Cobicistat

Cobicistat (GS-9350) is a potent and selective inhibitor of CYP3A with IC50 of 30-285 nM.

Cobicistat (GS-9350) is a potent, and selective inhibitor of human cytochrome P450 3A (CYP3A) enzymes as a pharmacoenhancer. GS-9350 inhibits CYP3A with IC50 spectrum from 30 nM to 285 nM. In contrast to ritonavir, GS-9350 is devoid of anti-HIV activity, with IC50 of > 30μM against HIV-1 protease and EC50 of > 30μM in MT-2 HIV infection assay, and is thus more suitable for use in boosting anti-HIV drugs without risking selection of potential drug-resistant HIV variants. GS-9350 shows reduced liability for drug interactions and may have potential improvements in tolerability over ritonavir.

Cobicistat, a selective, mechanism-based CYP3A inhibitor, was discovered and developed by Gilead Sciences, Inc. In 2013, European Medicines Agency (EMA) approved cobicistat (Tybost) for the treatment of HIV-1 infection in combination with protease inhibitors (PIs) atazanavir or darunavir. Interestingly, cobicistat does not interact with HIV directly, but instead serves as a pharmacokinetic enhancer to boost the anti-HIV effect of atazanavir or darunavir through blockade of CYP3A. Cobicistat slows CYP-mediated metabolism of atazanavir and darunavir, resulting in prolonged systemic exposure of the drug(s). Cobicistat is also available as part of a fixed-dose combination tablet (Stribild) of four additional drugs with CYP3A liabilities (elvitegravir, cobicistat, emtricitabine and tenofovir disoproxil fumarate), which was approved in U.S. in 2012, and subsequently approved in Europe and Japan in 2013.

Gilead (United States)

Antiretroviral;Labeled Cobicistat, intended for use as an internal standard for the quantification of Cobicistat by GC- or LC-mass spectrometry.

Isotope labelled analogue of Cobicistat (C633150), a HIV protease inhibitor and have been coadministered with low-dose ritonavir (R535000) as a pharmacoenhancer, significantly increasing their plasma concentrations.

Cobicistat is a HIV protease inhibitor and have been coadministered with low-dose ritonavir (R535000) as a pharmacoenhancer, significantly increasing their plasma concentrations.

ChEBI: Cobicistat is a monocarboxylic acid amide obtained by formal condensation of the carboxy group of (2S)-2-({[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)carbamoyl}amino)-4-(morpholin-4-yl)butanoic acid with the amino group of 1,3-thiazol-5-ylmethyl [(2R,5R)-5-amino-1,6-diphenylhexan-2-yl]carbamate. Acts as a pharmacoenhancer in treatment of HIV-1 by inhibiting P450 enzymes that metabolise other medications.. It has a role as a P450 inhibitor. It is a member of 1,3-thiazoles, a member of morpholines, a member of ureas, a carbamate ester and a monocarboxylic acid amide.

Tybost

Pharmacokinetic enhancer used to increase the effect of atazanavir and darunavir

Commercial L-methionine (24) was treated with bromoacetic acid at elevated temperatures to afford aminolactone salt 25 in 70% yield. This material was then reacted with methyl aminomethylthiazole (26) in the presence of CDI and diisopropylethylamine to arrive at urea 27 in 91% yield. Next, lactone 27 underwent a ring-opening sequence upon exposure to trimethylsilyl iodide (TMSI) giving intermediate 28. The iodide was then displaced by morpholine, followed by treatment with oxalic acid to deliver the L-thiazole morpholine ethyl ester as the oxalate salt 29 in 71% yield for the sequence. Base-mediated hydrolysis of ethyl ester 29, followed by treatment of carboxylate 30 with mono-carbonate hydrochloride 31 in the presence of EDCI and HOBT, provided cobicistat (V) in 76% yield for two steps.

Potentially hazardous interactions with other drugsAlpha-blockers: concentration of alfuzosin possibly increased - avoid.
Anti-arrhythmics: concentration of amiodarone possibly increased - avoid.
Antibacterials: concentration reduced by rifabutin and rifampicin - adjust cobicistat dose, avoid with rifampicin.
Anticoagulants: avoid with apixaban; anticoagulant effect of rivaroxaban possibly enhanced - avoid.
Antidepressants: concentration possibly reduced by St John’s wort - avoid.
Antiepileptics: concentration of cobicistat possibly reduced by carbamazepine, fosphenytoin phenobarbital, phenytoin and primidone - avoid.
Antifungals: concentration of itraconazole and ketoconazole possibly increased - reduce antifungal dose.
Antipsychotics: concentration of lurasidone and pimozide possibly increased - avoid.
Antivirals: concentration of daclatasvir and maraviroc possibly increased - reduce daclatasvir and maraviroc dose; avoid with dasabuvir, nevirapine, ombitasvir, paritaprevir, ritonavir and simeprevir; concentration of elbasvir and grazoprevir increased - avoid; concentration of olaparib possibly increased - avoid or reduce olaparib dose; concentration of both drugs reduced with tipranavir - avoid.
Anxiolytics: avoid with oral midazolam.
Avanafil: concentration of avanafil possibly increased - avoid.
Bosentan: avoid concomitant use.
Cardiac glycosides: concentration of digoxin possibly increased - reduce initial dose of digoxin.
Corticosteroids: concentration of corticosteroids possibly increased avoid or use with caution.
Cytotoxics: concentration of ibrutinib possibly increased - reduce ibrutinib dose; concentration of olaparib possibly increased - avoid or reduce dose of olaparib.
Domperidone: possible increased risk of ventricular arrhythmias - avoid.
Ergot alkaloids: concentration of ergot alkaloids possibly increased - avoid.
Immunosuppression: concentration of ciclosporin, sirolimus and tacrolimus possibly increased.
Lipid-lowering drugs: concentration of atorvastatin possibly increased - reduce atorvastatin dose; avoid with simvastatin.
Oestrogens: metabolism of oestrogens accelerated, reduced contraceptive effect - avoid or use with caution.
Salmeterol: avoid concomitant use. Sildenafil: concentration of sildenafil possibly increased - avoid sildenafil for pulmonary arterial hypertension, reduce dose for erectile dysfunction.
Tadalafil: concentration of tadalafil possibly increased - reduce dose of tadalafil.
Vardenafil: concentration of vardenafil possibly increased - reduce dose of vardenafil.

Cobicistat is metabolised via CYP3A (major)- and CYP2D6 (minor)-mediated oxidation. Following oral administration of [14C]-cobicistat, 99% of circulating radioactivity in plasma was unchanged cobicistat. Low levels of metabolites are observed in urine and faeces and do not contribute to the CYP3A inhibitory activity of cobicistat.
Following oral administration of [14C]-cobicistat, 86% and 8.2% of the dose were recovered in faeces and urine, respectively.

[1] deeks ed. cobicistat: a review of its use as a pharmacokinetic enhancer of atazanavir and darunavir in patients with hiv-1 infection. drugs. 2014 feb;74(2):195-206.