インジナビル 化学特性,用途語,生産方法
説明
Crixivan was launched in Australia, Switzerland, the UK and the US
as an orally-bioavailable HIV-1 protease inhibitor. The compound can be prepared by
coupling an optically active piperazine derivative with an epoxide derivative (now
commercially available). The synthesis of the proteins, reverse transcriptase,
integrase, structural proteins and a protease, required by the virus to complete its
lifecycle, can be interupted if the protease enzyme is not capable of cleaving a proform
polypeptide chain into these components. lndinavir inhibits this process and is
more potent than the first approved protease inhibitor saquinavir. This effect was
noted by the increase in CD4
+ cells and a decrease in HIV RNA levels. Since
indinavir is metabolized by the CYP3A4 isozyme, care must be taken with patients
with hepatic insufficiency and to sex-related differences in the level of this enzyme.
Other than nephrolithiasis (5%), indinavir is relatively safe and well tolerated.
適応症
Indinavir (Crixivan) is a potent inhibitor of HIV reverse
transcriptase. It produces the side effects common
to all protease inhibitors and also may produce
nephrolithiasis, urolithiasis, and possibly renal insufficiency
or renal failure. This problem occurs more frequently
in children (approximately 30%) than adults
(approximately 10%) and can be minimized by drinking
at least 1.5 L of water daily. Additional side effects include
asymptomatic hyperbilirubinemia, alopecia, ingrown
toenails, and paronychia. Hemolytic anemia
rarely occurs. Rifampin should not be given with indinavir.
獲得抵抗性
The major mutations in the protease enzyme associated with
loss of the antiretroviral activity occur at positions 46, 82 and
84. Generally, the level of resistance rises with the number of
point mutations.
一般的な説明
When administered with a high-fat diet, indinavir(Crixivan) achieves a maximum serum concentration of77% of the administered dose. The drug is 60% bound inthe plasma. It is extensively metabolized by CYP3A4, andseven metabolites have been identified. Oral bioavailabilityis good, with a t
max of 0.8±0.3 hour. The half-life ofelimination is 1.8 hour, and the elimination products aredetectable in feces and urine. Indinavir also causes dyslipidemia.The available dosage forms are capsules of 200 mg,333 mg, and 400 mg.
応用例（製薬）
A synthetic compound formulated as the sulfate for oral
administration.
薬物動態学
Oral absorption: c. 65%v
C
max 800 mg thrice daily: c. 8.97 mg/L
C
min 800 mg thrice daily: c. 0.15 mg/L
Plasma half-life: c. 2 h
Volume of distribution: c. 0.4–1.74 L/kg
Plasma protein binding: c. 60%
Absorption and distribution
It is rapidly absorbed and not significantly affected by intake with food. Distribution in the body has not been fully characterized. It penetrates well into the CNS. The semen:plasma ratio is 1.9. It is distributed into breast milk.
Metabolism and excretion
Seven major metabolites have been described, including a glucuronide conjugate and six oxidative metabolites. Around 83% of the dose is recovered in feces and 18% in urine, 10% as unchanged drug. The effect of renal impairment has not been studied. It should be used with caution in the presence of hepatic impairment, particularly if severe.
臨床応用
Treatment of adult HIV infection (in combination with other antiretroviral
drugs)
副作用
The principal side effect is nephrolithiasis, including flank pain
with or without hematuria. There is good evidence that indinavir
directly causes nephrolithiasis as a result of crystallization
in the urinary tract. Indirect hyperbilirubinemia occurs in
about 10% of patients associated with inhibition of bilirubinconjugating
activity occurring as a result of competitive inhibition
of uridine diphosphate (UDP)-glucuronosyltransferase.
Ritonavir-boosted indinavir is associated with a dyslipidemia
profile characteristic of those treated with other
protease
inhibitors boosted with a 200 mg dose of ritonavir
per day. Insulin resistance and hyperglycemia have also been
associated with ritonavir-boosted indinavir.
代謝
The usual oral dose for indinavir alone or in combination with other antiviral agents is one 800 mg capsule every 8 hours. The drug is well absorbed if given on an empty stomach or 1 hour before or 2 hours after a light meal with water. The dose is reduced to 600 mg every 8 hours if given concurrently with ketoconazole. Indinavir activity is increased when combined with RT inhibitors.
インジナビル 上流と下流の製品情報
原材料
準備製品