FDA核准Etravirine用於多重抗藥性HIV


  【24drs.com】November 30, 2009 — 美國食品藥物管理局(FDA)以傳統方式核准etravirine 100-mg錠劑(商品名Intelence,Tibotec Therapeutics公司)與其他抗反轉錄病毒藥物,用於已經有治療經驗的成人病患、有病毒複製且HIV-1病毒株對於非核苷酸反轉錄酶抑制劑(nonnucleoside reverse transcriptase inhibitor,NNRTI)和其他抗反轉錄病毒藥物有抗藥性者之HIV-1感染治療。
  
  臨床研究者、杜克大學感染科醫學副教授Charles Hicks醫師在該藥廠的新聞稿中表示,在48週的效果與耐受性研究中,etravirine成為許多已經有治療經驗、對NNRTIs或其他抗反轉錄病毒藥物有抗藥性之成人病患的重要選項。
  
  FDA之前的快速核准是根據對兩個進行中的24週雙盲安慰劑控制第3期研究(Duet-1和Duet-2)、1,203名16歲以上、臨床惡化、有使用抗反轉錄病毒藥物治療HIV-1感染的經驗,顯示出對至少1種NNRTI、核苷酸反轉錄酶抑制劑(nucleotide reverse transcriptase inhibitor [N(t)RTI])以及蛋白酶抑制劑有抗藥性之病患的彙整資料進行的優先回顧。
  
  新的48週資料支持之前的發現,顯示將每天2次的etravirine加入原本的背景治療(darunavir/ritonavir加2種N(t)RTIs、併用或不併用enfuvirtide)中,病毒負載量在60%的病患小於50 copies/mL,只有接受原本的背景治療組則為38% (P < .0001)。
  
  接受etravirine治療的病患中,最常見的副作用為紅疹(10%、只有背景治療組為3%)以及週邊神經病變(4% vs 2%)。
  
  研究中,在開始時,K103N是最盛行的NNRTI替代品,並不影響對etravirine的反應。不過,開始時以V179D、V179F、V179T、Y181V或G190S替代,且出現3種以上美國國際AIDS協會定義之NNRTI替代品,與減少病毒反應有關。
  
  治療失敗的病患中,最常使用的是V179F、V179I、Y181C和Y181I替代品,一般出現在其他多種NNRTI抗藥性相關替代品的背景中。含etravirine之處方,在病毒治療失敗之後,預期會對delavirdine、efavirenz和/或nevirapine有交叉抗藥性。
  
  Etravirine應在餐後服用、每天2次、每次200-mg(2錠)。並未研究它在16歲以下和孕婦的安全性和效果。嚴重肝功能不佳(Child-Pugh類別C)病患需謹慎使用。
  
  FDA警告表示,etravirine治療曾有嚴重且可能致命的皮膚反應報告,包括史蒂文斯–強生症候群、過敏反應、毒性表皮壞死溶解以及多形性紅斑。若出現嚴重過敏、嚴重紅疹、紅疹伴有全身性症狀或肝轉胺酶升高,應立即中止治療。
  
  Etravirine不應和NNRTIs、蛋白酶抑制劑未併用ritonavir時、ritonavir-強化之tipranavir、fosamprenavir或atazanavir同時服用。Ritonavir-強化之 lopinavir應小心使用。
  
  FDA表示,同時使用etravirine和具有細胞色素P 450同功酶(cytochrome P 450 isoenzyme) 3A (CYP 3A)、CYP 2C9、和/或CYP 2C19等性質之藥物時,其治療效果和副作用情況會改變。同時使用carbamazepine、phenobarbital、phenytoin、rifampin、rifapentin、rifapentin (與ritonavir-強化之蛋白酶抑制劑)或金絲桃為禁忌。

FDA Approves Etravirine for Multidrug-Resistant HIV

By Yael Waknine
Medscape Medical News

November 30, 2009 — The US Food and Drug Administration (FDA) has granted traditional approval for etravirine 100-mg tablets (Intelence, Tibotec Therapeutics) with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to a nonnucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

"With its efficacy and tolerability demonstrated in 48-week studies, etravirine has become an important option for many treatment-experienced patients with resistance to NNRTIs or other antiretrovirals," said clinical investigator Charles Hicks, MD, associate professor of medicine at Duke University's Division of Infectious Diseases in Durham, North Carolina, in a company news release.

Prior accelerated approval from the FDA was based on a priority review of pooled 24-week data from two 24-week, ongoing, double-blind, placebo-controlled phase 3 studies (Duet-1 and Duet-2) of 1203 patients aged 16 years and older with clinically advanced, highly antiretroviral treatment–experienced HIV-1 infection who had documented resistance to at least 1 NNRTI, nucleotide reverse transcriptase inhibitor (N(t)RTI), and protease inhibitor.

New 48-week data supported earlier findings, showing that the addition of twice-daily etravirine to background therapy (darunavir/ritonavir plus 2 N(t)RTIs with or without enfuvirtide) yielded viral loads of fewer than 50 copies/mL in 60% of patients vs 38% of those receiving optimized background therapy alone (P < .0001).

The most commonly reported adverse events in patients receiving etravirine therapy were rash (10% vs 3% for background therapy alone) and peripheral neuropathy (4% vs 2%).

In the studies, K103N was the most prevalent NNRTI substitution at baseline and did not affect response to etravirine. However, baseline substitutions V179D, V179F, V179T, Y181V, or G190S and the presence of 3 or more International AIDS Society-USA–defined NNRTI substitutions were linked to decreased virologic response.

Patients in whom therapy failed most commonly had V179F, V179I, Y181C, and Y181I substitutions that usually emerged in a background of multiple other NNRTI resistance–associated substitutions. Cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen.

Etravirine should be administered as a 200-mg dose (2 tablets) twice daily after a meal. Its safety and efficacy have not been studied in patients younger than 16 years and in pregnant women. Caution is advised in patients with severe hepatic impairment (Child-Pugh Class C).

The FDA warns that severe and potentially life-threatening skin reactions have been reported with etravirine therapy, including cases of Stevens-Johnson syndrome, hypersensitivity reactions, toxic epidermal necrolysis, and erythema multiforme. Treatment should be immediately discontinued for signs of severe hypersensitivity, severe rash, or rash with systemic symptoms or liver transaminase elevations.

Etravirine should not be coadministered with NNRTIs, protease inhibitors given without ritonavir, or ritonavir-boosted tipranavir, fosamprenavir, or atazanavir. Ritonavir-boosted lopinavir should be used with caution.

Concomitant use of etravirine with drugs that are substrates of cytochrome P 450 isoenzyme 3A (CYP 3A), CYP 2C9, and/or CYP 2C19 may alter its therapeutic effect or adverse event profile, the FDA said. Coadministration of carbamazepine, phenobarbital, phenytoin, rifampin, rifapentin, rifapentin (with ritonavir-boosted protease inhibitors), or St. John's wort is contraindicated.

    
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