HIV-1

体外活性：达芦那韦对其他可用蛋白酶抑制剂耐药的 HIV 菌株表现出有效的活性。 Darunavir 抑制 L-MDR1 细胞中 P-糖蛋白介导的钙黄绿素-乙酰氧基甲酯的流出，抑制效力为 121 mM。 Darunavir 是一种蛋白质抑制剂，它模拟 gag-pol 多肽第 167 和 168 位的苯丙氨酸序列，并与 HIV 蛋白酶的活性位点结合，从而抑制其活性。 Darunavir 在浓度高达 5 μM 时可阻断每种 HIV-1 变体的感染性和复制。 Darunavir 对选定的 19 种重组临床分离株显示出强大的 ARV 活性，这些重组临床分离株携带多种蛋白酶突变，平均对五种其他蛋白质抑制剂具有抗性。 Darunavir 可抑制 1501 种 PI 耐药病毒中的 75%，其半数最大有效浓度 (EC50) < 10 nM。激酶测定：达芦那韦对野生型 HIV-1 蛋白酶的 Ki 为 1 nM。细胞测定：在 MT-2 细胞的体外研究中，达芦那韦的效力大于沙奎那韦、安普那韦、奈非那韦、茚地那韦、洛匹那韦和利托那韦。达芦那韦主要通过肝细胞色素 P450 (CYP) 酶（主要是 CYP3A）代谢。 “增强”剂量的利托那韦充当 CYP3A 抑制剂，从而增加地瑞那韦的生物利用度。

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对一组多重耐药病毒的已知HIV-1蛋白酶抑制剂的筛选揭示了TMC126对耐药突变体的有效活性。与amprenavir相比，TMC126亲和力的提高主要是由于P2口袋中蛋白的主干上多了一个氢键。对TMC126的苯磺酰胺P2'取代基上的取代模式进行修饰，产生了一个有趣的SAR，其相似的类似物TMC114被发现对突变型和野生型病毒具有相似的抗病毒活性。对野生型和突变型酶的x射线和热力学研究表明，TMC114对HIV-1蛋白酶具有极高的焓驱动亲和力。从野生型病毒开始，体外选择抗TMC114的突变体是非常困难的；这与其他相似物的情况不同。因此，P2口袋中与主链相连的额外氢键不能作为TMC114抗病毒特性的唯一解释。[1]

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研究人员设计、合成并鉴定了UIC-94017 (TMC114)，这是一种新型的非肽人类免疫缺陷病毒1型（HIV-1）蛋白酶抑制剂（PI），含有3(R)、3a(S)、6a(R)-双-四氢呋喃脲（bis-THF）和磺胺异构体，对实验室HIV-1菌株和主要临床分离株具有极强的抑制作用(50%抑制浓度[IC50]， ~ 0.003 μM；IC90, ~ 0.009 μM)具有最小的细胞毒性（CD4+ MT-2细胞的细胞毒性浓度为50%，74 μM）。UIC-94017对暴露于沙奎那韦、茚地那韦、奈非那韦或利托那韦的HIV-1NL4-3突变体的感染和复制具有阻断作用（IC50, 0.003 ~ 0.029 μM），但对amprenavir耐药的HIV-1NL4-3突变体的抑制作用较弱（IC50, 0.22 μM）。UIC-94017对从接受多种抗病毒药物后对现有抗病毒方案无反应的患者中分离出的多pi耐药临床HIV-1变体也有效。结构分析表明，UIC-94017与蛋白酶活性位点氨基酸主链（Asp-29和Asp-30）的密切接触对于其抗多重pi抗性HIV-1变体的效力和广谱活性是重要的。[2]

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尽管抗逆转录病毒疗法（ART）可以抑制外周HIV，但由于大脑中抗逆转录病毒药物水平不足，患者仍然患有神经HIV。因此，本研究的重点是开发一种基于聚乳酸-羟基乙酸（PLGA）纳米颗粒的darunavir （DRV）抗逆转录病毒药物传递系统，该系统采用鼻内途径，可以克服药物代谢稳定性和血脑屏障（BBB）渗透性的限制。对PLGA-DRV的理化性质进行了表征。结果表明，PLGA-DRV制剂在血脑屏障存在的情况下直接抑制U1巨噬细胞中的HIV复制，而不诱导细胞毒性。然而，PLGA-DRV并不比单独的DRV更能抑制HIV复制。值得注意的是，在用DRV或PLGA-DRV处理U1细胞时，总抗氧化能力保持不变。与单独的DRV相比，PLGA-DRV进一步降低了活性氧，表明该配方降低了氧化应激。氧化应激通常会因HIV感染而增加，从而导致炎症增加。虽然PLGA-DRV配方并没有进一步降低炎症反应，但该配方并没有引起hiv感染的U1巨噬细胞的炎症反应。正如预期的那样，体外实验表明，PLGA-DRV对U1巨噬细胞的渗透性高于单独使用DRV。［3］

