Cobicistat, Elvitegravir, Emtricitabine, And Tenofovir Disoproxil Fumarate

Introduction Overview

Generic Name

cobicistat, elvitegravir, emtricitabine, and tenofovir disoproxil fumarate

Brand Name

Stribild

Dosage Form

Oral tablet

Drug Class

Antiviral combinations

Pharmacokinetics

Absorption:
Stribild is administered orally as a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. Absorption of all constituents is enhanced when taken with food, leading to higher plasma concentrations. Elvitegravir, absorbed primarily in the gastrointestinal tract, exhibits moderate bioavailability, which is significantly increased by concomitant administration of cobicistat, a pharmacokinetic enhancer that inhibits CYP3A enzymes, thereby reducing elvitegravir metabolism. Emtricitabine and tenofovir disoproxil fumarate, the prodrug of tenofovir, also exhibit good oral absorption with bioavailability of approximately 93% and 25%, respectively. The presence of certain antacids or polyvalent cation-containing products can reduce absorption due to chelation, thus concomitant use should be timed appropriately.

Distribution:
After absorption, elvitegravir displays extensive plasma protein binding (approximately 98-99%), mainly to albumin and alpha-1 acid glycoprotein, which restricts its free circulating fraction. Cobicistat similarly binds highly to plasma proteins (approximately 97-98%). Emtricitabine and tenofovir demonstrate lower protein binding, around 4% and <0.7%, respectively, allowing for wide tissue distribution. The volume of distribution varies between components; elvitegravir has a moderate volume indicating distribution primarily in plasma and tissues. All components penetrate well into peripheral blood mononuclear cells, important for antiviral efficacy. Elvitegravir and cobicistat concentrations in seminal and cerebrospinal fluids are relatively low, but sufficient for antiviral activity.

Metabolism:
Elvitegravir undergoes extensive hepatic metabolism predominantly via cytochrome P450 3A (CYP3A) enzymes, resulting in multiple inactive metabolites. Cobicistat acts as a potent CYP3A inhibitor, intentionally administered to boost elvitegravir systemic exposure by slowing its metabolism without intrinsic antiviral activity of its own. Emtricitabine undergoes minimal hepatic metabolism and is primarily cleared unchanged in urine. Tenofovir disoproxil fumarate is a prodrug hydrolyzed in plasma to tenofovir, which is further phosphorylated intracellularly to its active metabolite tenofovir diphosphate; tenofovir itself undergoes minimal metabolism.

Elimination:
Elvitegravir and cobicistat are primarily eliminated via hepatic metabolism and biliary excretion, with fecal elimination of metabolites being significant; renal elimination is minor for these two components. Emtricitabine is eliminated primarily by renal excretion of unchanged drug via glomerular filtration and active tubular secretion, with a half-life of approximately 10 hours. Tenofovir, following conversion from its prodrug form, is also eliminated via renal excretion by glomerular filtration and active tubular secretion, with a half-life of approximately 17 hours. Due to the renal elimination pathways, dosage adjustments may be necessary in patients with renal impairment for components emtricitabine and tenofovir. Cobicistat has a moderate half-life of approximately 3-4 hours but extends the half-life of elvitegravir through enzyme inhibition. Overall, the interplay between pharmacokinetics of each component informs the once-daily dosing schedule, emphasizing the need for monitoring renal function and potential drug interactions.

Dosage Forms

Available Dosage Forms:
Stribild is available as a fixed-dose oral tablet containing the following strengths of active ingredients: 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate. The tablets are film-coated and intended for once-daily oral administration. Tablets can be swallowed whole or crushed and mixed with liquid nutrition for patients who have difficulty swallowing, with clinical studies showing no clinically significant alteration in pharmacokinetics except a mild difference in maximum concentration.

Dosages for Adults and Adolescents:
The recommended dosage for adults and pediatric patients 12 years and older weighing at least 55 pounds (25 kilograms) is one Stribild tablet taken orally once daily with food. The drug is used either as initial therapy for treatment-naive patients or as replacement therapy for virologically suppressed patients meeting specific criteria, including no history of resistance to the components. The fixed-dose single tablet regimen simplifies treatment adherence.

