Chemical formula: C₄₀H₅₀N₈O₆ Molecular mass: 738.89 g/mol PubChem compound: 25154714
Daclatasvir is an inhibitor of nonstructural protein 5A (NS5A), a multifunctional protein that is an essential component of the HCV replication complex. Daclatasvir inhibits both viral RNA replication and virion assembly.
Daclatasvir is an inhibitor of HCV genotypes 1a and 1b replication in cell-based replicon assays with effective concentration (50% reduction, EC50) values of 0.003-0.050 and 0.001-0.009 nM, respectively, depending on the assay method. The daclatasvir EC50 values in the replicon system were 0.003-1.25 nM for genotypes 3a, 4a, 5a and 6a, and 0.034-19 nM for genotype 2a as well as 0.020 nM for infectious genotype 2a (JFH-1) virus.
Daclatasvir showed additive to synergistic interactions with interferon alfa, HCV nonstructural protein 3 (NS3) PIs, HCV nonstructural protein 5B (NS5B) non-nucleoside inhibitors, and HCV NS5B nucleoside analogues in combination studies using the cell-based HCV replicon system. No antagonism of antiviral activity was observed.
No clinically relevant antiviral activity was observed against a variety of RNA and DNA viruses, including HIV, confirming that daclatasvir, which inhibits a HCV-specific target, is highly selective for HCV.
Substitutions conferring daclatasvir resistance in genotypes 1-4 were observed in the N-terminal 100 amino acid region of NS5A in a cell-based replicon system. L31V and Y93H were frequently observed resistance substitutions in genotype 1b, while M28T, L31V/M, Q30E/H/R, and Y93C/H/N were frequently observed resistance substitutions in genotype 1a. These substitutions conferred low level resistance (EC50 <1 nM) for genotype 1b, and higher levels of resistance for genotype 1a (EC50 up to 350 nM). The most resistant variants with single amino acid substitution in genotype 2a and genotype 3a were F28S (EC50 >300 nM) and Y93H (EC50 >1,000 nM), respectively. In genotype 4, amino acid substitutions at 30 and 93 (EC50 <16 nM) were frequently selected.
HCV replicons expressing daclatasvir-associated resistance substitutions remained fully sensitive to interferon alfa and other anti-HCV agents with different mechanisms of action, such as NS3 protease and NS5B polymerase (nucleoside and non-nucleoside) inhibitors.
The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in patients with chronic HCV. Following multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin in treatment-naïve patients with genotype 1 chronic HCV, the geometric mean (CV%) daclatasvir Cmax was 1534 (58) ng/ml, AUC0-24h was 14122 (70) ng•h/ml, and Cmin was 232 (83) ng/ml. n Absorption Daclatasvir administered as
Daclatasvir administered as a tablet was readily absorbed following multiple oral doses with peak plasma concentrations occurring between 1 and 2 hours.
Daclatasvir Cmax, AUC, and Cmin increased in a near dose-proportional manner. Steady state was achieved after 4 days of once-daily administration. At the 60 mg dose, exposure to daclatasvir was similar between healthy subjects and HCV-infected patients. In vitro and in vivo studies showed that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%.
In healthy subjects, administration of daclatasvir 60 mg tablet after a high-fat meal decreased daclatasvir Cmax and AUC by 28% and 23%, respectively, compared with administration under fasting conditions. Administration of daclatasvir 60 mg tablet after a light meal resulted in no reduction in daclatasvir exposure.
At steady state, protein binding of daclatasvir in HCV-infected patients was approximately 99% and independent of dose at the dose range studied (1 mg to 100 mg). In patients who received daclatasvir 60 mg tablet orally followed by 100 μg [13C, 15N]-daclatasvir intravenous dose, estimated volume of distribution at steady state was 47 l. In vitro studies indicate that daclatasvir is actively and passively transported into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters, but not by organic anion transporter (OAT) 2, sodium-taurocholate cotransporting polypeptide (NTCP), or OATPs.
Daclatasvir is an inhibitor of P-gp, OATP 1B1 and BCRP. In vitro daclatasvir is an inhibitor of renal uptake transporters, OAT1 and 3, and OCT2, but is not expected to have a clinical effect on the pharmacokinetics of substrates of these transporters.
In vitro and in vivo studies demonstrate that daclatasvir is a substrate of CYP3A, with CYP3A4 being the major CYP isoform responsible for the metabolism. No metabolites circulated at levels more than 5% of the parent concentration. Daclatasvir in vitro did not inhibit (IC50>40 μM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.
