renal impairment. When used with tenofovir disoproxil fumarate (TDF), there is an increased risk of renal failure and Fanconi syndrome (a disorder of kidney tubule function). Your doctor will monitor your creatinine clearance and urine glucose/protein regularly.
• Hepatotoxicity: Patients with underlying liver disease, such as chronic Hepatitis B or C, are at an increased risk for severe hepatic adverse events. Liver function tests (LFTs) should be performed prior to and during treatment.
• Sulfa Allergy: Cobicistat itself does not contain sulfonamide, but it is often used with darunavir (Prezcobix), which does. If you have a sulfa allergy, discuss this with your doctor before taking a Cobicistat-boosted darunavir regimen.
• Fat Redistribution: Patients should be aware of the potential for changes in body fat distribution, which is a known effect of long-term antiretroviral therapy.

Before starting Cobicistat and throughout your treatment, your healthcare provider will require regular laboratory monitoring:

1. 1Renal Function: Estimated creatinine clearance (CrCl) must be calculated before starting. For many combinations, if CrCl is <70 mL/min, the drug should not be started.
2. 2Liver Function: Monitoring of AST, ALT, and bilirubin levels, especially in patients with co-infections.
3. 3Viral Load and CD4 Count: To ensure the HIV treatment is working effectively.
4. 4Lipid Panel: Monitoring of cholesterol and triglycerides.
5. 5Blood Glucose: Monitoring for new-onset diabetes or hyperglycemia.

Cobicistat is not generally known to cause significant impairment of driving or the ability to operate machinery. However, some patients report dizziness or fatigue. You should observe how you react to the medication before engaging in activities that require mental alertness.

There is no direct contraindication between alcohol and Cobicistat. However, chronic heavy alcohol use can damage the liver, which may complicate HIV treatment and increase the risk of hepatotoxicity. Furthermore, alcohol can sometimes worsen the gastrointestinal side effects of the medication.

Never stop taking Cobicistat without consulting your doctor. HIV treatment requires 100% adherence to prevent the virus from mutating and becoming resistant to drugs. If you stop the booster, the levels of your other HIV medications will drop rapidly, allowing the virus to replicate. There is no 'withdrawal syndrome' like that seen with antidepressants, but the risk of treatment failure is high.

> Important: Discuss all your medical conditions, especially kidney or liver disease, with your healthcare provider before starting Cobicistat.

Cobicistat has one of the most extensive lists of drug interactions in modern medicine. The following medications must NEVER be used with Cobicistat because the interaction can cause life-threatening toxicity:

• Alpha-1 Adrenoreceptor Antagonists: Alfuzosin (can cause severe low blood pressure).
• Antiarrhythmics: Amiodarone, Quinidine (can cause fatal heart rhythm disturbances).
• Anticonvulsants: Carbamazepine, Phenobarbital, Phenytoin (these reduce Cobicistat levels, leading to HIV treatment failure).
• Antimycobacterials: Rifampin (severely reduces Cobicistat levels).
• Ergot Derivatives: Ergotamine, Dihydroergotamine (can cause 'ergotism'—severe constriction of blood vessels leading to tissue death/gangrene).
• GI Motility Agents: Cisapride.
• Herbal Products: St. John’s Wort.
• Lipid-modifying Agents: Lovastatin, Simvastatin (dramatically increases risk of rhabdomyolysis—muscle breakdown and kidney failure).
• PDE5 Inhibitors: Sildenafil when used for pulmonary arterial hypertension (PAH).
• Sedative/Hypnotics: Triazolam, orally administered Midazolam.
• Antipsychotics: Lurasidone, Pimozide.

• Corticosteroids: Fluticasone, Budesonide, Mometasone. Cobicistat increases the levels of these steroids, which can lead to Cushing’s Syndrome (weight gain, moon face) and adrenal suppression. This can occur even with inhaled or nasal sprays.
• Statins: Atorvastatin and Rosuvastatin should be used at the lowest possible dose with frequent monitoring.
• PDE5 Inhibitors: Sildenafil, Tadalafil, or Vardenafil used for erectile dysfunction should be used at greatly reduced doses (e.g., Sildenafil 25mg every 48 hours) due to the risk of severe hypotension and priapism.
• Anticoagulants: Rivaroxaban and Apixaban levels are increased, significantly raising the risk of life-threatening bleeding.

