Daclatasvir
Daklinza®, BMS-790052
Daclatasvir is a highly potent and selective direct-acting antiviral (DAA) that targets the hepatitis C virus. It interferes with viral replication by inhibiting nonstructural protein 5A (NS5A), leading to suppression of RNA synthesis, virion assembly and secretion.
Daclatasvir is active against HCV genotypes 1a, 1b, 2 and 3. It is also expected to be efficacious in patients with genotype 4 infection (based on extrapolations from studies with daclatasvir in combination with peginterferon and ribavirin). Daclatasvir has not been clinically studied in patients with HCV genotypes 5 and 6. In combination studies using cell-based HCV replicon system, daclatasvir demonstrated additive to synergistic effects with interferon alfa and various anti-HCV agents, including nonstructural protein 3 (NS3) protease inhibitors, as well as nonstructural protein 5B (NS5B) nucleoside and non-nucleoside inhibitors.
Daclatasvir is approved Canada for use as combination therarpy with other agents for the treatment of chronic hepatitis C in adults with HCV genotypes 1, 2, or 3* and compensated liver disease, including cirrhosis. Note that use in patients with HCV genotype 3 infections has been issued marketing authorization with conditions, pending the results of a trial to confirm its clinical benefit.
30 mg film-coated tablets, DIN 02444747
60 mg film-coated tablets, DIN 02444755
Manufacturer recommends not chewing or crushing the tablet as it has a very unpleasant taste. 2450
The usual dose of daclatasvir is 60 mg once daily with or without meals. Monotherapy with daclatasvir is not recommended.
Indication:
Treatment of chronic hepatitis C virus (HCV) infection in adults with HCV genotypes 1, 2, or 3* and compensate liver disease, including cirrhosis, in combination with other agents (as below).
Note 1: The safety and efficacy of daclatasvir have not been established for the following patient populations:
Note 2: Use of daclatasvir in patients with HCV genotype 3 infections has been issued marketing authorization with conditions, pending the results of a trial to confirm its clinical benefit.
HCV Genotype | Regimen | Duration |
Genotype 1 | ||
Treatment-naïve (a) or treatment-experienced (b) without cirrhosis | Daclatasvir + sofosbuvir | 12 weeks (e) |
Treatment-naïve or treatment-experienced with compensated cirrhosis (g) | 24 weeks (f) | |
Genotype 2 | ||
Treatment-naïve with or without compensated cirrhosis (d) | Daclatasvir + sofosbuvir | 24 weeks |
Treatment-experienced (c) without cirrhosis (d) | 24 weeks | |
Genotype 3 | ||
Treatment-naïve or treatment-experienced (c) without cirrhosis | Daclatasvir + sofosbuvir | 12 weeks |
Treatment-naïve or treatment-experienced (c) with compensated cirrhosis (d) | Daclatasvir + sofosbuvir | 24 weeks |
Genotype 4 (use is based on extrapolation from genotype 1 studies, per manufacturer) | ||
Without cirrhosis | Daclatasvir + sofosbuvir | 12 weeks (e) |
Compensated cirrhosis (d) | 24 weeks (f) | |
| Daclatasvir + peginterferon + ribavirin (weight-based) | 24 weeks of daclatasvir in combination w/ 24-48 weeks of peginterferon alfa and ribavirin (g) |
a. No prior exposure to any interferon, ribavirin, or other HCV-specific direct-acting antiviral agent. b. Prior null or partial response to an interferon- or protease inhibitor-based treatment. c. For the treatment of HCV genotype 2 and 3 infections, daclatasvir-sofosbuvir combination has only been studied in treatment-naïve patients with a treatment duration of 24 weeks. Clinical trial experience has been extrapolated to treatment-experienced patients. d. The addition of ribavirin to daclatasvir-sofosbuvir can be considered in patients with compensated cirrhosis. e. In patients with prior treatment (including NS3/4A inhibitor), consider treatment duration of 24 weeks f. In treatment-naïve patients with cirrhosis and positive prognostic factors (i.e., IL28B CC genotype, low baseline viral load), can consider treatment duration of 12 weeks g. Per SPC: · If the patient has HCV RNA undetectable at both treatment weeks 4 and 12, all 3 components of the regimen should be continued for a total duration of 24 weeks. · If the patient achieves HCV RNA undetectable, but not at both treatment weeks 4 and 12, daclatasvir should be discontinued at 24 weeks and peginterferon alfa and ribavirin continued for a total duration of 48 weeks. · Refer to Summary of Product Characteristics regarding virologic treatment stopping rules. |
Dose Adjustment and Treatment Interruptions
Discontinuation
Dosage Adjustments when use with concomitant agents
Missed Doses
If the missed dose is remembered MORE than 20 hours after the scheduled dose, the dose should be skipped and the next dose should be taken at the appropriate time
No data are currently available on pediatric dosing. Pediatric studies to investigate the safety and efficacy of daclatasvir in children and adolescents aged below 18 years are planned.