Darunavir 可有效对抗野生型和 PI 耐药性 HIV，口服生物利用度为 37%。常与利托那韦联合使用，可将生物利用度提高至82%.。

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药物动力学。[1]
第二个选择标准是一组药代动力学相关特性。表6给出了三种不同物种（大鼠、狗和人类来源的肝微粒体）在37°C孵育30分钟后，代谢稳定性为母体化合物剩余百分比。代谢程度是通过使用LC-MS直接测量反应混合物中残留的母体化合物来确定的。1b和1d似乎非常不稳定。Darunavir (TMC114)的稳定性与其他蛋白酶抑制剂相当。表6中包含了2和IDV作为参考。
在动物的口服吸收研究中也观察到同样的趋势。狗口服PEG400溶液80 mg/kg的数据见表7。Darunavir (TMC114)在Cmax和AUC方面明显优于1b和1d。在这次评估中，化合物1b只观察到少量可能的代谢物1i。与2的单磷酸前药fosamprenavir类似，我们研究了化合物1h Darunavir (TMC114)的单磷酸酯的行为。这类前体药物的主要优点是其优越的固态特性，这超出了本出版物的范围。我们只研究了更高生物利用度的潜力。大鼠单次口服PEG400，剂量为20 mg/kg；母体化合物和单磷酸盐的行为方式相似。对于2及其前药，以前也有类似的报道。

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重要的是，体内实验，特别是在野生型小鼠中鼻内给药PLGA-DRV，表明与游离Darunavir (TMC114)/DRV相比，Darunavir (TMC114)/DRV的脑血浆比率显著增加。总的来说，这项研究的发现证明了PLGA-DRV纳米制剂在减少巨噬细胞中的HIV发病机制和增强药物向大脑的递送方面的潜力，为治疗HIV相关神经系统疾病提供了一条有希望的途径。［3］

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Darunavir对野生型和pi耐药HIV有效，口服生物利用度为37%。它需要与利托那韦联合使用，将生物利用度提高到82%。本研究的目的是评估darunvir - sln的体内疗效，并证明淋巴转运是提高药物生物利用度的重要途径。以GMS为脂质，采用热均质技术制备了SLN。与市售片剂（92.6%）相比，SLN在12小时的体外药物释放延迟（80.6%）。冻干SLN在37℃和4℃时的体外表观通透性分别为24 × 10-6和5.6 × 10-6。氯丙嗪和制霉菌素等内吞过程抑制剂的存在使其分别降至18.8 × 10-6和20.2 × 10-6，确定了内吞机制参与了SLN的摄取。大鼠体内药代动力学研究表明，与市售片剂相比，SLN的AUC（26）有所增加（13.22），而淋巴摄取抑制剂环己亚胺的存在将SLN的AUC降低至17.19，这进一步证明了淋巴摄取参与了生物利用度的提高。在给予darunaviv -SLN的大鼠淋巴液中检测到darunavir，进一步证实了SLN被淋巴系统吸收的结论。［6］

Darunavir 对野生型 HIV-1 蛋白酶的 Ki 为 1 nM。
等温滴定量热法。[1]
用等温滴定量热计VP-ITC测定了抑制剂结合的热力学参数。用于所有蛋白酶和抑制剂溶液的缓冲液由10 mM pH 5.0的醋酸钠，2% DMSO和2 mM三（2-羧乙基）膦（TCEP）组成。采用置换滴定法，分别以乙酰胃抑素和茚地那韦为弱结合剂，获得Darunavir (TMC114)对多重耐药蛋白酶的结合亲和力。17,27,28还对紧密结合抑制剂进行了直接滴定实验，以证实位移法得到的焓变。每个实验至少进行两次。ITC实验的细节已在其他地方公布。

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基因分型。[1]
基因型分析采用基于自动化群体的全序列分析。测序结果显示，与野生型（HXB2）参考序列相比，氨基酸发生了变化。 耐药菌株的体外筛选。MT-4-LTR-EGFP细胞在初始浓度为EC50的2至3倍的抑制剂化合物存在下，以0.01至0.001 CCID50/细胞的感染倍数感染。每隔3 ~ 4天进行继代培养，并在显微镜下对病毒诱导的荧光和细胞病变效果进行评分。培养物在相同浓度的化合物中进行继代培养，直到病毒完全突破，然后在更高的化合物浓度下选择能够在最高可能的抑制剂浓度下生长的变体。

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x射线晶体学。[1]
一种具有L63P、V82T和I84V取代的多重耐药HIV-1蛋白酶与Darunavir (TMC114)和2的复合物结晶。两种结构都在P212121空间群中结晶，每个不对称单元有一个二聚体。Darunavir (TMC114)配合物的数据是在美国加州伯克利的Lawrence-Berkeley实验室的先进光源同步加速器的低温条件下收集的。Darunavir (TMC114)晶体配合物的衍射分辨率为1.35 Å， r因子为16.8%。含2复合物的数据在室温下通过安装在Rigaku旋转阳极源上的r轴IV成像板系统采集。与2的配合物的分辨率为2.2 Å。x射线晶体学实验的细节和细化统计已在其他地方发表x射线结构已提交到蛋白质数据库（pdb代码1T7I和1T7J）。