• Oral Contraceptives: Cobicistat can change the levels of estrogen and progestin. Patients should use an alternative or additional method of contraception (like condoms).
• Antifungals: Ketoconazole, Itraconazole, and Voriconazole can increase Cobicistat levels, and vice versa.
• Antidepressants: SSRIs like Sertraline or TCAs like Amitriptyline may require dose adjustments.

• Grapefruit and Grapefruit Juice: Grapefruit is a natural inhibitor of CYP3A4. Consuming it with Cobicistat can lead to excessively high levels of the drug and its boosted partners, increasing the risk of toxicity. It should be avoided.
• High-Fat Meals: While food is required for absorption, extremely high-fat meals might alter the absorption profile, though standard meals are generally recommended.

• St. John’s Wort: This is a potent inducer of CYP3A4 and will cause Cobicistat to be cleared from the body too quickly, leading to HIV treatment failure. It is strictly contraindicated.
• Garlic Supplements: High-dose garlic supplements may theoretically induce CYP3A4, though moderate culinary use is usually fine.

• Serum Creatinine: As mentioned, Cobicistat increases serum creatinine by inhibiting tubular secretion. This will result in an artificially low 'estimated' CrCl or eGFR. This does not reflect a change in the actual filtration rate, but it can make it difficult to interpret kidney function tests.

For each major interaction, the mechanism is usually CYP3A inhibition, which leads to increased toxicity of the 'victim' drug. Management strategies involve either avoiding the combination, reducing the dose of the other drug, or switching to a non-CYP3A metabolized alternative.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. Do not start any new over-the-counter medication without checking with your pharmacist.

Cobicistat is strictly contraindicated in the following circumstances:

1. 1Hypersensitivity: Any patient with a known history of clinically significant hypersensitivity (e.g., severe rash, anaphylaxis) to Cobicistat or any of the excipients in the formulation must not take the drug.
2. 2Co-administration with Highly CYP3A-Dependent Drugs: As detailed in the interactions section, Cobicistat must not be used with drugs where elevated plasma concentrations are associated with serious or life-threatening events. This includes drugs like alfuzosin, amiodarone, ergot derivatives, and simvastatin.
3. 3Co-administration with Potent CYP3A Inducers: Drugs that significantly lower Cobicistat levels (like rifampin or St. John's Wort) are contraindicated because they will lead to a loss of virologic response and potential resistance to the entire HIV treatment regimen.
4. 4Severe Renal Impairment (for specific combinations): While Tybost alone has more flexibility, combination products like Stribild are absolutely contraindicated in patients with an estimated CrCl below 70 mL/min at initiation.

These conditions require a careful risk-benefit analysis by a specialist:

• Severe Hepatic Impairment: Due to a lack of data, Cobicistat is generally not recommended for those with Child-Pugh Class C liver disease.
• Pregnancy: Cobicistat is not recommended for use during pregnancy because its levels drop significantly during the second and third trimesters, which could lead to viral breakthrough and transmission to the fetus.
• Concurrent use of Nephrotoxic Agents: Use with other drugs known to harm the kidneys (like high-dose NSAIDs or aminoglycosides) requires extreme caution.

There is no known cross-sensitivity between Cobicistat and other classes of antiretrovirals (like NRTIs or NNRTIs). However, because Cobicistat is almost always taken with a protease inhibitor, patients should be screened for allergies to the partner drug (e.g., atazanavir or darunavir). Patients with a history of severe 'sulfa' allergy should be cautious with darunavir/cobicistat combinations, although Cobicistat itself is not a sulfonamide.

> Important: Your healthcare provider will evaluate your complete medical history and current medication list before prescribing Cobicistat to ensure it is safe for you.

FDA Pregnancy Category: Not formally assigned under the new PLLR system, but caution is advised.

Data from clinical registries and studies indicate that Cobicistat-boosted regimens result in significantly lower exposures of the boosted drugs (like darunavir or atazanavir) during the second and third trimesters of pregnancy. This reduction in drug levels increases the risk of 'virologic failure' (the virus becoming detectable again) and the risk of mother-to-child transmission of HIV.