Following single-dose oral administration of 14C–daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% as unchanged drug) and 6.6% was excreted in the urine (primarily as unchanged drug). These data indicate that the liver is the major clearance organ for daclatasvir in humans. In vitro studies indicate that daclatasvir is actively and passively transported into hepatocytes. The active transport is mediated by OCT1 and other unidentified uptake transporters. Following multiple-dose administration of daclatasvir in HCV-infected patients, the terminal elimination half-life of daclatasvir ranged from 12 to 15 hours. In patients who received daclatasvir 60 mg tablet orally followed by 100 μg [13C, 15N]-daclatasvir intravenous dose, the total clearance was 4.24 l/h.
The pharmacokinetics of daclatasvir following a single 60 mg oral dose were studied in non-HCV infected subjects with renal impairment. Daclatasvir unbound AUC was estimated to be 18%, 39% and 51% higher for subjects with creatinine clearance (CLcr) values of 60, 30 and 15 ml/min, respectively, relative to subjects with normal renal function. Subjects with end-stage renal disease requiring haemodialysis had a 27% increase in daclatasvir AUC and a 20% increase in unbound AUC compared to subjects with normal renal function (see section 4.2). n
The pharmacokinetics of daclatasvir following a single 30 mg oral dose were studied in non-HCV infected subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment compared with unimpaired subjects. The C max and AUC of total daclatasvir (free and protein-bound drug) were lower in subjects with hepatic impairment; however, hepatic impairment did not have a clinically significant effect on the free drug concentrations of daclatasvir (see section 4.2).
Population pharmacokinetic analysis of data from clinical studies indicated that age had no apparent effect on the pharmacokinetics of daclatasvir.
The pharmacokinetics of daclatasvir in paediatric patients have not been evaluated.
Population pharmacokinetic analysis identified gender as a statistically significant covariate on daclatasvir apparent oral clearance (CL/F) with female subjects having slightly lower CL/F, but the magnitude of the effect on daclatasvir exposure is not clinically important.
Population pharmacokinetic analysis of data from clinical studies identified race (categories “other” [patients who are not white, black or Asian] and “black”) as a statistically significant covariate on daclatasvir apparent oral clearance (CL/F) and apparent volume of distribution (Vc/F) resulting in slightly higher exposures compared to white patients, but the magnitude of the effect on daclatasvir exposure is not clinically important.
In repeat-dose toxicology studies in animals, hepatic effects (Kupffer-cell hypertrophy/ hyperplasia, mononuclear cell infiltrates and bile duct hyperplasia) and adrenal gland effects (changes in cytoplasmic vacuolation and adrenal cortical hypertrophy/hyperplasia) were observed at exposures similar or slightly higher than the clinical AUC exposure. In dogs, bone marrow hypocellularity with correlating clinical pathology changes were observed at exposures 9-fold the clinical AUC exposure. None of these effects have been observed in humans.
Daclatasvir was not carcinogenic in mice or in rats at exposures 8-fold or 4-fold, respectively, the clinical AUC exposure. No evidence of mutagenic or clastogenic activity was observed in in vitro mutagenesis (Ames) tests, mammalian mutation assays in Chinese hamster ovary cells, or in an in vivo oral micronucleus study in rats.
Daclatasvir had no effects on fertility in female rats at any dose tested. The highest AUC value in unaffected females was 18-fold the clinical AUC exposure. In male rats, effects on reproductive endpoints were limited to reduced prostate/seminal vesicle weights, and minimally increased dysmorphic sperm at 200 mg/kg/day; however, neither finding adversely affected fertility or the number of viable conceptuses sired. The AUC associated with this dose in males is 19-fold the clinical AUC exposure.
Daclatasvir is embryotoxic and teratogenic in rats and rabbits at exposures at or above 4-fold (rat) and 16-fold (rabbit) the clinical AUC exposure. Developmental toxicity consisted of increased embryofoetal lethality, reduced foetal body weights and increased incidence of foetal malformations and variations. In rats, malformations mainly affected the brain, skull, eyes, ears, nose, lip, palate or limbs and in rabbits, the ribs and cardiovascular area. Maternal toxicity including mortality, abortions, adverse clinical signs, decreases in body weight and food consumption was noted in both species at exposures 25-fold (rat) and 72-fold (rabbit) the clinical AUC exposure.
In a study of pre- and postnatal development in rats, there was neither maternal nor developmental toxicity at doses up to 50 mg/kg/day, associated with AUC values 2-fold the clinical AUC exposure. At the highest dose (100 mg/kg/day), maternal toxicity included mortality and dystocia; developmental toxicity included slight reductions in offspring viability in the peri- and neonatal periods; and reductions in birth weight that persisted into adulthood. The AUC value associated with this dose is 4-fold the clinical AUC exposure.
Daclatasvir was excreted into the milk of lactating rats with concentrations 1.7- to 2-fold maternal plasma levels.
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