Mechanism of Action

Fixed-dose combination of antiretroviral drugs elvitegravir (EVG), boosted by the CYP3A inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir alafenamide(TAF)

Pharmacodynamics (PD)

Effect on QT interval is not known

Pharmacokinetics (PK)

Median Tmax: EVG: 4 hours; COBI: 3 hours; FTC: 3 hours; TAF: 1 hour

Food Effect: EVG AUC was increased by 34% and 87% when GENVOYA was co-administered with a light meal and high fat meal, respectively. No clinically meaningful food effect on COBI, FTC or TAF was observed.

Median Terminal half-lives: EVG: 12.9 hours; COBI: 3.5 hours ; FTC: 10 hours; TAF: 0.51 hours

Metabolism: EVG: CYP3A (major) and UGT1A1/3 (minor): COBI: CYP3A (major) and CYP2D6 (minor): FTC: Not significantly metabolized; TAF: Cathepsin A (major), carboxylesterase 1 (minor), and CYP3A (minimal)

Excretion: FTC is excreted renally; TFV (the primary metabolite of TAF) is excreted renally; EVG and COBI metabolites are primarily eliminated in feces

Plasma protein binding: EVG: ~99%;  COBI: ~98% ; FTC: <4%; TAF: ~80%

PK-PD Analysis

No exposure-response relationships for safety or efficacy were identified for any of the components of GENVOYA at the approved recommended dosage.

Population PK

No dosage adjustment is recommended based on race or gender

Special Populations

No dosage adjustment is recommended based on creatinine clearance ≥30 mL/min, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, or age ≥12 to ≤75 years.

Renal Impairment: GENVOYA is not recommended in patients with estimated creatinine clearance below 30 mL/min.

Hepatic Impairment: GENVOYA is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Drug Interactions

GENVOYA can alter the concentration of drugs metabolized by CYP3A or CYP2D6.

Coadministration of GENVOYA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events, and drugs that may lead to reduced efficacy of GENVOYA and possible resistance, such as potent CYP450 inducers.

Coadministration of GENVOYA is not recommended with rifabutin, rifapentine, salmeterol, and/or colchicine in patients in patients with renal or hepatic impairment.

Consider alternatives to the coadministration of GENVOYA with oxcarbazepine, systemic dexamethasone, and/or inhaled/nasal fluticasone.

Consider alternatives to the coadministration of GENVOYA with contraceptive patch, vaginal ring, injectable contraceptives, and oral contraceptives containing progestogens other than norgestimate.

Dose reduction may be necessary for sedative/hypnotics, neuroleptics, midazolam, and beta blockers when coadministered with GENVOYA.

Specific dosage regimens are required for phosphodiesterase-5 inhibitors, colchicine, and bosentan when coadministered with GENVOYA.

Initiate with the lowest starting dose of atorvastatin when coadministered with GENVOYA and titrate carefully while monitoring for safety.

Separate GENVOYA and antacid administration by at least 2 hours.

The maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day when coadministered with GENVOYA. Assessment of benefit/risk is recommended to justify use with voriconazole.

Source

 

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