Similar safety and effectiveness of daclatasvir were observed in patients. No dose adjustment of daclatasvir is required for elderly patients.2638
The pharmacokinetics of single dose daclatasvir 60 mg were assessed in 12 HCV-negative subjects with end-stage renal disease (eGFR < 15 mL/min/1.73 m2) and in 12 subjects with normal renal function. The total and unbound AUC of daclatasvir were increased 1.8- and 1.5-fold, respectively in subjects with severe renal impairment compared to subjects with normal renal function. The increase in daclatasvir exposure was within exposures observed in population PK. A correlation between higher exposures and adverse events has not been shown.2403
Dose adjustment of daclatasvir in renal impairment is not required.2638
Dialysis: There are no dosage adjustments provided in the manufacturer’s labeling. However, owing to its large molecular weight (>exceeding 500g/mole) and high plasma binding, dialysis is unlikely to significantly reduce daclatasvir plasma concentrations.
In an open-label, parallel-group study of daclatasvir in subjects without active HCV with mild, moderate, or severe hepatic impairment (Child Pugh A, B, C, respectively), total daclatasvir drug exposures were lower versus healthy controls. Total daclatasvir exposures were similar to those observed in HCV-infected subjects in a previous study. Subjects with moderate or severe hepatic impairment and HCV-infected patients demonstrated a higher unbound fraction compared to healthy controls; thus, active unbound daclatasvir exposures were similar to controls. Daclatasvir dose adjustments are not required in hepatic failure.2318
Child-Pugh class A (mild impairment), B (moderate), or C (severe): No dosage adjustment is necessary.2638
Decompensated cirrhosis: The safety and efficacy of daclatasvir have not been established in patients with decompensated cirrhosis.2638
Daclatasvir can be taken without regards to meals. The table below summarizes the effect of food on exposure (relative to fasting state) in healthy subjects following administration of daclatasvir 60 mg tablet.
Condition | Effect on Cmax | Effect on AUC |
After high-fat meal | ↓ by 28% | ↓ by 23% |
After light meal | No effect | No effect |
Effect of Daclatasvir on Pharmacokinetics of Other Drugs
Daclatasvir is a weak CYP3A4 inducer. In general, dose adjustment of concomitantly administered CYP3A4 substrates is not necessary. Daclatasvir does not inhibit (IC50 >40 μM) CYP enzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 2D6.
Daclatasvir is an inhibitor of P-gp, organic anion transporting polypeptide (OATP) 1B1, organic cation transporter (OCT)1 and breast cancer resistance protein (BCRP). Co-administration of daclatasvir with substrates of P-gp, OATP 1B1, OCT1 or BCRP may produce an increase in their systemic exposure, potentially prolonging their therapeutic effect and risk of adverse reactions. Therefore, caution and regular monitoring for toxicity is recommended when daclatasvir is coadministered with the following agents with a narrow therapeutic range:
In vitro studies suggest that daclatasvir also inhibits renal uptake transporters, organic anion transporters (OAT) 1 and 3, but the inhibitory effects are not expected to be clinically relevant.
Effect of Other Drugs on Daclatasvir’s Pharmacokinetics
Strong CYP3A4 and P-gp inducers may lead to lower exposures of daclatasvir. Therefore, coadministration with the following agents is contraindicated.
Moderate CYP3A4 and P-gp inducers may decrease the plasma levels and therapeutic effect of daclatasvir.
