| Active Ingredient | DACLATASVIR DIHYDROCHLORIDE |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| DAKLINZA | (NDA) 206843 | BRISTOL-MYERS SQUIBB | TABLET;ORAL | EQ 30MG BASE, EQ 60MG BASE | EQ 60MG BASE | July 24, 2015 | July 24, 2020 | - | 1 New molecular entity (NME) | P Priority review drug | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | N,N′-[[1,1′-biphenyl]-4,4′-diylbis[1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]bis-, C,C′-dimethyl ester, hydrochloride (1:2) |
| CAS No | 1009119-64-5 |
| Molecular Formula | C40H50N8O6•2HCl |
| Molecular Weight | 738.88 (free base) |
| Appearance | white to yellow crystalline powder |
| Solubility | It is freely soluble in water, dimethyl sulfoxide, methanol; soluble in ethanol (95%); practically insoluble in dichloromethane, tetrahydrofuran, acetonitrile, acetone and ethyl acetate. |
| Water Solubility | (>700 mg/mL) |
| Polymorphism | Polymorphism has been observed for daclatasvir hydrochloride. Although two neat crystalline dihydrochloride salts, N1 and N-2 have been identified in screening studies, it has been confirmed that the form N-2 is the thermodynamically most stable polymorph and only this form produced by the proposed synthetic process. |
| pKa (Strongest Acidic) | 3.82 (Predicted) |
| pKa (Strongest Basic) | 6.09 (Predicted) |
| Log P | 4.74 (Predicted) |
| Identification | IR/Raman, HPLC |
| Degradation | The results from the forced degradation studies showed that daclatasvir hydrochloride is susceptible to degradation in solution at basic conditions and at high intensity UV and visible light. Minor degradation is observed under oxidative conditions. |
| Hygroscopic | non-hygroscopic |
| Photostability study | Photo sensitive |
| Melting Point | - |
| BCS Class | - |
| Manufacture of API | The synthesis of API involves an alkylation and formation of the imidazole ring, a coupling reaction and the formation of the hydrochloride salt. Daclatasvir is a chiral molecule with four stereocenters (1,1’, 2, 2;) in the S configuration. The synthetic strategy and process design such as starting material and reagent selection, process parameters, and in-process controls ensure the desired configuration at each of the four chiral centers. In addition, the established control strategy minimizes epimerization and eliminates other diastereomeric impurity formation in each step. |
| Parameters | Details |
|---|---|
| Indications and Usage | DAKLINZA is indicated for use with sofosbuvir for the treatment of patients with chronic hepatitis C virus (HCV) genotype 3. |
| Dosage and Administration | The recommended dosage of DAKLINZA is 60 mg, taken orally, once daily in combination with sofosbuvir for 12 weeks. DAKLINZA may be taken with or without food. |
| Mechanism of action | Daclatasvir is a direct-acting antiviral agent (DAA) against the hepatitis C virus. |
| Absorption |
The pharmacokinetic properties of daclatasvir were evaluated in healthy adult subjects and in subjects with chronic HCV. Administration of daclatasvir tablets in HCV-infected subjects resulted in approximately dose-proportional increases in Cmax, AUC, and Cmin up to 60 mg once daily. Steady state is anticipated after approximately 4 days of once-daily daclatasvir administration. Exposure of daclatasvir was similar between healthy and HCV-infected subjects. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%. In HCV-infected subjects following multiple oral doses of daclatasvir tablet ranging from 1 mg to 100 mg once daily, peak plasma concentrations occurred within 2 hours post dose. In vitro studies with human Caco-2 cells indicated that daclatasvir is a substrate of P-gp. The absolute bioavailability of the tablet formulation is 67%. |
| Food Effect | In healthy subjects, administration of a daclatasvir 60 mg tablet after a high-fat, high-caloric meal (approximately 951 total kcal, 492 kcal from fat, 312 kcal from carbohydrates, 144 kcal from protein) decreased daclatasvir Cmax and AUC(0-inf) by 28% and 23%, respectively, compared with fasted conditions. A food effect was not observed with administration of a daclatasvir 60 mg tablet after a low-fat, low-caloric meal (approximately 277 total kcal, 41 kcal from fat, 190 kcal from carbohydrates, 44 kcal from protein) compared with fasted conditions. |
| Distribution | With multiple dosing, protein binding of daclatasvir in HCV-infected subjects was approximately 99% and independent of dose at the dose range studied (1-100 mg). In subjects 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. |
| Metabolism | Daclatasvir is a substrate of CYP3A, with CYP3A4 being the primary CYP isoform responsible for metabolism. Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, the majority of radioactivity in plasma was predominately attributed to parent drug (97% or greater). |
