Ledipasvir is an inhibitor of the hepatitis C virus NS5A, with EC₅₀ values of 34 pM against GT1a and 4 pM against GT1b replicon.

EC50: 34 pM (GT1a), 4 pM (GT1b)^[1]

Ledipasvir has GT1a and 1b EC₅₀ values of 31 and 4 pM, respectively, and protein-adjusted EC₅₀ values of 210 pM (GT1a) and 27 pM (GT1b) and the intrinsic EC₅₀ of 39 is 310 fM for GT1a and 40 fM for GT1b. Ledipasvir is highly protein-bound both in human serum and in the cell-culture medium (containing 10% BSA) of the replicon assay^[1]. Ledipasvir exhibits an EC₅₀ value of 141 nM against the JFH/3a-NS5A replicon^[2].

Ledipasvir is remarkable not only on the basis of its high replicon potency but also on the basis of its low clearance, good bioavailability, and long half-lives in rat, dog, and monkey and low predicted clearance in human. The pharmacokinetics of Ledipasvir is measured in rats and dogs. Ledipasvir shows good half-lives (rat 1.83 ± 0.22 hr, dog 2.63 ± 0.18 hr) in plasma, low systemic clearance (CL), and moderate volumes of distribution (Vss) that are greater than total body water volume^[1].

• [1]. Link JO, et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):2033-46.

  [2]. Hernandez D, et al. Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013 May;57(1):13-8.

Intravenous (IV) administration is dosed via infusion over 30 min in a vehicle containing 5% ethanol, 20% PEG400, and 75% water (pH adjusted to 3.0 with HCl) ^[1].
Oral dosing is administered by gavage in a vehicle containing 5% ethanol, 45% PEG 400, and 50% of 50 mM citrate buffer, pH 3 ^[1].

Rat, Dog and Monkey^[1]
Pharmacokinetic studies are performed in male naı̈ve Sprague-Dawley(SD) rats, non-naı̈ve beagle dogs, and cynomolgus monkeys (three animals per dosing route). Intravenous (IV) administration is dosed via infusion over 30 min in a vehicle containing 5% ethanol, 20% PEG400, and 75% water (pH adjusted to 3.0 with HCl). Oral dosing is administered by gavage in a vehicle containing 5% ethanol, 45% PEG 400, and 50% of 50 mM citrate buffer, pH 3. Blood samples are collected over a 24 h period postdose into Vacutainer tubes containing EDTA-K2. Plasma was isolated, and the concentration of the test compound in plasma was determined with LC/MS/MS after protein precipitation with acetonitrile. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Link JO, et al. Discovery of ledipasvir (GS-5885): a potent, once-daily oral NS5A inhibitor for the treatment of hepatitis C virus infection. J Med Chem. 2014 Mar 13;57(5):2033-46.

  [2]. Hernandez D, et al. Natural prevalence of NS5A polymorphisms in subjects infected with hepatitis C virus genotype 3 and their effects on the antiviral activity of NS5A inhibitors. J Clin Virol. 2013 May;57(1):13-8.

889.0

C₄₉H₅₄F₂N₈O₆

1256388-51-8

Room temperature in continental US; may vary elsewhere

10 mM in DMSO

* "<1 mg/ml"="" means="" slightly="" soluble="" or="" insoluble.="" "≥"="" means="" soluble,="" but="" saturation="">