Abstract
Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1–2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers. Daclatasvir exposure is similar between healthy subjects and subjects infected with hepatitis C virus. Intrinsic factors such as age, race, or sex do not impact daclatasvir exposure. No dose adjustment is necessary for patients with any degree of hepatic or renal impairment. Daclatasvir has low-to-moderate clearance with the predominant route of elimination via cytochrome P450 3A4-mediated metabolism and P-glycoprotein excretion and intestinal secretion. Renal clearance is a minor route of elimination for daclatasvir. As a result, the dose of daclatasvir should be reduced from 60 to 30 mg once daily when co-administered with strong inhibitors of cytochrome P450 3A4. No dose adjustment is required when daclatasvir is co-administered with moderate inhibitors of cytochrome P450 3A4. The dose of daclatasvir should be increased from 60 to 90 mg once daily when co-administered with moderate inducers of cytochrome P450 3A4. Co-administration of daclatasvir with strong inducers of cytochrome P450 3A4 is contraindicated. Concurrent medications with inhibitory effects on P-glycoprotein without concurrent inhibition of cytochrome P450 3A4 are unlikely to cause marked changes in daclatasvir exposure, as the clearance of daclatasvir is through both cytochrome P450 3A4 and P-glycoprotein. The potential for daclatasvir to affect the pharmacokinetics of concomitantly administered drugs that are substrates of the cytochrome P450 enzyme system is low. In vitro, daclatasvir is a weak-to-moderate inhibitor of transporters including organic cation transporter 1, P-glycoprotein, organic transporting polypeptide 1B1, organic transporting polypeptide 1B3, and breast cancer resistance protein, although in clinical studies, daclatasvir has not altered the pharmacokinetics of concomitantly administered drugs that are substrates of these transporters to an appreciable degree, except for rosuvastatin. In summary, daclatasvir is a hepatitis C virus, non-structural protein 5a-selective inhibitor with a well-characterized pharmacokinetic profile that forms part of potent and well-tolerated all-oral treatment regimens for chronic hepatitis C virus infection.
Similar content being viewed by others
References
Polaris Observatory HCV Collaborators. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2:161–76.
National Institutes of Health. National Institutes of Health Consensus Development Conference Statement: management of hepatitis C: June 10–12, 2002. Hepatology. 2002;36(5 Suppl. 1):S3–20.
Rodriguez-Luna H, Douglas DD. Natural history of hepatitis C following liver transplantation. Curr Opin Infect Dis. 2004;17:363–71.
Global surveillance and control of hepatitis C. Report of a WHO consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat. 1999;6:35–47.
Yoshizawa H. Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future. Oncology. 2002;62(Suppl. 1):8–17.
Manns MP, van Han T. Novel therapies for hepatitis C: one pill fits all? Nat Rev Drug Discov. 2013;12:595–610.
AASLD and IDSA. Recomendations for testing, managing and treatment hepatitis C November. 2016. http://www.hcvguidelines.org. Accessed 10 Nov 2016.
European Association for the Study of the Liver (EASL). EASL recommendations on treatment of hepatitis C. J Hepatol. 2016. https://doi.org/10.1016/j.jhep.2016.09.001 (In press).
Gao M, Nettles R, Belema M, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465:96–100.
Daklinza (daclatasvir) Film-coated tablets: summary of product characteristics. Uxbridge, UK: Bristol-Myers Squibb Pharmaceutical Limited; 2016.
Daclatasvir. Package insert. Princeton, New Jersey, USA: Bristol-Myers Squibb; 2017.
Center for Drug Evaluation and Research. Clinical pharmacology and biopharmaceutics review(s). Daclatasvir. Application no. 20-6843. 2014.
Li W, Zhao W, Liu X, et al. Biotransformation of daclatasvir in vitro and in nonclinical species: formation of the main metabolite by pyrrolidine d-oxidation and rearrangement. Drug Metab Dispos. 2016;44:809–20.
Bifano M, Sevinsky H, Stonier M, Jiang H, Bertz RJ. Daclatasvir, an HCV NS5A replication complex inhibitor, has minimal effect on pharmacokinetics of midazolam, a sensitive probe for cytochrome P450 3A4. Rev Antivir Ther Infect Dis. 2013;6:17.
Bifano M, Sevinsky H, Persson A, et al. Single-dose pharmacokinetics of daclatasvir (DCV; BMS-790052) in subjects with hepatic impairment compared with healthy subjects. In: Presented at the American Association for the Study of Liver Diseases; 5 Nov 2011; San Fransisco (CA).
Bifano M, Sevinsky H, Hwang C, et al. Effect of the coadministration of daclatasvir on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and norgestimate. Antivir Ther. 2014;19:511–9.
Bifano M, Connolly S, Hwang C, et al. The effect of co-administration of the proton-pump inhibitor omeprazole on the pharmacokinetics of daclatasvir in healthy subjects. In: Presented at the 48th Annual Meeting of the European Association for the Study of the Liver; 24–28 Apr 2013; Amsterdam.
Bifano M, Hwang C, Oosterhuis B, et al. Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir. