2013年9月26日，Tybost（cobicistat150mg）获欧盟委员会（EC）批准，作为每日一次的药代动力学增强剂，提高特定艾滋病（HIV）药物的血药浓度。Tybost旨在作为HIV蛋白酶抑制剂阿扎那韦（atazanavir，300mg，每天一次）和地瑞那韦（darunavir，800mg，每天一次）的增强剂，作为抗逆转录病毒联合疗法的一部分，用于HIV-1成人感染者的治疗。此次批准，适用于所有28个欧盟成员国。 Tybost的获批，是基于关键性III期研究（Study114）的48周数据，研究结果证明了在与一种抗逆转录病毒疗法【阿扎那韦（atazanavir）+Truvada（恩曲他滨200mg+替诺福韦245mg）】联合用于初治HIV-1成人感染者时Tybost相较于利托那韦（ritanovi）的非劣性（non-inferior）。此外，药代动力学数据表明，Tybost提升atazanavir和darunavir血药浓度的水平，与ritonavir相似。Tybost仅适用于与atazanavir或darunavir联合用药。 Study114研究中，Tybost的耐受性良好，大部分不良事件为轻度至中度。最常见的不良反应为黄疸、眼黄疸、恶心。 Tybost是四合一型抗HIV新药Stribild（elvitegravir150mg/cobicistat150mg/emtricitabine200mg/tenofovirdisoproxil(asfumarate)245mg）的一个组成部分。Stribild是一种每日一次的单一片剂，分别于2012年8月和2013年5月获FDA和欧盟批准，用于HIV-1成人感染者。 Tybost (cobicistat): an alternative to ritonavir for boosting antiretrovirals Gilead has launched a new pharmacokinetic enhancer to increase plasma levels of protease inhibitors in adults with HIV. Cobicistat has no inherent antiretroviral activity but is a strong CYP3A4 inhibitor that prevents the breakdown of HIV protease inhibitors which are metabolised via the CYP3A pathway, thereby increasing plasma levels of these drugs. It can be used instead of ritonavir in patients taking atazanavir or darunavir for the treatment of HIV-1 infection. Tybost is available as a film-coated tablet containing 150mg cobicistat, to be taken once daily with food at the same time as atazanavir 300mg or darunavir 800mg. Interaction warning Prescribers must be aware of the high potential of cobicistat for interaction with other drugs. Cobicistat strongly inhibits CYP3A4 and its use in combination with drugs that are extensively metabolised by this pathway and undergo a high degree of first-pass metabolism is contraindicated. Such drugs include amiodarone, quinidine, statins, alfuzosin, pimozide, sildenafil, oral midazolam and ergot derivatives. Concomitant use of cobicistat with strong CYP3A4 inducers, such as carbamazepine, phenytoin, phenobarbital, rifampicin and St John's wort, is also contraindicated. Cobicistat is not recommended for use in combination with drugs that are moderate to weak inhibitors or inducers of CYP3A4 and should be used with caution in patients taking any drug that is metabolised via the CYP3A metabolic pathway. Cobicistat also inhibits the transporters P-glycoprotein, BCRP, MATE1, OATP1B1 and OATP1B3, and can result in increased plasma concentrations of drugs that are substrates of these transport systems. New Drugs Online Report for cobicistat Information Generic Name: cobicistat   Trade Name: Tybost  Entry Type: New molecular entity   Development and Regulatory status UK: Launched  EU: Launched  US: Approved (Licensed)  UK launch Plans: Available only to registered users Actual UK launch date: February 2014  Comments Sep 14: Approved in the US. Cobicistat may be used as a booster for combinations that include atazanvir and darunavir [16]. 30/09/2014 12:12:03  Apr 14: Filing re-submitted in the US. Decision on approval expected by 3 Oct 14 [15] 23/04/2014 08:16:53  Feb 14: Tybost 150mg tablets launched in the UK. Net price for 30 tabs, £21.38 [14]. 25/02/2014 10:47:54  Oct 13: UK price for Tybost is still to be finalised; launch date has not yet been set [13]. 11/10/2013 11:03:03  Sep 13: Approved in the EU as a boosting agent for the HIV protease inhibitors atazanavir 300mg once daily and darunavir 800mg once daily as part of antiretroviral combination therapy in adults with HIV-1 infection [12]. 27/09/2013 19:14:23  Jul 13: EU positive opinion for Tybost to be used as a pharmacokinetic enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of antiretroviral combination therapy in HIV-1 infected adults [11]. 26/07/2013 14:01:56  April 13: Complete response letter from US FDA - states that it cannot approve the application in its current form. The letter states that during recent inspections, deficiencies in documentation and validation of certain quality testing procedures and methods were observed. Gilead is working with FDA to address the questions raised in the Complete Response Letters and move the applications forward. [10] 30/04/2013 08:24:16  Mar 13: No further update 26/03/2013 17:18:13  Jun 12: Filed in the US [8]. 29/06/2012 22:54:09  May 12: Plan to file in US in 3Q 2012 [7] 28/05/2012 15:15:33  May 12: Filed in EU. Review of the MAA for cobicistat will be conducted under the centralised licensing procedure. [6] 25/05/2012 08:22:15  Dec 11: Plan to file in US 2Q 2012 [6] 23/12/2011 15:42:08  Trial or other data Jul 12: Full trial data have been announced for study 114. Mean increases in CD4 cell counts were 213 cells/mm3 for cobicistat pts & 219 cells/mm3 for ritonavir pts at 48 weeks (p=0.67). Twenty-five pts (7%) discontinued treatment due to adverse events in each arm of the study. The most common adverse events occurring in greater than or equal to 10% of pts in either treatment arm included jaundice (21% in the cobicistat arm vs. 16% in the ritonavir arm), ocular icterus (18% in both arms), nausea (18% vs. 16%), diarrhoea (15% vs. 20%), headache (11% vs. 16%), nasopharyngitis (11% vs. 15%), hyperbilirubinaemia (11% vs. 10%) & upper respiratory infection (10% vs. 8%) [9]. 07/08/2012 11:17:50 Dec 11: P3 Study 114 results. After 48 wks treatment, 85% of 344 pts taking cobicistat-boosted atazanavir plus Truvada (emtricitabine + tenofovir) achieved HIV RNA viral load of <50 copies/mL, vs. 87% of 348 pts taking ritonavir-boosted atazanavir plus Truvada (95% CI -7.4% to 3.0%). Discontinuation rates due to adverse events were 7.3% (cobicistat) and 7.2% (ritonavir). Small increases in serum creatinine seen: at week 48: increase from baseline was 0.14mg/dL with cobicistat vs. 0.09mg/dL with ritonavir. The increase is seen within days of starting cobicistat but is reversible on stopping. [4] 06/12/2011 08:44:37 Oct 11: Bristol-Myers Squibb is woring with Gilead to develop a fixed-dose combination of atazanavir and cobicistat. Gilead is currently studying atazanavir and cobicistat in PII and PIII studies in HIV-1 treatment-naïve patients. Bristol-Myers Squibb will be responsible for the formulation, manufacturing, development, registration, distribution and commercialization of the combination worldwide [3]. 27/10/2011 19:29:33 Sep 11: NCT01440569 - A PIIIb, open-label, single arm study to evaluate the safety and efficacy of cobicistat-boosted darunavir plus two fully active nucleoside reverse transcriptase inhibitors in 300 HIV 1 infected (investigator chosen), treatment-naïve and -experienced adults with no darunavir resistance-associated mutations. The primary safety endpoint is the onset of any treatment emergent Grade 3 or Grade 4 AEs over 24 weeks. The study will start Sep 11 and is due to complete May 13 [2]. 27/09/2011 10:06:17 NCT01363011: A phase 3 open-label safety study of cobicistat-containing highly active antiretroviral regimens in 100 HIV-1 infected patients with mild to moderate renal impairment. The primary endpoint is change from baseline to week 24 in estimated creatinine clearance. Secondary outcomes include the proportion of subjects achieving virologic response at weeks 24 and 48 (HIV-1 RNA < 50 copies/mL). There are two cohorts: a treatment naïve cohort and a cohort already receiving treatment who will undergo a ‘pharmacoenhancer switch’ from a retonavir containing regimen. The study started in May 11 and is due to complete Nov 12 [1]. 15/08/2011 16:25:46 Evidence Based Evaluations EPAR References   Available only to registered users  Category BNF Category: HIV infection (05.03.01) Pharmacology: Pharmacoenhancing agent - increases systemic levels of coadministered agents that are metabolised by CYP3A   Epidemiology: An estimated 83,000 people were living with HIV in 2008 in the UK; about 27% were unaware of their infection. In 2008, there were 7,298 new diagnoses of HIV.   Indication: HIV infection  Additional Details: booster  Method(s) of Administration   Oral  Company Information Name: Gilead Sciences  US Name: Gilead Sciences  Further Information Anticipated commissioning route (England) NHSE  High cost drug list? Yes Implications Available only to registered users