Cobicistat

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Structural formula
Structural formula of cobicistat
General
Surname Cobicistat
other names
  • 1,3-thiazol-5-ylmethyl [(2 R , 5 R ) -5 - {[(2 S ) -2 - [(methyl {[2- (propan-2-yl) -1,3-thiazole- 4-yl] methyl} carbamoyl) amino] -4- (morpholin-4-yl) butanoyl] amino} -1,6-diphenylhexan-2-yl] carbamate
  • (1,3-Thiazol-5-yl) methyl (5 S , 8 R , 11 R ) -8,11-dibenzyl-2-methyl-5- [2- (morpholin-4-yl) ethyl] -1- [2- (propan-2-yl) -1,3-thiazol-4-yl] -3,6-dioxo-2,4,7,12-tetraazatridecan-13-oate
Molecular formula C 40 H 53 N 7 O 5 S 2
External identifiers / databases
CAS number 1004316-88-4
PubChem 25151504
DrugBank DB09065
Wikidata Q5138908
Drug information
ATC code

V03 AX03

Mechanism of action

Inhibition of the CYP3A enzymes

properties
Molar mass 776.02272 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling
no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Cobicistat is a drug that is given in combination with HIV drugs to make them more effective. By inhibiting the 3A enzymes of the cytochrome P450 superfamily (CYP3A), cobicistat causes certain virus-inhibiting active substances to break down more slowly and thus their effectiveness in the body for a longer period of time.

Chemical properties

Cobicistat has three chiral centers; the synthesis is stereospecific , resulting in the pure isomer . Cobicistat has three pK a values: 1.8 ( thiazole group ), 2.5 (alkylthiazole group) and 6.4 ( morpholine group ). The substance is a white to pale yellow, strongly hygroscopic powder, soluble in 0.1N hydrochloric acid (pH 1.9), slightly soluble at pH 4.5, practically insoluble in water and at pH 6.8 to 8.2, slightly soluble in methanol . Cobicistat is an amorphous solid with a glass transition temperature of 35 ° C. Because of the low glass transition temperature, cobicistat undergoes a phase transition from a foam to a rubber-like material, induced by moisture and temperature, under ambient conditions.

Pharmacological effect

Cobicistat selectively inhibits the enzymes of the CYP3A subfamily of cytochrome P450, including the important CYP3A4 isoenzyme. The inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure (“booster” effect) of CYP3A substrates which, due to the CYP3A-dependent metabolism, have limited oral bioavailability and a short half-life , such as atazanavir , darunavir and elvitegravir .

Cobicistat also increases the intestinal absorption of HIV protease inhibitors by transport proteins .

Cobicistat itself shows no in vitro antiviral activity against HIV-1 , hepatitis B virus (HBV) or hepatitis C virus (HCV).

application areas

Cobicistat is used as a pharmacokinetic enhancer (“booster”) of antiretroviral agents used for HIV treatment (e.g. atazanavir, darunavir, or elvitegravir, individually or in a fixed combination, see section “Finished medicinal products”), as part of combination antiretroviral therapy in adults infected with human immunodeficiency virus 1 (HIV-1).

Side effects and restrictions on use

Drugs that are mainly metabolized by CYP3A and that are subject to a pronounced first-pass effect suggest a particularly high increase in exposure with simultaneous use of cobicistat. The concomitant use of cobicistat with active substances whose clearance is highly dependent on CYP3A and in which elevated plasma levels are associated with serious and / or life-threatening side effects is therefore contraindicated .

Strong inducers of CYP3A can lower the plasma concentration of cobicistat and thus also that of the boosted antiviral, which can reduce the therapeutic efficacy.

Finished medicinal products

Monopreparations : Tybost (EU, CH, USA)

Combination preparations
  • Cobicistat + atazanavir: Evotaz (EU, CH, USA)
  • Cobicistat + darunavir: Rezolsta (EU, CH), Prezcobix (USA, CDN)
  • Cobicistat + elvitegravir + emtricitabine + tenofovir alafenamide : Genvoya (EU, CH)
  • Cobicistat + elvitegravir + emtricitabine + tenofovir disoproxil : Stribild (EU, CH)
  • Cobicistat + darunavir + emtricitabine + tenofovir alafenamide : Symtuza (EU)

Early benefit assessments according to § 35a SGB V

The IQWiG has the combination of cobicistat with darunavir , emtricitabine and Tenofoviralafenamid (trade name Symtuza rated) for four indications: treatment-naïve adolescents, pre-treated adolescents, treatment-naïve adults and naïve adults infected with HIV-1. In the latter group, there was a further distinction between people with and without an indication for switching. No additional benefit compared to the respective appropriate comparator therapy has therefore been proven in any of these groups; In pretreated adults without an indication to switch, there was even a hint of greater harm in relation to diseases of the nervous system and thus of a lower benefit compared to the comparator therapy. In its resolution of March 2018, the Federal Joint Committee (G-BA) did not differentiate between the indication for the switch and found that no additional benefit had been proven for any of the four indications.