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药敏试验。[2]
HIV-1LAI、HIV-1Ba-L、HIV-2EHO、HIV-2ROD和原代HIV-1分离株对各种药物的敏感性按照前面的描述进行了测定，并进行了轻微的修改。简单地说，将MT-2细胞（2 × 104/ml）暴露于96孔微培养板中存在或不存在不同浓度药物的100 50%组织培养感染剂量（TCID50s）的HIV-1LAI、HIV-1Ba-L、HIV-2EHO或HIV-2ROD中，在37℃下孵育7天。100μl后介质被从每个好,3 - (4 5-dimetylthiazol-2-yl) 2, 5-diphenyltetrazolium溴化(MTT)解决方案(10μl, 7.5毫克/毫升磷酸盐)被添加到每个在盘子上,其次是孵化2 h的37°C。孵化溶解甲瓒晶体后,100μl的酸化异丙醇含有4%(卷/期)特里同x - 100添加到每个好,光密度测定动力学标。所有测定均为重复或三次。
为了测定原代HIV-1分离株对药物的敏感性，植物血凝素激活的外周血单个核细胞(PHA-PBMCs；106/ml)暴露于每个原代HIV-1分离物的50个tcid50中，并在96孔微培养板中以10倍连续稀释的方式在存在或不存在不同浓度药物的情况下进行培养。为了确定某些实验室HIV-1毒株的药物敏感性，如前所述，使用MT-4细胞作为靶细胞，并进行了轻微修改。简而言之，将MT-4细胞（105/ml）暴露于100个耐药HIV-1菌株的tcid50中，存在或不存在不同浓度的药物，并在37℃下孵育。培养第7天，收集上清液，采用全自动化学发光酶免疫分析系统测定p24 Gag蛋白的含量。将抑制p24 Gag蛋白产生50%的药物浓度（50%抑制浓度[IC50s]）与无药对照细胞培养的p24产生水平进行比较，确定药物浓度。所有试验均为三份。

使用 MT-2 细胞的体外研究表明，达芦那韦比沙奎那韦、安普那韦、奈非那韦、茚地那韦、洛匹那韦和利托那韦具有更高的效力。负责达芦那韦代谢的主要肝细胞色素 P450 (CYP) 酶是 CYP3A。 “增强”剂量的利托那韦通过抑制 CYP3A 来增加达芦那韦的生物利用度。

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病毒学, 细胞和病毒。[1]
MT-4细胞是人类t淋巴母细胞样细胞，对HIV感染高度敏感，产生快速而强烈的细胞病变作用。MT4-LTR-EGFP细胞是在HIV-1长末端重复序列（LTR）控制下，用含有绿色荧光蛋白（EGFP）编码序列的载体稳定转染MT4细胞。当这些细胞被HIV感染后，病毒反激活蛋白Tat激活LTR启动子，进而触发EGFP编码序列的转录。所有细胞在添加胎牛血清和抗生素的RPMI 1640培养基中，在37℃、5% CO2气氛的加湿培养箱中培养。 用于化合物谱分析的HIV毒株为野生型HIV-1株IIIB和来自临床分离株的重组HIV毒株。它们是通过将MT-4细胞与样品衍生的病毒蛋白酶（PR）和逆转录酶（RT）编码序列和蛋白酶和RT编码区缺失的HIV-1 hxb2衍生的原病毒克隆共转染而构建的。

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抗病毒化验。[1]
采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑（MTT）比色法测定化合物对野生型HIV和临床样本衍生重组病毒的抗病毒活性。简单地说，将不同浓度的测试化合物添加到平底微滴板的孔中。随后，将病毒和MT-4细胞分别加入最终浓度为200 - 250 50%细胞培养感染剂量(CCID50)/孔和30 000细胞/孔。37℃、5% CO2孵育5天后，用MTT法测定复制病毒的细胞病变效应（CPE）。 抗病毒实验的结果用pEC50（=−log EC50）表示，其中EC50定义为化合物与无药对照相比达到50% CPE的浓度。使用含有相同化合物浓度范围但不含病毒的模拟感染细胞培养物平行测定测试化合物的细胞毒性。

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抗pi的HIV-1的体外生成。[2]
MT-4细胞（105/ml）暴露于HIV-1NL4-3 （500 tcid50）中，在初始浓度为0.01 ~ 0.03 μM的各种pi存在下培养。通过测定MT-4细胞产生的p24 Gag的量来监测病毒的复制。在第7天收获培养上清，在每种药物浓度增加的情况下，用于感染新鲜的MT-4细胞进行下一轮培养。当病毒在药物存在下开始繁殖时，药物浓度通常会增加两到三倍。从感染细胞的裂解物中获得的前病毒DNA样本进行核苷酸测序。选药过程持续到药物浓度达到5 μM。

Animal Studies [3]
Ten twelve-week-old male and female Balb/c mice were acclimated to the animal facility for at least 7 days. Five mice per cage were housed in a sterile room with 12/12 h light–dark cycles. Temperature and humidity were maintained at a constant level in the room. There was free access to food and water. Detailed information for dosing in Balb/c mice can be found in our previous study [29]. A 2.5 mg/kg dosage of Darunavir (TMC114)/DRV or PLGA-DRV NPs was given via intranasal (IN) and intravenous (IV). For the IN group, the minimum concentration of Darunavir (TMC114)/DRV is 1.25 mg/mL to ensure that the dosing volume for each mouse is less than 2 µL per gram of mice. Given the constraints on the EE (%) of Darunavir (TMC114)/DRV in PLGA, we selected a dosage of 2.5 mg/kg, representing the highest dose achievable within the scope of this study.

