Fosamprenavir (Amprenavir phosphate)
(Synonyms: 福沙那韦; Amprenavir phosphate; GW 433908) 目录号 : GC32362
Fosamprenavir (Amprenavir phosphate) (Amprenavir phosphate；GW 433908) 是抗逆转录病毒蛋白酶抑制剂 Amprenavir 的磷酸酯前药，具有改善的溶解度。
Cas No.:226700-79-4
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Fosamprenavir (Amprenavir phosphate;GW 433908) is a phosphate ester prodrug of the antiretroviral protease inhibitor Amprenavir, with improved solubility[1]. Anti-HIV infection[1].
[1]. Falcoz C, et al. Pharmacokinetics of GW433908, a prodrug of amprenavir, in healthy male volunteers. J Clin Pharmacol. 2002 Aug;42(8):887-98.
| Cas No. | 226700-79-4 | SDF | |
| 别名 | 福沙那韦; Amprenavir phosphate; GW 433908 | ||
| Canonical SMILES | O=C(O[C@@H]1COCC1)N[C@@H](CC2=CC=CC=C2)[C@H](OP(O)(O)=O)CN(S(=O)(C3=CC=C(N)C=C3)=O)CC(C)C | ||
| 分子式 | C25H36N3O9PS | 分子量 | 585.61 |
| 溶解度 | DMSO : ≥ 100 mg/mL (170.76 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7076 mL | 8.5381 mL | 17.0762 mL |
| 5 mM | 0.3415 mL | 1.7076 mL | 3.4152 mL |
| 10 mM | 0.1708 mL | 0.8538 mL | 1.7076 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Fosamprenavir : clinical pharmacokinetics and drug interactions of the amprenavir prodrug
Clin Pharmacokinet 2006;45(2):137-68.PMID:16485915DOI:10.2165/00003088-200645020-00002.
Fosamprenavir is one of the most recently approved HIV-1 protease inhibitors (PIs) and offers reductions in pill number and pill size, and omits the need for food and fluid requirements associated with the earlier-approved HIV-1 PIs. Three Fosamprenavir dosage regimens are approved by the US FDA for the treatment of HIV-1 PI-naive patients, including Fosamprenavir 1,400 mg twice daily, Fosamprenavir 1,400 mg once daily plus ritonavir 200mg once daily, and Fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily. Coadministration of Fosamprenavir with ritonavir significantly increases plasma amprenavir exposure. The Fosamprenavir 700 mg twice daily plus ritonavir 100mg twice daily regimen maintains the highest plasma amprenavir concentrations throughout the dosing interval; this is the only approved regimen for the treatment of HIV-1 PI-experienced patients and is the only regimen approved in the European Union. Fosamprenavir is the phosphate ester prodrug of the HIV-1 PI amprenavir, and is rapidly and extensively converted to amprenavir after oral administration. Plasma amprenavir concentrations are quantifiable within 15 minutes of dosing and peak at 1.5-2 hours after Fosamprenavir dosing. Food does not affect the absorption of amprenavir following administration of the Fosamprenavir tablet formulation; therefore, Fosamprenavir tablets may be administered without regard to food intake. Amprenavir has a large volume of distribution, is 90% bound to plasma proteins and is a substrate of P-glycoprotein. With <1% of a dose excreted in urine, the renal route is not an important elimination pathway, while the principal route of amprenavir elimination is hepatic metabolism by cytochrome P450 (CYP) 3A4. Amprenavir is also an inhibitor and inducer of CYP3A4. Furthermore, Fosamprenavir is commonly administered in combination with low-dose ritonavir, which is also extensively metabolised by CYP3A4, and is a more potent CYP3A4 inhibitor than amprenavir. This potent CYP3A4 inhibition contraindicates the coadministration of certain CYP3A4 substrates and requires others to be co-administered with caution. However, Fosamprenavir can be co-administered with many other antiretroviral agents, including drugs of the nucleoside/nucleotide reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor and HIV entry inhibitor classes. Coadministration with other HIV-1 PIs continues to be studied.The extensive Fosamprenavir and amprenavir clinical drug interaction information provides guidance on how to co-administer Fosamprenavir and Fosamprenavir plus ritonavir with many other commonly co-prescribed medications, such as gastric acid suppressants, HMG-CoA reductase inhibitors, antibacterials and antifungal agents.
In vitro behavior of a phosphate ester prodrug of amprenavir in human intestinal fluids and in the Caco-2 system: illustration of intraluminal supersaturation
Int J Pharm 2007 May 24;336(2):302-9.PMID:17207947DOI:10.1016/j.ijpharm.2006.12.011.
