ダルナビル 化学特性,用途語,生産方法
効能
抗ウイルス薬, HIVプロテアーゼ阻害薬
説明
Darunavir is the latest weapon in the arsenal of agents to combat human
immunodeficiency virus type 1(HIV-1). As an HIV-1 protease inhibitor, its mechanism
of action involves blocking the cleavage of the gag and gag–pol polyproteins
into functional proteins essential for the production of infectious progeny
virus; the result is the production of immature, noninfectious viral particles.
Compared to predecessor HIV protease inhibitors, darunavir retains activity
against resistant stains, a critical factor with the continual emergence of multidrug-
resistant (MDR) mutants. Despite experiencing a 13-fold reduction in binding
to MDR HIV-1 protease, this binding is 1.5 orders of magnitude tighter than
the first-generation protease inhibitors. Furthermore, darunavir exhibits less than
a 10-fold decrease in susceptibility in cell culture against 90% of 3309 clinical
isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir,
ritonavir, saquinavir, and tipranavir. In contrast, darunavir-resistant viruses display
limited susceptibility to only tipranavir, suggesting limited cross-resistance
between these two protease inhibitors. To avoid the issues of the peptide-based
protease inhibitors, darunavir has evolved from a structure-based design effort to
minimize peptidic features and reduce molecular weight and complexity.
化学的特性
White Amorphous Solid
定義
ChEBI: 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.
獲得抵抗性
Darunavir is less affected than other protease inhibitors
by mutations to resistance, but subgroups with more than
10 cumulative mutations show a >10-fold (median value)
decrease in susceptibility. The major resistance mutations
occur at positions 50 (150V), 54 (I50M/L), 76 (L76V) and
84 (I84V) of the protease gene.
応用例（製薬）
A synthetic compound formulated as the ethanolate for oral
use in combination with ritonavir.
薬物動態学
Oral absorption: c. 82%
C
max 600 mg once daily + ritonavir 100
mg twice daily:
c. 6500 μg/L
C
min 600 mg oral + ritonavir
100 mg twice daily:
c. 3578 μg/L
Plasma half-life: c. 15 h
Volume of distribution: c. 131 L
Plasma protein binding: c. 95%
A single 600 mg dose given orally in combination with ritonavir
100 mg every 12 h increased the systemic exposure of
darunavir approximately 14-fold. The relative bioavailability
is 30% lower when administered with food in the presence of
low-dose ritonavir. Distribution into human CSF, semen or
breast milk has not yet been determined.
At least three oxidative metabolites, mediated predominantly
through CYP3A4, have been identified in humans;
all are at least 10-fold less active than the parent compound
against HIV. Around 80% and 14% of the dose is found in the
feces and urine, respectively. It should be used with caution
in mild–moderate hepatic impairment and avoided in patients
with more severe impairment.
臨床応用
Treatment of HIV infection (in combination with other antiretroviral drugs)
副作用
In phase III studies the most common adverse events were
diarrhea, nausea, headache and nasopharyngitis. Patients coinfected
with hepatitis B or C did not have a higher incidence
of adverse events.
ダルナビル 上流と下流の製品情報
原材料
準備製品