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Darunavir is an oral nonpeptidic HIV-1 protease inhibitor (PI) that is used, together with a low boosting dose of ritonavir, as part of an antiretroviral therapy (ART) regimen in treatment-experienced and -naive patients with HIV-1 infection. Compared with early-generation PIs, boosted darunavir has a high genetic barrier to resistance and is active against multidrug-resistant HIV isolates. In clinical trials in treatment-experienced patients with HIV-1 infection receiving an optimized background regimen (OBR), twice-daily boosted darunavir was more effective than investigator-selected ritonavir-boosted control PIs (CPIs) or ritonavir-boosted lopinavir. In clinical trials in treatment-naive patients with HIV-1 infection receiving a fixed background regimen, once-daily boosted darunavir was noninferior to boosted lopinavir at 48 weeks and more effective than boosted lopinavir at 96weeks. Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials. It was associated with a lower incidence of diarrhoea than CPIs or lopinavir in treatment-experienced or -naive patients, and fewer lipid abnormalities than lopinavir in treatment-naive patients. Thus, for the management of treatment-experienced or -naive patients with HIV-1 infection, a ritonavir-boosted darunavir-based ART regimen is a valuable treatment option. PHARMACOLOGICAL PROPERTIES: Darunavir is an oral nonpeptidic HIV-1 PI that selectively inhibits the cleavage of HIV gag and gag-pol polyproteins, thereby preventing viral maturation. Darunavir is highly potent against laboratory strains and clinical isolates of wild-type and multidrug-resistant HIV and has limited cytotoxicity. In an in vitro study in MT-2 cells, the potency of darunavir was greater than that of saquinavir, amprenavir, nelfinavir, indinavir, lopinavir and ritonavir. Darunavir binds with high affinity to HIV-1 protease, including multidrug-resistant proteases, and retains potency against multidrug-resistant HIV-1 strains. Although some potential may exist for cross-resistance with amprenavir, darunavir did not display cross-resistance with other PIs in vitro. In a 24-week analysis of pooled data from the POWER 1 and 2 studies in treatment-experienced patients, 11 protease mutations associated with a reduced response to boosted darunavir were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V). The presence of at least three darunavir resistance-associated mutations (prevalent in approximately 7-9% of treatment-experienced patients) together with a high number of protease resistance-associated mutations were required to confer darunavir resistance. In the 48-week analysis of treatment-experienced patients with virological failure in the the TITAN study, fewer in the boosted darunavir group than in the boosted lopinavir group developed additional mutations or lost susceptibility to PIs compared with baseline. In treatment-naive patients, no primary PI-resistance-associated mutations developed in patients with an available genotype at baseline and endpoint during 96 weeks of treatment with boosted darunavir or boosted lopinavir. Oral darunavir, boosted with low-dose ritonavir, is rapidly absorbed, generally reaching peak plasma concentrations within 2.5-4 hours. The bioavailability of oral darunavir is increased by about 30% when taken with food. Darunavir is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, primarily CYP3A. The 'boosting' dose of ritonavir acts an an inhibitor of CYP3A, thereby increasing darunavir bioavailability. Drug interactions can result when darunavir is coadministered with other drugs that are inducers or inhibitors of, or act as substrates for, CYP3A. The mean elimination half-life of boosted darunavir is approximately 15 hours. THERAPEUTIC EFFICACY: In treatment-experienced patients with HIV-1 infection, the therapeutic efficacy of oral twice-daily darunavir 600 mg, boosted with ritonavir 100 mg, versus that of investigator selected boosted CPIs (POWER studies) or versus twice-daily boosted lopinavir (administered as a fixed dose combination of lopinavir/ritonavir 400/100 mg) [TITAN study] has been evaluated in phase IIb and III studies. All patients received concurrent treatment with an OBR. Significantly more patients receiving boosted darunavir achieved a viral load reduction from baseline of >or=1 log(10) copies/mL (primary endpoint) than boosted CPI recipients at all timepoints, up to and including the final efficacy analysis at 144 weeks, in the combined analyses of POWER 1 and 2. The efficacy of boosted darunavir was noninferior to that of boosted lopinavir at 48 weeks, and was significantly better than boosted lopinavir at 48 and 96 weeks in the TITAN study, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a viral load of <400 copies/mL (primary endpoint). In the ARTEMIS study in treatment-naive patients with HIV-1 infection receiving a fixed background regimen of tenofovir and emtricitabine, once-daily boosted darunavir 800 mg was noninferior to boosted lopinavir 800 mg/day at 48 weeks. At 96 weeks, boosted darunavir was found to be more effective than boosted lopinavir, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a confirmed plasma viral load of <50 copies/mL (primary endpoint).[5]

