アムプレナビル 化学特性,用途語,生産方法
外観
白色～うすい褐色, 結晶性粉末～粉末
溶解性
エタノール及びアセトンに溶け、水にほとんど溶けない。
効能
抗ウイルス薬, HIVプロテアーゼ阻害薬
使用上の注意
不活性ガス封入
説明
Amprenavir was launched as Agenerase in the US for the treatment of
AIDS patients in combination with approved agent antiretroviral nucleoside
analogs. It is the fifth non-peptidic inhibitor of HIV-1 protease to be marketed in
this indication after the last approved Neflinavir. Amprenavir, designed via a
structure-based process, is the smallest molecule in the 《navir》 class and
exhibits a reduced peptidic character. An improved process for preparation
comprising four steps from a (1S, 2R)-2-hydroxy-3-aminopropylcarbamate has
been developed. Amprenavir is a potent inhibitor of HIV-1 aspartyl protease (Ki
= 0.6nM), an enzyme required by the virus to cleave pro-form polyproteins to
structural proteins during the last stage in the replication process. The
compound displays good oral bioavailability in humans and penetrates the CNS,
which is an important advantage in long-term treatment. Its plasma half-life is
approximately 10h. Treatment with Amprenavir in combination with nucleoside
analog reverse transcriptase inhibitors considerably decreases viral load and
restores CD4+ T-cell counts in patients with HIV infection.
化学的特性
Off-White to Pale Yellow
使用
A selective HIV protease inhibitor. An analogue of Ritonavir
適応症
Amprenavir (Agenerase) is administered twice daily,
providing the patient with an advantage over other protease
inhibitors that must be taken more frequently
(e.g., indinavir, saquinavir). Common side effects of am-prenavir include nausea, vomiting, diarrhea, and perioral
paraesthesias. Rash occurs in approximately 20 to
30% of patients and can be mild or severe (Stevens-
Johnson syndrome).
獲得抵抗性
Mutations at position 50, 76 and 84 of the protease enzyme
gene are associated with significantly reduced susceptibility.
一般的な説明
Amprenavir is a second-generation drug derived from hydroxyethylamine sulfonamide.
応用例（製薬）
A synthetic compound formulated as the calcium salt of the
oral prodrug fosamprenavir.
薬物動態学
Oral absorption: Not known/available
C
max 700 mg + ritonavir 100 mg:c. 6.08 mg/L
twice daily
C
min 700 mg + ritonavir 100 mg:c. 2.12 mg/L
twice daily
Plasma half-life: c. 7.7 h
Volume of distribution: c. 430 L
Plasma protein binding: c. 90%
Absorption
Fosamprenavir is rapidly and almost completely hydrolyzed to amprenavir and inorganic phosphate by cellular phosphatases in the gut epithelium as it is absorbed. Absolute bioavailability has not been established. It can be taken without regard to food.
Distribution
It penetrates moderately well into the CNS. The semen:plasma ratio is negligible. It is not known if it is distributed into breast milk.
Metabolism and excretion
It is extensively metabolized by the cytochrome P
450 (CYP) 3A4 enzyme system. Two major metabolites have been identified that appear to result from the oxidation of the tetrahydrofuran and aniline moieties. Around 14% of a dose is eliminated in the urine and 75% in feces, <3% as unchanged drug. Metabolites account for >90% of administered drug found in fecal samples. It should be used with caution and at reduced doses in adults with mild or moderate hepatic impairment; it is contraindicated in patients with severe hepatic impairment.
臨床応用
Treatment of HIV infection (in combination with other antiretroviral drugs)
副作用
The most common adverse events in patients receiving boosted
fosamprenavir were diarrhea, nausea, headache, fatigue,
vomiting
and rash. Ritonavir-boosted fosamprenavir is associated
with a dyslipidemia profile characteristic of those
treated with other protease inhibitors boosted with 200 mg
of ritonavir.
アムプレナビル 上流と下流の製品情報
原材料
準備製品