다루나비르

그림문자(GHS)

• 그림문자(GHS)

  

• 신호 어

  Warning

• 유해·위험 문구

  H302：삼키면 유해함

  H315：피부에 자극을 일으킴

  H319：눈에 심한 자극을 일으킴

  H335：호흡 자극성을 일으킬 수 있음

• 예방조치문구

  P261：분진·흄·가스·미스트·증기·...·스프레이의 흡입을 피하시오.

  P305+P351+P338：눈에 묻으면 몇 분간 물로 조심해서 씻으시오. 가능하면 콘택트렌즈를 제거하시오. 계속 씻으시오.

다루나비르 화학적 특성, 용도, 생산

• 개요

  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.

• 화학적 성질

  White Amorphous Solid

• 정의

  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.

• 원료

  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.

• Pharmaceutical Applications

  A synthetic compound formulated as the ethanolate for oral use in combination with ritonavir.

• Pharmacokinetics

  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.

• Clinical Use

  Treatment of HIV infection (in combination with other antiretroviral drugs)

• 부작용

  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.

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