Absorption, Distribution and Excretion
The absolute oral bioavailability of one single 600 mg dose of darunavir alone and with 100 mg of ritonavir twice a day was 37% and 82%, respectively. Exposure to darunavir in boosted patients has been found to be 11 times higher than in unboosted patients. Tmax is achieved approximately 2.4 to 4 hours after oral administration. When darunavir is taken with food, the Cmax and AUC of darunavir given with ritonavir increase by 30% when compared to the fasted state.
A mass balance study in healthy volunteers demonstrated that after single dose administration of 400 mg 14C-darunavir, given with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of radiolabeled darunavir was obtained in the feces and urine, respectively. Excretion of unchanged drug accounted for 8.0% of the darunavir dose in volunteers who were unboosted. In boosted darunavir administration, unchanged darunavir made up 48.8% of the excreted dose in boosted subjects due to inhibition of darunavir metabolism by ritonavir. Unchanged drug in the urine made up 1.2% of the administered dose in volunteers who where unboosted, and 7.7% in boosted volunteers.
The volume of distribution of darunavir in one pharmacokinetic study in conjunction with ritonavir was 206.5 L (with a range of 161.0–264.9) in healthy young adult volunteers. Another pharmacokinetic study revealed a volume of distribution of 220 L.
Darunavir has a low renal clearance. After intravenous administration, the clearance darunavir administered alone and with 100 mg ritonavir twice daily, was 32.8 L/h and 5.9 L/h, respectively.
Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).
Darunavir, co-administered with 100 mg ritonavir twice daily, was absorbed following oral administration with a Tmax of approximately 2.5-4 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone and after co-administration with 100 mg ritonavir twice daily was 37% and 82%, respectively.
Darunavir is distributed into milk in rats; not known whether the drug is distributed into human milk.
A mass balance study in healthy volunteers showed that after single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir, approximately 79.5% and 13.9% of the administered dose of (14)C-darunavir was recovered in the feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir. After intravenous administration, the clearance of darunavir, administered alone and co-administered with 100 mg twice daily ritonavir, was 32.8 L/hr and 5.9 L/hr, respectively.
For more Absorption, Distribution and Excretion (Complete) data for Darunavir (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Darunavir is heavily oxidized and metabolized by hepatic cytochrome enzymes, mainly CYP3A. Darunavir is extensively metabolized in subjects who do not receive a booster, primarily via carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation, as well as both benzylic aromatic hydroxylation and glucuronidation.
In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by CYP enzymes, primarily by CYP3A. A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir, the majority of the radioactivity in the plasma was due to darunavir. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 90% less than the activity of darunavir against wild-type HIV.
Absorption, metabolism, and excretion of darunavir, an inhibitor of human immunodeficiency virus protease, was studied in eight healthy male subjects after a single oral dose of 400 mg of ((14)C)darunavir given alone (unboosted subjects) or with ritonavir (100 mg b.i.d. 2 days before and 7 days after darunavir administration (boosted subjects)). ... Darunavir was extensively metabolized in unboosted subjects, mainly by carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation and to a lesser extent by benzylic aromatic hydroxylation and glucuronidation. Total excretion of unchanged darunavir accounted for 8.0% of the dose in unboosted subjects. Boosting with ritonavir resulted in significant inhibition of carbamate hydrolysis, isobutyl aliphatic hydroxylation, and aniline aromatic hydroxylation but had no effect on aromatic hydroxylation at the benzylic moiety, whereas excretion of glucuronide metabolites was markedly increased but still represented a minor pathway. Total excretion of unchanged darunavir accounted for 48.8% of the administered dose in boosted subjects as a result of the inhibition of darunavir metabolism by ritonavir. Unchanged darunavir in urine accounted for 1.2% of the administered dose in unboosted subjects and 7.7% in boosted subjects, indicating a low renal clearance.
Darunavir is metabolized by Phase I and Phase II biotransformation mechanisms. A large number of metabolites were detected in vitro using animal and human hepatocytes and microsomal preparations. The metabolic pathway was qualitatively similar in rats, dogs and humans. The most prevalent pathway was the Phase I biotransformation including carbamate hydrolysis, aliphatic hydroxylation at the isobutyl moiety and aromatic hydroxylation at the aniline moiety. Dogs were most representatives of human with carbamate hydrolysis predominating in both species. Darunavir was mainly metabolized by CYP3A. In mice and rats darunavir treatment induced hepatic microsomal CYP3A4. UDP-GT activity was additionally induced in rats. In dogs, no induction effects were observed. Darunavir is presented as a single enantiomer but no chiral inversion occurs in vivo.

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Biological Half-Life
The terminal elimination half-life of darunavir is approximately 15 hours when it is combined with ritonavir.
A mass balance study in healthy volunteers showed that after a single dose administration of 400 mg (14)C-darunavir, co-administered with 100 mg ritonavir ... The terminal elimination half-life of darunavir was approximately 15 hours when co-administered with ritonavir.
The pharmacokinetics of darunavir has been evaluated in vitro and in several species (mice, rats, dogs and rabbits), that were also used in the non-clinical pharmacology and toxicology studies. ... Following oral administration, ... elimination half-life was ... rapid with half-lives generally less than 5 hr.

