Overview
11 DESCRIPTION TYBOST (cobicistat) is a mechanism-based CYP3A inhibitor. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir. 12.2 Pharmacodynamics Effects on Pharmacokinetic Enhancement The effect of TYBOST on atazanavir pharmacokinetics was evaluated in the pharmacokinetic substudy (N=48) of Trial 114 in which participants with HIV-1 received atazanavir 300 mg coadministered with TYBOST 150 mg or atazanavir 300 mg coadministered with ritonavir 100 mg, both in combination with TRUVADA. The steady-state pharmacokinetic parameters of atazanavir were comparable when coadministered with TYBOST versus ritonavir groups as shown in Table 8 [see Clinical Studies (14.
Indications
- 1 INDICATIONS AND USAGE TYBOST is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 14 kg. ( 1.1 ) Limitations of Use : TYBOST is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data.
Common Doses
- 300 mg
- 150 mg
- 800 mg
- 90 mg
Dosage
2 DOSAGE AND ADMINISTRATION TYBOST must be coadministered with atazanavir or darunavir at the same time, with food, and in combination with other HIV-1 antiretroviral agents. ( 2.1 , 2.2 ) Recommended dosage in adults: ( 2.1 ) Adult Patient Populations Coadministered Agent Dosage TYBOST Dosage Treatment-naïve or treatment-experienced atazanavir 300 mg orally once daily 150 mg orally once daily Treatment-naïve or treatment-experienced with no darunavir resistance-associated substitutions darunavir 800 mg orally once daily Recommended dosage in pediatric patients: TYBOST 150 mg or TYBOST 90 mg...
Contraindications
- 4 CONTRAINDICATIONS The concomitant use of TYBOST with atazanavir or darunavir and the following drugs is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] . Alpha 1-adrenoreceptor antagonist: alfuzosin Antianginal: ranolazine Antiarrhythmic: dronedarone Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anti-gout: colchicine Antimycobacterial: rifampin Antineoplastics: irinotecan These contraindications apply only to TYBOST coadministered with atazanavir...
Side Effects
- 6 ADVERSE REACTIONS The following adverse reaction is described in greater detail in another section of the labeling: New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.2) ]. The most common adverse drug reactions observed with TYBOST in combination with atazanavir (incidence greater than 5%, Grades 2−4) are jaundice and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.
Interactions
- 7 DRUG INTERACTIONS TYBOST, in combination with atazanavir or darunavir, can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of TYBOST, atazanavir and darunavir. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 4 , 5.3 , 7 , 12.3 ) 7.1 Potential Effect of Cobicistat (Coadministered with Atazanavir or Darunavir) on the Pharmacokinetics of Concomitant Drugs Cobicistat is an inhibitor of CYP3A and CYP2D6.