Specific Patient Populations:
Stribild is not recommended for use in patients with severe renal impairment (estimated creatinine clearance below 70 mL/min) or end-stage renal disease as tenofovir accumulation may occur, leading to toxicities. Caution is advised in patients with hepatic impairment; however, no dosage adjustment is generally recommended for mild to moderate hepatic impairment. The drug is not recommended for use during pregnancy due to reduced exposure of elvitegravir and cobicistat in the second and third trimesters, potentially compromising efficacy. Patients who become pregnant should switch to alternative regimens. Lactating women with HIV should not breastfeed to prevent viral transmission. Furthermore, dosage may need adjustment or alternatives considered for patients taking concomitant medications that interact significantly with the CYP3A system due to cobicistat's inhibition.

Mechanism Of Action

Stribild is a fixed-dose combination antiretroviral therapy consisting of four active components, each contributing distinct mechanisms for controlling HIV-1 infection. Elvitegravir is the integrase strand transfer inhibitor (INSTI) that directly interrupts the HIV replication cycle by selectively inhibiting the HIV integrase enzyme, which mediates the integration of viral DNA into the host genome—a crucial step for viral replication. By binding to the integrase active site, elvitegravir prevents strand transfer, thereby blocking the proviral DNA formation and halting the progression of infection at the molecular level.

Cobicistat functions as a pharmacokinetic enhancer rather than possessing direct antiviral activity. It potently inhibits cytochrome P450 3A enzymes, particularly CYP3A4, resulting in increased plasma concentrations of elvitegravir by decreasing its metabolic clearance. This boosting effect allows elvitegravir to be dosed once daily, maintaining therapeutic levels and improving adherence. Cobicistat's selective inhibition enables the combination regimen's optimized pharmacokinetic profile without significant off-target effects.

Emtricitabine, a nucleoside reverse transcriptase inhibitor (NRTI), competitively inhibits HIV reverse transcriptase by mimicking natural nucleosides. When incorporated into the viral DNA chain during reverse transcription, emtricitabine acts as a chain terminator due to the absence of a 3’-OH group, thereby impeding DNA elongation. This inhibits conversion of viral RNA into DNA, preventing HIV replication in infected cells.

Tenofovir disoproxil fumarate, another NRTI, is a prodrug converted to tenofovir in plasma and then phosphorylated intracellularly to tenofovir diphosphate, the active metabolite. Tenofovir diphosphate similarly inhibits HIV reverse transcriptase by competing with deoxyadenosine 5’-triphosphate and causing chain termination upon incorporation. The complementary action of emtricitabine and tenofovir provides potent inhibition of reverse transcriptase, reducing viral load effectively.

Collectively, the combination of these four agents inhibits multiple steps in the HIV life cycle: elvitegravir blocks viral DNA integration; emtricitabine and tenofovir prevent viral DNA synthesis; and cobicistat enhances elvitegravir levels. This multi-mechanistic approach reduces the probability of resistance development and improves therapeutic outcomes. Clinical studies have demonstrated that Stribild rapidly reduces HIV RNA levels to below detectable limits in the majority of treated patients over 48 weeks, underscoring the effectiveness of its mechanism of action in HIV-1 management.

Pharmacological Actions

Potent inhibition of HIV-1 integrase enzyme (elvitegravir) preventing viral DNA integration into host genome.
Pharmacokinetic boosting via CYP3A inhibition by cobicistat, increasing plasma concentration of elvitegravir.
Inhibition of HIV-1 reverse transcriptase enzyme by emtricitabine and tenofovir diphosphates, blocking viral DNA synthesis.
Synergistic antiviral effect from combination targeting multiple viral replication stages.
Reduced risk of resistance owing to multi-target antiviral activity within a single tablet.
Sustained plasma drug levels enabling once-daily dosing and enhanced patient compliance.
Limited interactions with hepatic metabolism pathways due to selective enzyme inhibition by cobicistat.
Broad activity against various HIV-1 subtypes and strains with high genetic barrier to resistance.
Enhanced intracellular penetration allowing effective antiviral concentrations within target immune cells.
Minimal mitochondrial toxicity compared to older NRTIs due to selective action on viral enzymes.

Therapeutic Or Clinical Uses

Treatment of HIV-1 infection in antiretroviral treatment-naive adults and adolescents aged 12 years and older weighing at least 55 pounds (25 kg).
Replacement therapy for virologically suppressed patients (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known resistance mutations.
Complete single-tablet regimen simplifying therapy and enhancing adherence in HIV management.
Used as part of combination antiretroviral therapy to reduce HIV viral load and increase CD4+ T-cell counts.
Effective in patients without resistance to components in the regimen, especially when adherence to therapy is critical.
Not indicated as pre-exposure prophylaxis (PrEP) or for prevention of HIV transmission.
Used in patients with normal renal function; contraindicated or used with caution in moderate to severe renal impairment.
Option for patients who require a once-daily regimen with a fixed-dose combination pill.
May be used in patients with mild to moderate hepatic impairment without dosage adjustment.
Provides an alternative to regimens containing protease inhibitors or non-nucleoside reverse transcriptase inhibitors.