Strong CYP3A4 inhibitors may increase plasma levels of daclatasvir. Therefore, dose adjustment of daclatasvir (i.e., decrease to 30mg daily) is recommended when coadministered with the following agents:
P-gp and OCT1 inhibitors are likely to a have limited effect on daclatasvir exposure. No dose adjustment is recommended.
Other Drug-Drug Interactions
Cardiac arrhythmias such as severe bradycardia has been reported in patients receiving amiodarone in combination with daclatasvir and sofosbuvir. An alternate antiarrhythmic agent should be considered. If amiodarone is administered with daclatasvir and sofosbuvir, close monitoring is required.
The absolute bioavailability of the daclatasvir oral tablet formulation is 67%.
In chronic HCV-infected subjects, daclatasvir was 99% protein bound, and binding at steady state was independent of dose over the range of 1 to 100 mg.
The estimated Vd at steady state is 47 L (6.22 L/kg).
Following oral administration, the time to peak plasma concentration of daclatasvir was reached in 1 to 2 hours.
In chronic HCV-infected subjects, the terminal elimination half-life of daclatasvir was 10 to 15 hours.
Daclatasvir primarily undergoes biotransformation by CYP3A4. Metabolites were present at minimal levels in the plasma (<5%). While BMS-805215 is an active metabolite, it is also 100-fold less potent than the parent compound. In the plasma, BMS-805215 accounts for only trace amounts to 2% of the drug.
In vitro studies demonstrate that daclatasvir is also a substrate of P-glycoprotein. Daclatasvir is actively transported into hepatocytes by OCT1 and other unidentified uptake transporters, but not by OAT2, NTCP, or OATPs.
Following single-dose oral administration of carbon-labeled daclatasvir in healthy subjects, 88% of the total dose was recovered in feces (53% as unchanged drug) and 6.6% was recovered in the urine (primarily as unchanged drug).
The pharmacokinetic properties of daclatasvir were evaluated in healthy and HCV-infected adult subjects. Therapeutic drug concentrations of daclatasvir were achieved after 4 days of once-daily administration. At steady state, exposure to daclatasvir (at the 60 mg dose) was comparable between both groups (as below). Daclatasvir Cmax, AUC, and Cmin increased in a near dose-proportional manner.
Following multiple oral doses of daclatasvir 60 mg once daily in combination with peginterferon alfa and ribavirin:
Although data from clinical trials on patients greater than 65 years of age are limited, population pharmacokinetic analyses suggest that age had no apparent effect on daclatasvir exposures. Gender and race were identified as statistically significant covariates in these analyses; however, the magnitude of the effect on the pharmacokinetics of daclatasvir was not found to be clinically meaningful.
Genotype |
Effective Concentration (50% reduction, EC50) Values |
1a |
0.003-0.050 nM |
1b |
0.001-0.009 nM |
2a |
0.034-19 nM |
3a, 4a, 5a and 6a |
0.003-1.25 nM |
Studies of daclatasvir use during human pregnancy have not been conducted and it is unknown if daclatasvir crosses the placenta. However, developmental toxicities (embryotoxic and teratogenic effects) and maternal toxicity were observed in animal studies with daclatasvir. Therefore, daclatasvir is NOT recommended for use in pregnant women, nor in women of childbearing potential not using highly effective contraception. In addition, use of a reliable form of contraception should continue for 5 weeks following completion of daclatasvir treatment.
Extreme caution must be exercised to avoid pregnancy when daclatasvir is used with ribavirin, as the latter may cause birth defects and/or death of the exposed fetus. Ribavirin should not be started unless there is a negative pregnancy test obtained immediately before initiation of therapy.
For treatment regimens containing daclatasvir, sofosbuvir and ribavirin, women of child-bearing potential and their male partners must use two forms of effective contraception during treatment and for at least 6 months following treatment completion. Monthly pregnancy tests should be performed.
Based on currently available evidence, the potential for toxicity in a newborn/infant cannot be excluded. Data from animal studies, however, indicate that daclatasvir was detectable in the milk of lactating rats at concentrations 1.7-fold and 2-fold the maternal plasma levels. As infant risk from drug exposure cannot be ruled out, breastfeeding is not recommended during therapy with daclatasvir.2638
In cell culture
In HCV replicons, resistance-associated substitutions were observed in genotypes 1 to 6 in the N-terminal 100 amino acid region of NS5A.
Genotype | Relevant Observed Variants | Level of Resistance Conferred by Polymorphism |
1a | M28T, L31V/M, Q30E/H/R, Y93C/H/N | · High (EC50 up to 350 nM for Y93H) |
1b | L31V and Y93H | · Low (EC50 <1 nM) for single amino acid substitutions · Higher with 2 amino acid substitutions (L31V-Y93H: EC50 ≥38 nM) |
2a | L31M, F28S | · Low to moderate if L31M (EC50 = 9-19nM) · High if F28S (EC50 >500nM) |
3 | Y93H | · High (EC50 >1,000 nM) |
4a | Residues 30 and 93 | · Low to moderate (EC50 <16 nM) · In general, variants in genotype 4a did not appear to reduce daclatasvir potency (EC50 = 0.007 to 0.0013 nM) |
5a | L31F | · Low to moderate (EC50 = 6.8nM) |
6a | P32L | · High (EC50 = 250nM) |
In clinical studies
Daclatasvir in combination with sofosbuvir
With the exception of one subject with virologic failure (HCV genotype 3), all participants the in phase 2 study AI444040 with baseline daclatasvir resistance-associated NS5A variants achieved sustained virologic response. In the single genotype 3 subject who experience virologic failure, NS5A resistance-associated substitutions A30K and S62I were observed both at baseline and at treatment failure. N5SB polymorphisms associated with sofosbuvir resistance were not detected.
Daclatasvir in combination with peginterferon alfa and ribavirin
The majority of treatment-naïve subjects with baseline daclatasvir resistance-associated NS5A variants achieved SVR. Among treatment-naïve subjects and prior nonresponders who were deem treatment failures (N=210), emergent NS5A resistance-associated variants were seen in genotype 1a (139/153) and 1b (49/57) virus. The most frequently detected polymorphisms at failure included Q30E or Q30R in combination with L31M.
Persistence of resistance mutations
In patients who received 14 day monotherapy treatment with daclatasvir, HCV NS5A resistant polymorphisms were observed for up to 6 months following treatment cessation, suggesting possible long-term persistence of resistance.2928 2930
N/A.
HCV replicons with resistance-associated variants to daclatasvir retained sensitivity to interferon alfa and other DAAs (i.e., NS3 protease and NS5B polymerase nucleoside and non-nucleoside inhibitors).
Daclatasvir-associated resistance mutations confer cross-resistance to other first generation HCV NS5A inhibitors.2929
The efficacy of daclatasvir as part of a retreatment regimen in patients with prior exposure to a nonstructural protein 5A (NS5A) replication complex inhibitor has not been established.2638
Adverse Reactions
Common (incidence >10%):
Serious:
Laboratory Abnormalities
In a study evaluating daclatasvir in combination with sofosbuvir with or without ribavirin, one patient (who was in the ribavirin treatment group) had a Grade 3 hemoglobin decrease. Laboratory abnormalities among patients treated with daclatasvir, peginterferon alfa and ribavirin were otherwise comparable to those among patients who received placebo, peginterferon and ribavirin.
Determination of hepatitis C genotype prior to initiation of therapy.
HCV RNA levels at Week 4, 12 and 24, or at end of treatment.
If daclatasvir and sofosbuvir are administered with amiodarone, close monitoring for bradycardia is recommended.2638
Store at room temperature (15-30°C) in original container.
Bristol-Myers Squibb
Note: The web app has been optimized for the following browsers: Google Chrome, Apple Safari. Other web browsers (e.g. Mozilla Firefox, Internet Explorer, Opera, etc) may experience performance issues. Please use one of the optimized browser versions, or download our mobile application.
The information in this website/app is intended for use by and with experienced physicians and pharmacists. The information is not intended to replace sound professional judgment in individual situations, and should be used in conjunction with other reliable sources of information. Due to the rapidly changing nature of information about HIV treatment and therapies, users are advised to recheck the information contained herein with the original source before applying it to patient care. Decisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about HIV-related illness and the treatments in question.
Neither Toronto General Hospital, Alberta Health Services, the Ottawa Hospital, nor the authors and contributors are responsible for deletions or inaccuracies in information or for claims of injury resulting from any such deletions or inaccuracies. Mention of specific drugs, drug doses or drug combinations within this website does not constitute endorsement by the authors, Toronto General Hospital, Alberta Health Services or the Ottawa Hospital.
The opinions expressed herein are those of its authors and do not necessarily reflect the views and opinions of Abbvie, Gilead Canada, Merck Canada Inc., and ViiV Healthcare.
We emphasize that program only checks for interactions between HIV or HCV drugs and other drugs, it will NOT check for interactions between sets of non-HIV or HCV drugs.
Also, program content focuses primarily on pharmacokinetic based interactions, and will not include comprehensive data on pharmacodynamics interactions, including QT prolongation.
Last updated: January 10, 2016
Please read these Terms, Conditions & Disclaimer carefully before using the www.hivclinic.ca website (the "Service") operated by Immunodeficiency Clinic ("us", "we", or "our").
By using this site, you signify your assent to these Terms and Conditions. If you do not agree to all of these Terms and Conditions of use, do not use this site. The Immunodeficiency Clinic may revise and update these Terms and Conditions without notice at any time. Your continued usage of the Immunodeficiency Clinic Web site (the "site") will mean you accept those changes.
Any Web sites linked from the site are created by organizations outside the Immunodeficiency Clinic. Those organizations are responsible for the information contained within their sites. We do not recommend and do not endorse the content on any third-party websites. We are not responsible for the content of linked third-party sites or third-party advertisements and do not make any representations regarding their content or accuracy. Your use of third-party websites is at your own risk and subject to the terms and conditions of use for such sites. Any specific comments regarding these sites should be directed to that individual organization.
These Terms shall be governed and construed in accordance with the laws of Ontario, Canada, without regard to its conflict of law provisions. Our failure to enforce any right or provision of these Terms will not be considered a waiver of those rights. If any provision of these Terms is held to be invalid or unenforceable by a court, the remaining provisions of these Terms will remain in effect. These Terms constitute the entire agreement between us regarding our Service, and supersede and replace any prior agreements we might have between us regarding the Service.
We reserve the right, at our sole discretion, to modify or replace these Terms at any time. If a revision is material we will try to provide at least 30 days notice prior to any new terms taking effect. What constitutes a material change will be determined at our sole discretion. By continuing to access or use our Service after those revisions become effective, you agree to be bound by the revised terms. If you do not agree to the new terms, please stop using the Service.
Thank you for visiting the HIV/HCV Drug Therapy Guide housed on the Toronto General Hospital Immunodeficiency Clinic Web site. General aggregate user data that will be tracked for both the web-based and mobile applications includes country of origin, new vs. returning visitor to the site, browsers used and sections of the guide that are used most frequently. Any identifying personal information will not be collected.
Accessing information from the HIV/HCV Drug Therapy Guide: This web-based application is housed on the Toronto General Hospital Immunodeficiency Clinic Web site at app.hivclinic.ca. Future updates will include an application for mobile devices also.
The Toronto General Hospital website has been in operation since 2000. The main objectives of the drug information portion of the website/app are to provide a comprehensive and centralized repository of current data on HIV/HCV drug therapy for health care professionals with a main focus on drug interactions, and to promote safe and rational prescribing of antiretrovirals and directly acting antivirals. The website/app content is updated regularly, and includes information from key international HIV/HCV conferences and recent publications in the medical/pharmacy literature.
The primary editors of the website/app content are:
The ongoing contributions of Michelle Foisy, PharmD, founding co-editor, as well as the following people are also gratefully acknowledged: Michelle Bender, Alison Wong, Bill Cornish, Margaret Ackman, Tony Antoniou, Cara Hills-Nieminen, Natalie Dayneka, Dominic Martel, Denise Kreutzwiser, Cherry Hui, Sanjeev Sockalingham.
Contact us at: app@hivclinic.ca
HIV/HCV Drug Therapy Guide. UHN- Toronto General Hospital, Immunodeficiency Clinic; 2022 [insert date cited e.g. cited 2022 Jan 10]. Available from: https://app.hivclinic.ca/
Thank you for visiting. We hope you find your visit to be worthwhile and useful.
Please submit application error reports here for correction by webmaster Tom Tranmer.