Hepatotoxicity
Some degree of serum aminotransferase elevations occur in a high proportion of patients taking darunavir containing antiretroviral regimens. Moderate-to-severe elevations in serum aminotransferase levels (above 5 times the upper limit of normal) are found in 3% to 10% of patients overall, and rates are higher in patients with HIV-HCV coinfection. In clinical trials of darunavir elevations in serum ALT above 5 times ULN occurred in 2% to 3% of patients, but no subject developed clinically apparent liver injury with jaundice. The serum enzyme elevations during therapy are usually asymptomatic and self-limited and can resolve even with continuation of the medication. Clinically apparent acute liver injury due to darunavir has been reported since its approval and more widescale use, but none have been well characterized for clinical features. Assigning causality to a specific anti-HIV medication is often difficult because most patients are taking multiple antiviral agents and many have accompanying chronic hepatitis B or C or nonalcoholic steatohepatitis. In reported cases, the liver injury generally arises after 1 to 8 weeks of therapy and the pattern of serum enzyme elevations is usually, but not always, hepatocellular. Signs of hypersensitivity (fever, rash, eosinophilia) are rare, as is autoantibody formation. The acute liver injury is usually self-limited and resolves within a few weeks of stopping darunavir. However, fatal instances have been reported, at least to the sponsor and monitoring of liver enzymes during therapy is recommended.
Finally, initiation of darunavir based highly active antiretroviral therapy can lead to exacerbation of an underlying chronic hepatitis B or C in coinfected individuals, typically arising 2 to 12 months after starting therapy and associated with a hepatocellular pattern of serum enzyme elevations and increases in serum levels of hepatitis B virus (HBV) DNA or hepatitis C virus (HCV) RNA. Darunavir therapy has not been clearly linked to lactic acidosis and acute fatty liver that is reported in association with several nucleoside analogue reverse transcriptase inhibitors.
Likelihood score: C (probable, rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of darunavir up to 800 mg daily with ritonavir produce low to unmeasurable levels in milk and would not be expected to cause any adverse effects in breastfed infants. The combination of darunavir and cobicistat is expected to produce similar results. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma alpha 1-acid glycoprotein (AAG).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal doses of darunavir up to 800 mg daily with ritonavir produce low to unmeasurable levels in milk and would not be expected to cause any adverse effects in breastfed infants. The combination of darunavir and cobicistat is expected to produce similar results. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials, with most events being mild to moderate in severity. At 48-week analyses, the most common adverse events associated with once- or twice-daily boosted darunavir in treatment-experienced or -naive patients were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. The most common boosted darunavir-related grade 2-4 laboratory abnormalities in treatment-experienced patients included increased triglycerides and increased total cholesterol. Overall, boosted darunavir was associated with less diarrhoea than CPIs or boosted lopinavir in treatment-experienced and -naive patients, and a lower incidence of grade 2-4 elevations in triglycerides and total cholesterol than boosted lopinavir in treatment-naive patients. Treatment discontinuation because of adverse events occurred in 3% of boosted darunavir recipients and 7% of boosted lopinavir recipients during 48 weeks of therapy in treatment-naive patients. PHARMACOECONOMIC CONSIDERATIONS: Healthcare costs in the UK and US were estimated to be lower with boosted darunavir than with investigator-selected CPIs in treatment-experienced patients with HIV-1 infection in two 1-year cost analyses conducted from the perspective of a healthcare provider and using predicted costs based on CD4+ cell counts and clinical data from the POWER studies. The higher acquisition cost of boosted darunavir compared with CPIs was more than offset by the better efficacy of darunavir. In modelled cost-effectiveness analyses, boosted darunavir was predicted to be cost effective compared with other boosted CPIs in heavily pretreated adults from a healthcare payer perspective in Europe and from a societal perspective in the US. In a further model of a subgroup of patients with at least one primary International AIDS Society-USA PI mutation, boosted darunavir was predicted to be cost effective compared with boosted lopinavir from a healthcare payer perspective in Europe. The incremental costs per quality-adjusted life-year gained were within commonly accepted thresholds in all cost-effectiveness analyses.[5]

[1]. Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem. 2005 Mar 24;48(6):1813-22.

[2]. Novel bis-tetrahydrofuranylurethane-containing nonpeptidic protease inhibitor (PI) UIC-94017 (TMC114) with potent activity against multi-PI-resistant human immunodeficiency virus in vitro. Antimicrob Agents Chemother. 2003 Oct;47(10):

[3]. Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice. Pharmaceutics . 2024 Apr 19;16(4):555.

[4]. High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. J Mol Biol. 2004 Apr 23;338(2):341-52.

[5]. Darunavir: a review of its use in the management of HIV infection in adults. Drugs. 2009;69(4):477-503.

[6]. In-vivo bioavailability and lymphatic uptake evaluation of lipid nanoparticulates of darunavir. Drug Deliv. 2016 Sep;23(7):2581-2586.

Darunavir (brand name: Prezista) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children. Darunavir is always used in combination with a pharmacokinetic enhancer — either ritonavir (brand name: Norvir) or cobicistat (brand name: Tybost) — and other HIV medicines.
When darunavir is taken with ritonavir, it may be used in adults and children 3 years of age and older who weigh at least 22 lb (10 kg).
When darunavir is taken with cobicistat, it may be used in adults and children weighing at least 88 lb (40 kg) who meet certain requirements, as determined by a health care provider.
(A fixed-dose combination tablet containing darunavir and cobicistat [brand name: Prezcobix] is also available.)
Darunavir Ethanolate is the ethanolate form of darunavir, a human immunodeficiency virus type 1 (HIV-1) protease nonpeptidic inhibitor, with activity against HIV. Upon oral administration, darunavir selectively targets and binds to the active site of HIV-1 protease, and inhibits the dimerization and catalytic activity of HIV-1 protease. This inhibits the proteolytic cleavage of viral Gag and Gag-Pol polyproteins in HIV-infected cells. This inhibition leads to the production of immature, non-infectious viral proteins that are unable to form mature virions, and prevents HIV replication.
An HIV PROTEASE INHIBITOR that is used in the treatment of AIDS and HIV INFECTIONS. Due to the emergence of ANTIVIRAL DRUG RESISTANCE when used alone, it is administered in combination with other ANTI-HIV AGENTS.
See also: Cobicistat; darunavir ethanolate (component of).

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Drug Indication
Rezolsta, is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus 1 (HIV 1) infection in adults aged 18 years or older. Genotypic testing should guide the use of Rezolsta.
PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight. PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg). In deciding to initiate treatment with PREZISTA co administered with cobicistat or low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA. PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection. PREZISTA 75 mg, 150 mg, and 600 mg tablets may be used to provide suitable dose regimens: For the treatment of HIV 1 infection in antiretroviral treatment (ART) experienced adult patients, including those that have been highly pre treated. For the treatment of HIV 1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight. In deciding to initiate treatment with PREZISTA co administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA. PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection. PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg). PREZISTA 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV 1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are: antiretroviral therapy (ART) naïve. ART experienced with no darunavir resistance associated mutations (DRV RAMs) and who have plasma HIV 1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L. In deciding to initiate treatment with PREZISTA in such ART experienced patients, genotypic testing should guide the use of PREZISTA.