Side Or Adverse Effects

Nausea and gastrointestinal disturbances, including diarrhea and abdominal discomfort.
Lactic acidosis presenting with muscle pain, respiratory distress, gastrointestinal symptoms, and fatigue, a rare but potentially fatal complication.
Renal adverse events manifesting as increased serum creatinine, reduced creatinine clearance, or proximal renal tubulopathy.
Hepatotoxicity characterized by elevated liver enzymes, jaundice, dark urine, clay-colored stools, and abdominal pain.
Hypersensitivity reactions including rash, urticaria, angioedema, and, rarely, anaphylaxis or severe skin reactions.
Immune reconstitution inflammatory syndrome (IRIS), where restoring immune function may cause paradoxical worsening of pre-existing infections.
Fatigue, headache, dizziness, and insomnia reported in some patients.
Potential for weight gain with integrase strand transfer inhibitors, including elvitegravir, over prolonged treatment.
Laboratory abnormalities including increased creatine kinase and mild elevations in bilirubin or transaminases.
Bone mineral density decrease with prolonged tenofovir use, necessitating monitoring in at-risk patients.
Interactions leading to increased exposure and toxicity of concomitant medications.
Potential for exacerbation or reactivation of hepatitis B infection upon discontinuation.
Proteinuria and glycosuria as manifestations of proximal tubule dysfunction.
Rare cases of pancreatitis and neuropathy have been reported.
Allergic reactions necessitating immediate medical intervention.

Precautions

Monitor renal function prior to initiation and periodically during therapy due to tenofovir-associated nephrotoxicity.
Evaluate hepatic function, especially in patients co-infected with hepatitis B or C viruses.
Avoid use in pregnancy; women planning pregnancy should consider alternative regimens.
Do not discontinue therapy abruptly to prevent viral rebound and resistance; carefully monitor hepatitis B co-infected patients when stopping treatment.
Avoid concomitant use with nephrotoxic drugs and counsel patients to report symptoms indicating renal impairment.
Use with caution in patients with pre-existing hepatic or renal disease.
Advise patients about potential interactions with over-the-counter products including antacids and supplements containing polyvalent cations.
Assess for drug-drug interactions owing to cobicistat's inhibition of CYP3A enzymes.
Educate patients to adhere strictly to dosing schedule with food for optimal absorption.
Warn about possibility of immune reconstitution syndrome during initial therapy phases.
Advise females against breastfeeding due to risk of HIV transmission through breast milk.
Consider alternative birth control methods when using Stribild with hormonal contraceptives due to potential interaction.
Use caution in patients with a history of psychiatric illness given drug-drug interactions with antipsychotics.
Patients should report any signs of allergic reactions or severe side effects promptly.
Regular monitoring of viral loads and CD4 counts to assess therapeutic efficacy and detect resistance.

Warnings

Potential for severe hepatotoxicity, including liver failure; prompt evaluation of symptoms such as jaundice or dark urine is essential.
Risk of lactic acidosis and severe hepatomegaly with steatosis, which can be fatal; particularly in females, obese patients, and those with prolonged therapy.
Do not use Stribild during pregnancy due to significantly reduced drug exposure and risk of virologic failure.
Serious hypersensitivity reactions requiring immediate discontinuation have been reported.
Risk of renal impairment, including acute renal failure and Fanconi syndrome; baseline and ongoing renal function testing recommended.
Immune reconstitution inflammatory syndrome may occur, necessitating careful clinical evaluation when symptoms arise.
Significant drug interactions due to cobicistat’s inhibition of CYP3A enzymes can lead to toxicity or loss of efficacy.
Withdrawal of Stribild in patients co-infected with hepatitis B virus can cause exacerbations; close monitoring is required after discontinuation.
Avoid concomitant use with agents highly dependent on CYP3A for clearance and with narrow therapeutic index.
Not indicated nor effective for prevention of HIV infection (PrEP); use in such settings is contraindicated.
Cobicistat may cause increases in serum creatinine without affecting actual renal glomerular function; interpret lab results accordingly.
Advise against abrupt discontinuation without medical guidance to prevent viral resistance development.
Use caution with concomitant medications that prolong QT interval or have proarrhythmic potential.
Patients should not consume St. John’s Wort or other CYP3A inducers as they may reduce Stribild plasma levels.
Adverse effects on bone mineral density warrant caution in patients with osteoporosis or at high fracture risk.