As a result of their improved aqueous solubility, the development of phosphate ester prodrugs is an interesting approach to increase intestinal absorption of poorly water-soluble drugs. Absorption of a drug from its phosphate ester prodrug is based on intestinal dephosphorylation of the prodrug which may result in intraluminal supersaturation of the parent drug, followed by an increased absorptive flux across the intestinal mucosa. In this study, we evaluated the behavior of Fosamprenavir, a phosphate ester prodrug of amprenavir, in the Caco-2 system and in aspirated human intestinal fluids (HIF), both showing phosphatase activity. Starting from a solution of Fosamprenavir in HIF, a supersaturated solution of amprenavir was generated and maintained during a time period sufficient for absorption. Moreover, supersaturation of amprenavir resulted in an enhanced flux across Caco-2 monolayers. To our knowledge, this is the first illustration of supersaturation in real intestinal media. Next, we showed an inhibitory effect of inorganic phosphate on the dephosphorylation of Fosamprenavir, both in the Caco-2 model and in HIF. As a consequence, phosphate-buffered media, including fasted state simulated intestinal fluid (FaSSIF), are incompatible with the study of phosphate ester prodrugs and should be replaced with media containing a biorelevant phosphate concentration (0.4-1 mM) and another buffering compound such as 2-morpholinoethanesulfonic acid (MES).
Population pharmacokinetic modeling and simulation of amprenavir following Fosamprenavir/ritonavir administration for dose optimization in HIV infected pediatric patients
J Clin Pharmacol 2014 Feb;54(2):206-14.PMID:25272370DOI:10.1002/jcph.205.
Fosamprenavir (FPV) is the phosphate ester prodrug of the HIV-1 protease inhibitor amprenavir (APV). A pediatric population pharmacokinetic model for APV was developed and simulation was used to identify dosing regimens for pediatric patients receiving FPV in combination with ritonavir (RTV) which resulted in concentrations similar to those in adults receiving FPV/RTV 700/100 mg BID. Pharmacokinetic data was obtained from HIV infected subjects aged 2 months to 18 years receiving either FPV or FPV/RTV. A two-compartment model with first order absorption and elimination was an appropriate structural model. Significant covariates in the model included RTV coadministration on clearance, fed status on bioavailability for the oral suspension, body weight on clearance and volume terms, black race on clearance, and age on clearance. The following FPV/RTV twice daily dosing regimens in pediatric patients delivered plasma APV exposure similar to adults: 45/7 mg/kg in patients weighing <11 kg, 30/3 mg/kg in patients weighing 11 to <15 kg, 23/3 mg/kg in patients weighing 15 to <20 kg, and 18/3 mg/kg in patients weighting 鈮?0 kg. Additionally children weighing 鈮?9 kg can receive the adult regimen.
Prodrugs of HIV protease inhibitors
Curr Pharm Des 2003;9(22):1755-70.PMID:12871195DOI:10.2174/1381612033454441.
Despite the efficiency of the present polytherapies against AIDS, HIV replication continues indicating difficulties in drug adherence, drug-drug interactions, resistance issues, and the existence of reservoirs or sanctuaries for the virus. Moreover, most of the current FDA-approved HIV protease inhibitors (PIs) display disadvantageous physicochemical and pharmacological properties such as low water solubility, low oral bioavailability and/or low level of penetration into the HIV sanctuaries resulting from their in vivo binding to the plasma proteins and to the Multi-Drug-Resistant P-glycoprotein, their rapid metabolization and inactivation by the liver cytochrome P450 enzymes. To overcome these suboptimal pharmacokinetics, high daily doses must be ingested, which complicate patient adherence to the prescribed regimen and contribute to the appearance of serious long-term metabolic complications and to the decrease of the viral treatment outcome. Another attractive alternative aimed at improving the safety, pharmacokinetics, and therapeutic potency of the current PIs is to modify these PIs into pharmacologically inactive prodrugs which are converted in vivo into their parent active drug. The present review is dedicated to the different prodrug approaches, including the "lipophilic", "hydrophilic", "active transport" and "double-drug" prodrug strategies, which have been applied more particularly to the current HIV PIs used in clinic. Among the strategies explored up to now, the most successful one was the "hydrophilic" prodrug approach which has led to the discovery of Fosamprenavir, a phosphate ester prodrug of amprenavir, which has reached phase III clinical trials. This success gives strong support for the search of PI prodrugs as a therapeutic alternative in addition to the development of new and well-tolerated PIs.
Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of Fosamprenavir in the fasted and fed state
Pharm Res 2007 Oct;24(10):1862-9.PMID:17443397DOI:10.1007/s11095-007-9307-3.
Purpose: The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. Methods: A single tablet of Fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. Results: The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of Fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of Fosamprenavir in the stomach. In the fasted state, gastric dissolution of Fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the Fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. Conclusion: For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of Fosamprenavir.