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Darunavir is an N,N-disubstituted benzenesulfonamide bearing an unsubstituted amino group at the 4-position, used for the treatment of HIV infection. A second-generation HIV protease inhibitor, darunavir was designed to form robust interactions with the protease enzyme from many strains of HIV, including those from treatment-experienced patients with multiple resistance mutations to other protease inhibitors. It has a role as a HIV protease inhibitor and an antiviral drug. It is a furofuran, a carbamate ester and a sulfonamide.
Darunavir (brand name: Prezista) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children. Darunavir is always used in combination with a pharmacokinetic enhancer — either ritonavir (brand name: Norvir) or cobicistat (brand name: Tybost) — and other HIV medicines.
When darunavir is taken with ritonavir, it may be used in adults and children 3 years of age and older who weigh at least 22 lb (10 kg).
When darunavir is taken with cobicistat, it may be used in adults and children weighing at least 88 lb (40 kg) who meet certain requirements, as determined by a health care provider.
(A fixed-dose combination tablet containing darunavir and cobicistat [brand name: Prezcobix] is also available.)
Darunavir is a protease inhibitor used with other HIV protease inhibitor drugs as well as [ritonavir] for the effective management of HIV-1 infection. As a second-generation protease inhibitor, darunavir is designed to combat resistance to standard HIV therapy. It was initially approved by the FDA in 2006. Darunavir is being studied as a possible treatment for SARS-CoV-2, the coronavirus responsible for COVID-19, due to in vitro evidence supporting its ability to combat this infection. Clinical trials are underway and are expected to conclude in August 2020.
Darunavir is a Protease Inhibitor. The mechanism of action of darunavir is as a HIV Protease Inhibitor, and Cytochrome P450 3A Inhibitor, and Cytochrome P450 2D6 Inhibitor.
Darunavir is an antiretroviral protease inhibitor that is used in the therapy and prevention of human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS). Darunavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels and has been linked to rare instances of clinically apparent, acute liver injury. In HBV or HCV coinfected patients, highly active antiretroviral therapy with darunavir may result of an exacerbation of the underlying chronic hepatitis B or C.
Darunavir is a human immunodeficiency virus type 1 (HIV-1) protease nonpeptidic inhibitor, with activity against HIV. Upon oral administration, darunavir selectively targets and binds to the active site of HIV-1 protease, and inhibits the dimerization and catalytic activity of HIV-1 protease. This inhibits the proteolytic cleavage of viral Gag and Gag-Pol polyproteins in HIV-infected cells. This inhibition leads to the production of immature, non-infectious viral proteins that are unable to form mature virions, and prevents HIV replication.
An HIV PROTEASE INHIBITOR that is used in the treatment of AIDS and HIV INFECTIONS. Due to the emergence of ANTIVIRAL DRUG RESISTANCE when used alone, it is administered in combination with other ANTI-HIV AGENTS.

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Drug Indication
Darunavir, co-administered with ritonavir, and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) in children age 3 or above and adults with HIV-1 infection.
FDA Label
Darunavir, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection (see section 4. 2). Darunavir Mylan 75 mg, 150 mg, 300 mg and 600 mg tablets may be used to provide suitable dose regimens (see section 4. 2): For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated. For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight. In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir (see sections 4. 2, 4. 4 and 5. 1). Darunavir co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection.  Darunavir co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg) (see section 4. 2).  Darunavir Mylan 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are:  antiretroviral therapy (ART)-naïve (see section 4. 2).  ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 10⁶/L. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir (see sections 4. 2, 4. 3, 4. 4 and 5. 1).
400 and 800 mgDarunavir Krka, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection. Darunavir Krka 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are: antiretroviral therapy (ART)-naïve (see section 4. 2). ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir (see sections 4. 2, 4. 3, 4. 4 and 5. 1). 600 mg Darunavir Krka, co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection. Darunavir Krka 600 mg tablets may be used to provide suitable dose regimens (see section 4. 2): For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated. For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight. In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir.
PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adult and paediatric patients from the age of 3 years and at least 15 kg body weight. PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg). In deciding to initiate treatment with PREZISTA co administered with cobicistat or low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA. PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection. PREZISTA 75 mg, 150 mg, and 600 mg tablets may be used to provide suitable dose regimens: For the treatment of HIV 1 infection in antiretroviral treatment (ART) experienced adult patients, including those that have been highly pre treated. For the treatment of HIV 1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight. In deciding to initiate treatment with PREZISTA co administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of PREZISTA. PREZISTA, co administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV 1) infection. PREZISTA, co administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV 1) infection in adults and adolescents (aged 12 years and older, weighing at least 40 kg). PREZISTA 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV 1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are: antiretroviral therapy (ART) naïve. ART experienced with no darunavir resistance associated mutations (DRV RAMs) and who have plasma HIV 1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/L. In deciding to initiate treatment with PREZISTA in such ART experienced patients, genotypic testing should guide the use of PREZISTA.
400mg and 800 mg Film-coated TabletsDarunavir Krka d. d. , co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection. Darunavir Krka d. d. , co-administered with cobicistat is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection in adult patients (see section 4. 2). Darunavir Krka d. d. 400 mg and 800 mg tablets may be used to provide suitable dose regimens for the treatment of HIV-1 infection in adult and paediatric patients from the age of 3 years and at least 40 kg body weight who are: antiretroviral therapy (ART)-naïve (see section 4. 2). ART-experienced with no darunavir resistance associated mutations (DRV-RAMs) and who have plasma HIV-1 RNA < 100,000 copies/ml and CD4+ cell count ≥ 100 cells x 106/l. In deciding to initiate treatment with darunavir in such ART-experienced patients, genotypic testing should guide the use of darunavir (see sections 4. 2, 4. 3, 4. 4 and 5. 1). 600mg Film-coated TabletsDarunavir Krka d. d. , co-administered with low dose ritonavir is indicated in combination with other antiretroviral medicinal products for the treatment of patients with human immunodeficiency virus (HIV-1) infection. Darunavir Krka d. d. 600 mg tablets may be used to provide suitable dose regimens (see section 4. 2): For the treatment of HIV-1 infection in antiretroviral treatment (ART)-experienced adult patients, including those that have been highly pre-treated. For the treatment of HIV-1 infection in paediatric patients from the age of 3 years and at least 15 kg body weight. In deciding to initiate treatment with darunavir co-administered with low dose ritonavir, careful consideration should be given to the treatment history of the individual patient and the patterns of mutations associated with different agents. Genotypic or phenotypic testing (when available) and treatment history should guide the use of darunavir.
Treatment of human immunodeficiency virus (HIV-1) infection