| Elimination |
Following single-dose oral administration of 25 mg 14C-daclatasvir in healthy subjects, 88% of total radioactivity was recovered in feces (53% of the dose as unchanged daclatasvir) and 6.6% of the dose was excreted in the urine (primarily as unchanged daclatasvir). Following multipledose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg [13C,15N]-daclatasvir intravenous dose, the total clearance was 4.2 L/h. |
| Peak plasma time (Tmax) | 2 hours |
| Half life | 12 to 15 hours |
| Bioavailability | 67% |
| Age, gender |
Population pharmacokinetic analysis in HCV-infected subjects showed that within the age range (18-79 years) analyzed, age did not have a clinically relevant effect on the pharmacokinetics of daclatasvir. The pharmacokinetics of daclatasvir in pediatric patients has not been evaluated. Population pharmacokinetic analyses in HCV-infected subjects estimated that female subjects have a 30% higher daclatasvir AUC compared to male subjects. This difference in daclatasvir AUC is not considered clinically relevant. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| 30737 | A | II | August 11, 2016 | CIPLA LTD |
| 30975 | A | II | October 7, 2016 | HETERO LABS LTD |
| Parameters | Details | ||
|---|---|---|---|
| Strength | 30MG | 60MG | |
| Excipients used | anhydrous lactose (58 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and Opadry green | anhydrous lactose (116 mg), microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate, and Opadry green | |
| Composition of coating material | Opadry green contains hypromellose, titanium dioxide, polyethylene glycol 400, FD&C blue #2/indigo carmine aluminum lake, and yellow iron oxide | ||
| Composition of caspule shell | - | ||
| Pharmaceutical Development |
During the development the relevant physicochemical and biological properties of the drug substance (E.g. polymorphic form, particle size and impurity level) that could influence the performance of the drug product and its manufacturability were studied. A drug-excipient compatibility study showed that microcrystalline cellulose, anhydrous lactose, croscarmellose sodium, silicon dioxide, and magnesium stearate are compatible with the drug substance under dry conditions. 30MG daclatasvir equivalent to 33MG daclatasvir dihydrochloride and 60MG mg daclatasvir equivalent to 66MG daclatasvir dihydrochloride. |
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| Manufacture of the product |
The manufacturing process is a dry granulation process that is applicable to both tablets strengths and includes the following unit operations: pre-blending, roller compaction, final blending (lubrication), tablet compression, film coating and packaging. The process is considered to be a standard manufacturing process. |
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| Tablet / Capsule Image |
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| Appearance | green, biconvex, pentagonal, and debossed with “BMS” on one side and “213” on the other side | light green, biconvex, pentagonal, and debossed with “BMS” on one side and “215” on the other side | |
| Imprint code / Engraving / Debossment | debossed with “BMS” on one side and “213” on the other side | debossed with “BMS” on one side and “215” on the other side | |
| Score | no score | no score | |
| Color | Green | Light Green | |
| Shape | Pentagonal | Pentagonal | |
| Dimension | 7mm | 9mm | |
| Mfg by | Bristol-Myers Squibb Company (EU) | ||
| Mfg for | Bristol-Myers Squibb Company (US) | ||
| Marketed by | Bristol-Myers Squibb Company (EU) | ||
| Distributed by | - | ||
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N206843 | 1 | 8329159 | April 13, 2028 | Y | - | - | - | Download |
| N206843 | 1 | 8629171 | June 13, 2031 | Y | Y | U - 1724 | - | Download |
| N206843 | 1 | 8642025 | August 11, 2027 | Y | Y | U - 1725 | - | Download |
| N206843 | 1 | 8900566 | August 8, 2027 | - | - | U - 1725 | - | Download |
| N206843 | 1 | 9421192 | August 8, 2027 | DS | - | U-1724 U-1725 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II (Paddle) | 75 | Phosphate Buffer, pH 6.8 with 0.75% Brij 35 | 1000 | 10, 15, 20, 30 and 45 | March 17, 2016 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | Download |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | DAKLINZA | Download |
| UK | DAKLINZA | Download |
| US | DAKLINZA | Download |
| Exclusivity Code:Exclusivity Expiration; D-161:Feb 5, 2019; D-162:Feb 5, 2019; I-726:Feb 5, 2019; I-727: Feb 5, 2019 |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