• Recommendation: Cobicistat-containing regimens are not recommended to be initiated during pregnancy. Women who become pregnant while on a Cobicistat-containing regimen should be switched to an alternative, more stable regimen (such as one boosted by ritonavir, which has more data in pregnancy).

In the United States and other regions where clean water and infant formula are accessible, the CDC and health authorities recommend that HIV-infected mothers do not breastfeed their infants. This is to avoid the risk of postnatal transmission of HIV-1. It is not known if Cobicistat is excreted in human milk, though it is present in the milk of lactating rats. Because of the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, breastfeeding should be avoided.

Cobicistat is approved for use in pediatric patients with HIV-1 infection who weigh at least 35 kg. The safety and efficacy in children weighing less than 35 kg have not been established. In the 35 kg+ population, the pharmacokinetic profile and side effect profile are generally similar to those seen in adults. Long-term effects on growth and development are still being monitored in ongoing pediatric registries.

There is limited data on the use of Cobicistat in patients aged 65 and older. Clinical considerations for this group include:

• Renal Function: Natural age-related decline in GFR may make elderly patients more susceptible to the renal effects of Cobicistat, especially when used with tenofovir.
• Polypharmacy: Elderly patients are more likely to be taking medications for hypertension, high cholesterol, or heart disease, all of which have high potential for interaction with Cobicistat.
• Liver Function: Reduced hepatic reserve may alter the metabolism of the drug.

Cobicistat is not recommended for initiation in patients with a CrCl < 70 mL/min when part of a TDF-containing regimen. For standalone Tybost, no dose adjustment is required for the booster itself, but the partner drug (atazanavir or darunavir) may have its own renal restrictions. Cobicistat is not significantly removed by dialysis.

No dose adjustment is needed for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. It has not been studied in severe impairment (Class C), and use in such patients is generally avoided unless the benefits clearly outweigh the unknown risks.

> Important: Special populations require individualized medical assessment and frequent monitoring by an HIV specialist.

Cobicistat is a mechanism-based, 'suicide' inhibitor of the cytochrome P450 3A (CYP3A) family of enzymes. Unlike reversible inhibitors that simply sit in the enzyme's active site, Cobicistat undergoes a partial metabolic cycle by the enzyme, which results in the formation of a reactive intermediate. This intermediate then forms a covalent, irreversible bond with the heme prosthetic group of the CYP3A enzyme. This permanently 'kills' the enzyme molecule. To regain CYP3A activity, the body must synthesize new enzyme proteins. By effectively reducing the population of functional CYP3A4 enzymes in the liver and intestines, Cobicistat slows the oxidative metabolism of co-administered drugs like darunavir, atazanavir, and elvitegravir, thereby increasing their systemic exposure (AUC) and peak concentrations (Cmax).

The primary pharmacodynamic effect of Cobicistat is the inhibition of CYP3A. This effect is dose-dependent but reaches a plateau at the 150 mg dose. Cobicistat also inhibits the tubular secretion of creatinine by inhibiting transporters like MATE1 (Multidrug and Toxin Extrusion transporter 1). This results in a 10-15% increase in serum creatinine, which occurs within the first week of dosing and remains stable. Cobicistat does not have any effect on the QT interval or other cardiac electrophysiological parameters at therapeutic doses.

| Parameter | Value |

|---|---|

| Bioavailability | High (when taken with food) |

| Protein Binding | 97% - 98% |

| Half-life | ~3 to 4 hours |

| Tmax | 2 to 5 hours |

| Metabolism | Primarily CYP3A, minor CYP2D6 |

| Excretion | Fecal 86.2%, Renal 8.2% |

• Molecular Formula: C36H53N7O5S2
• Molecular Weight: 727.98 g/mol
• Solubility: Practically insoluble in water; soluble in methanol and ethanol.
• Structure: Cobicistat is a thiazolyl-methyl carbamate derivative. It is structurally related to ritonavir but lacks the valine-derived side chain and the hydroxyl group required for HIV protease inhibition, which explains its lack of antiviral activity.

Cobicistat is classified as a Cytochrome P450 3A Inhibitor [EPC] and a Pharmacokinetic Enhancer. It is the first drug in this class designed specifically for boosting without having its own antiviral properties. It is often grouped with 'Antiretroviral Adjunctive Agents.'