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Mechanism of Action
The HIV-1 protease enzyme is necessary for viral precursor protein processing and viral maturation in preparation for infection, and is therefore a target for antiretroviral therapy for HIV. Protease inhibitors are used as a part of highly active antiretroviral therapy (HAART) in patients diagnosed with HIV infection. It has been shown to effectively suppress the virus, leading to significantly decreased morbidity and mortality rates. Darunavir, a HIV protease inhibitor, prevents HIV replication through binding to the enzyme, stopping the dimerization and the catalytic activity of HIV-1 protease. In particular, it inhibits the cleavage of HIV encoded Gag-Pol proteins in cells that have been infected with the virus, halting the formation of mature virus particles, which spread the infection. The close contact that darunavir makes with the primary chains of the active site amino acids (Asp-29 and Asp-30) on the protease likely contributes to its potency and efficacy against resistant variants of HIV-1. Darunavir is known to bind to different sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer. Darunavir can adapt to changes in the shape of a protease enzyme due to its molecular flexibility.
Darunavir as a protease inhibitor inhibits the cleavage of HIV encoded gag-pol polyproteins in virus infected cells, thereby preventing the formation of mature and infectious new virions. It was selected for its potency against wild type HIV-1 and HIV strains resistant to currently approved protease inhibitors.
Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

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The compound UIC-94017 (TMC-114) is a second-generation HIV protease inhibitor with improved pharmacokinetics that is chemically related to the clinical inhibitor amprenavir. UIC-94017 is a broad-spectrum potent inhibitor active against HIV-1 clinical isolates with minimal cytotoxicity. We have determined the high-resolution crystal structures of UIC-94017 in complexes with wild-type HIV-1 protease (PR) and mutant proteases PR(V82A) and PR(I84V) that are common in drug-resistant HIV. The structures were refined at resolutions of 1.10-1.53A. The crystal structures of PR and PR(I84V) with UIC-94017 ternary complexes show that the inhibitor binds to the protease in two overlapping positions, while the PR(V82A) complex had one ordered inhibitor. In all three structures, UIC-94017 forms hydrogen bonds with the conserved main-chain atoms of Asp29 and Asp30 of the protease. These interactions are proposed to be critical for the potency of this compound against HIV isolates that are resistant to multiple protease inhibitors. Other small differences were observed in the interactions of the mutants with UIC-94017 as compared to PR. PR(V82A) showed differences in the position of the main-chain atoms of residue 82 compared to PR structure that better accommodated the inhibitor. Finally, the 1.10A resolution structure of PR(V82A) with UIC-94017 showed an unusual distribution of electron density for the catalytic aspartate residues, which is discussed in relation to the reaction mechanism.[4]

C29H43N3O8S

593.73

593.277

C, 58.67; H, 7.30; N, 7.08; O, 21.56; S, 5.40

635728-49-3

Darunavir;206361-99-1

23725083

White to off-white solid powder

4.426

169.03

4

10

12

41

856

5

S(C1C([H])=C([H])C(=C([H])C=1[H])N([H])[H])(N(C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H])C([H])([H])[C@]([H])([C@]([H])(C([H])([H])C1C([H])=C([H])C([H])=C([H])C=1[H])N([H])C(=O)O[C@@]1([H])C([H])([H])O[C@]2([H])[C@@]1([H])C([H])([H])C([H])([H])O2)O[H])(=O)=O.O([H])C([H])([H])C([H])([H])[H]

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InChI=1S/C27H37N3O7S.C2H6O/c1-18(2)15-30(38(33,34)21-10-8-20(28)9-11-21)16-24(31)23(14-19-6-4-3-5-7-19)29-27(32)37-25-17-36-26-22(25)12-13-35-26;1-2-3/h3-11,18,22-26,31H,12-17,28H2,1-2H3,(H,29,32);3H,2H2,1H3/t22-,23-,24+,25-,26+;/m0./s1

[(3aS,4R,6aR)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-yl] N-[(2S,3R)-4-[(4-aminophenyl)sulfonyl-(2-methylpropyl)amino]-3-hydroxy-1-phenylbutan-2-yl]carbamate;ethanol

Darunavir Ethanolate; TMC-114 Ethanolate; TMC114 Ethanolate; TMC 114 Ethanolate; UIC-94017 Ethanolate; UIC 94017 Ethanolate; UIC94017 Ethanolate; Trade name: Prezista

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.21 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.21 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.21 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。