Contraindication

Known hypersensitivity to cobicistat, elvitegravir, emtricitabine, tenofovir disoproxil fumarate, or any component of the formulation.
Concomitant use with medications highly dependent on CYP3A for clearance where elevated plasma concentrations can cause serious and/or life-threatening events, including alfuzosin, cisapride, oral midazolam, triazolam, rifampin, and ergot derivatives.
Severe renal impairment (creatinine clearance below 70 mL/min) or end-stage renal disease requiring dialysis.
Use during pregnancy due to substantially reduced exposure of active components leading to reduced efficacy.
Co-administration with other antiretroviral agents containing identical or overlapping components (e.g., adefovir, lamivudine, ritonavir, or tenofovir) to avoid toxicity and resistance development.
Concurrent use with simvastatin or lovastatin due to risk of rhabdomyolysis and myopathy.
Use with pimozide or lurasidone (antipsychotics) due to potential for serious cardiac adverse effects.
Concomitant use with sildenafil when used for pulmonary arterial hypertension (Revatio) due to increased risk of serious adverse events.
Use with St. John’s wort or other potent CYP3A inducers which may reduce therapeutic efficacy of Stribild.
Contraindicated in patients with severe hepatic impairment due to insufficient safety and efficacy data.
Use with carbamazepine, phenytoin, phenobarbital or other potent CYP inducers that reduce plasma concentrations of Stribild components.
Known allergy to any nucleotide or nucleoside reverse transcriptase inhibitors.

Drug Interactions

Cobicistat is a strong inhibitor of CYP3A enzymes leading to significant interactions with drugs metabolized via CYP3A4.
Concomitant use with alfuzosin, cisapride, oral midazolam, triazolam, or rifampin is contraindicated due to increased risk of toxicity or reduced efficacy.
Cholesterol-lowering drugs such as simvastatin and lovastatin have increased plasma concentrations when co-administered, heightening risk of myopathy or rhabdomyolysis.
Antipsychotic agents like pimozide and lurasidone may have additive cardiac risks when used with Stribild, necessitating avoidance.
Ergot derivatives including dihydroergotamine, ergotamine, and methylergonovine are contraindicated due to risk of ergot toxicity.
Seizure medications such as carbamazepine, phenytoin, and phenobarbital induce metabolism of elvitegravir and cobicistat, decreasing their therapeutic levels.
Use of St. John's wort significantly reduces plasma concentrations of Stribild components through CYP3A induction.
Hormonal contraceptives may have reduced efficacy or increased side effects when taken concomitantly.
Antacids containing magnesium or aluminum should be separated by at least 2 hours to avoid reduced absorption of Stribild.
Stribild inhibits renal tubular secretion affecting drugs cleared predominantly via renal secretion such as digoxin or metformin.
Concomitant use with direct oral anticoagulants requires close monitoring due to potential enhanced anticoagulant effects.
Many benzodiazepines metabolized by CYP3A may have increased sedative effects when taken with Stribild.
Caution with narcotic analgesics metabolized by CYP3A to avoid respiratory depression.
Salmeterol and other beta-2 agonists may interact, necessitating monitoring for cardiovascular effects.
Concomitant use with multiple antiretroviral agents containing overlapping components (e.g., ritonavir or lamivudine) can precipitate resistance or increased toxicity.

Preparations Of The Drug

Fixed-dose combination oral tablet containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate.
Film-coated tablets designed for once-daily administration with food to optimize absorption.
Packaging typically in bottles or blister packs to maintain stability and dosing integrity.
Tablets can be crushed and mixed with liquids or soft foods for patients with swallowing difficulties, without clinically significant alteration in pharmacokinetics.
Storage at room temperature, away from moisture and heat, in tightly closed containers to preserve efficacy.
Formulation excludes additional antiretroviral agents to prevent duplication of therapy and potential toxicity.
Available only by prescription for treatment of HIV-1 infection in specified populations.
Manufactured and distributed by Gilead Sciences, Inc., ensuring consistent quality and supply.
Includes comprehensive medication guides and patient information leaflets for safe and effective use.
No currently available parenteral or alternative formulations; only oral tablet is marketed.
Combination tablet intended to simplify complex antiretroviral therapy regimens, enhancing adherence.