As early as 2013, IQWiG evaluated the combination of cobicistat with elvitegravir , emtricitabine and tenofoviraldisoproxil (trade name Stribild ) for the treatment of adults with HIV-1. For treatment-naive adults, the institute saw an indication of a minor additional benefit compared to the ACT, but no hint of an additional benefit for previously treated patients. According to the G-BA decision, however, an additional benefit has not been proven for either of the two indications.

In another early benefit assessment, IQWiG examined Stribild in a new area of ​​application: the treatment of adolescents whose viruses are not known to have mutations associated with resistance to one of the antiretroviral agents and for whom a treatment regimen without tenofoviral disoproxil is not an option due to toxicities comes. In the absence of relevant study data, an additional benefit compared to the ACT is therefore not proven. The G-BA agreed with this assessment.

The combination of cobicistat with elvitegravir, emtricitabine and tenofovir alafenamide (trade name Genvoya ) also underwent two early benefit assessments. In the first dossier assessment, a distinction was made between several patient groups according to the previous treatment status, the age and gender of the persons affected and whether there was an indication for a changeover. According to the IQWiG, there is a hint of a lower benefit compared to the ACT for treatment-naive adults. For adult women pretreated with antivirals without an indication to switch, there is a hint of a minor added benefit; on the other hand, an added benefit has not been proven for pretreated men without an indication to switch and for adults with an indication to switch. For treatment-naive or pretreated adolescents, an additional benefit has also not been proven in the absence of suitable data. The G-BA distinguished only four groups (treatment-naive or antiviral pretreated adolescents and adults); according to him, an added benefit has not been proven for any of the four groups.

The second dossier assessment concerned the treatment of HIV-1 infected children and adolescents with Genvoya. According to IQWiG, an added benefit over the ACT is not proven due to a lack of relevant study data. This applies to both therapy-naive and antiviral pretreated children and adolescents. The G-BA came to the same conclusion.

Individual evidence

  1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
  2. ^ A b Assessment report - Tybost (International non-proprietary name: cobicistat), Procedure No. EMEA / H / C / 002572/0000 , European Medicines Agency, October 2013.
  3. ↑ a b c Product information texts Tybost, as of October 2013 , European Medicines Agency.
  4. Jump up ↑ E. Lepist, TKPhan, A. Roy, L. Tong, K. MacLennan, B. Murray, AS Ray: Cobicistat Boosts the Intestinal Absorption of Transport Substrates, Including HIV Protease Inhibitors and GS-7340, in Vitro . Antimicrobial Agents and Chemotherapy. 56 (10), pp. 5409-5413 (2012). doi: 10.1128 / AAC.01089-12
  5. ↑ A17-48 Darunavir-Cobicistat-Emtricitabine-Tenofovir alafenamide (HIV infection) - Benefit assessment according to Section 35a SGB V , accessed on September 7, 2018.
  6. ↑ Resolution of the Federal Joint Committee of March 16, 2018 on an amendment to the Drugs Directive (AM-RL): Annex XII - Darunavir / Cobicistat / Emtricitabine / Tenofovir alafenamide , accessed on September 7, 2018.
  7. ↑ A13-25 Elvitegravir / Cobicistat / Emtricitabine / Tenofovir disoproxil - Benefit assessment according to Section 35a SGB V , accessed on September 11, 2018.
  8. ↑ Resolution of the Federal Joint Committee of December 5, 2013 on an amendment to the Drugs Directive (AM-RL): Annex XII - Elvitegravir / Cobicistat / Emtricitabin / Tenofovir disoproxil , accessed on September 11, 2018.
  9. ↑ A17-59 Elvitegravir / Cobicistat / Emtricitabine / Tenofovir disoproxil (HIV-1 in adolescents) - benefit assessment according to Section 35a SGB V , accessed on September 11, 2018.
  10. ↑ Resolution of the Federal Joint Committee of May 3, 2018 on an amendment to the Drugs Directive (AM-RL): Annex XII - Elvitegravir / Cobicistat / Emtricitabine / Tenofovir disoproxil (new area of ​​application: HIV in adolescent patients 12 to <18 years) , accessed on 11 September 2018.
  11. ↑ A15-61 Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide - Benefit assessment according to Section 35a SGB V , accessed on September 11, 2018.
  12. ↑ A16-27 Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamid - Addendum to Commission A15-61 , accessed on September 11, 2018.
  13. ↑ Resolution of the Federal Joint Committee of June 16, 2016 on an amendment to the Drugs Directive (AM-RL): Annex XII - Elvitegravir / Cobicistat / Emtricitabin / Tenofovir alafenamide , accessed on September 11, 2018.
  14. ↑ A18-01 Elvitegravir / Cobicistat / Emtricitabine / Tenofovir alafenamide (HIV infection in children) - benefit assessment according to Section 35a SGB V , accessed on September 11, 2018.
  15. ↑ Resolution of the Federal Joint Committee of July 5, 2018 on an amendment to the Drugs Directive (AM-RL): Annex XII - Elvitegravir / Cobicistat / Emtricitabine / Tenofovirala fenamid (new field of application: HIV infection, patients 6 years and older) , accessed on 11 September 2018.