Cobicistat approved as pharmacokinetic (PK) booster for atazanavir and darunavir in EU prior to the US

Simon Collins, HIV i-Base

On 25 September 2013, Gilead announced that its pharmacokinetic booster cobicistat had been approved in Europe with an indication to boost once-daily use of either atazanavir (300 mg) or darunavir (800 mg), in combination with other ARVs in a combination. [1]

Approval is based on  results from a Phase 3 study (study 114) in which cobicistat was non-inferior compared to ritonavir at boosting atazanavir over 48 weeks. All patients also used tenofovir and FTC. Additional PK studies showed cobicistat and rintonavir produce a similar boosting effect on darunavir drug levels.

As with ritonavir, cobicistat has the potential to interact with a wide range of other drugs.

Cobicistat is a selective inhibitor of the cytochrome 450 3A4 liver enzyme responsible for metabolising atazanavir and darunavir which, similar to ritonavir, results in higher drug levels and slower clearance of the boosted drug. Cobicistat is also a CYP3A substrate, a weak CYP2D6 inhibitor and is metabolised,  to a minor extent,  by CYP2D6. The transporters that cobicistat inhibits include p-glycoprotein (P-gp),  BCRP,  OATP1B1 and OATP1B3.

Co-administration with the following medicinal products is contra-indicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect:

  • alpha 1 adrenoreceptor antagonists: alfuzosin
  • antiarrhythmics: amiodarone, quinidine
  • anticonvulsants: carbamazepine, phenobarbital, phenytoin
  • antimycobacterials: rifampicin
  • ergot derivatives: dihydroergotamine, ergometrine, ergotamine
  • gastrointestinal motility agents: cisapride
  • herbal products: St. John’s wort (Hypericum perforatum)
  • HMG-CoA reductase inhibitors: lovastatin, simvastatin
  • neuroleptics: pimozide,
  • PDE-5 inhibitors: sildenafil for treatment of pulmonary arterial hypertension
  • sedatives/hypnotics: orally administered midazolam, triazolam.

Until full prescribing information is available on the EMA website, please see the Gilead press statement for further details. [1]

In Study 114,  cobicistat was well tolerated and most adverse events were mild to moderate. The most common adverse reactions (incidence greater than or equal to 10 percent, all grades) were jaundice,  ocular icterus and nausea.

Based on the information in the SPC for Stribild, Cobicistat inhibits the tubular secretion of creatinine and may cause modest increases in serum creatinine and modest declines in creatinine clearance (see section 4.8). Patients who experience a confirmed increase in serum creatinine of greater than 26.5 μmol/L (0.3 mg/dL) from baseline should be closely monitored for renal safety.

If serum phosphate is < 0.48 mmol/L (1.5 mg/dL) or creatinine clearance is decreased to < 70 mL/min, renal function should be re-evaluated within one week, including measurements of blood glucose, blood potassium and urine glucose concentrations (see section 4.8). It is recommended that [Stribild] is discontinued in patients with creatinine clearance that falls to < 70 mL/min while on treatment unless it is considered that the potential benefit of this combination of antiretroviral agents for the individual patient outweighs the possible risks of continuing with therapy.

Cobicistat is dosed at 150 mg once-daily.

Cobicistat is marketed under the brand name Tybost.


This is a rare example of an HIV drug receiving approval in the EU prior to the US. 

Gilead submitted cobicistat as a single drug to the US Food and Drug Administration (FDA) in June 2012 but is currently working on resubmitting the application after receiving a Complete Response Letter in April 2013. [2]

Although the approval of an alternative PK booster to ritonavir has been a long-standing community demand, the differences between cobicistat and ritonavir are likely to be when coformulations with the boosted drugs, which are currently indevelopment, become available. 


  1. Gilead press statement. European Commission approves Gilead Sciences’ Tybost, a new boosting agent for HIV therapy.
  2. Gilead press statement. Gilead receives complete response letters from U.S. Food and Drug Administration for elvitegravir and cobicistat. (29 April 2013).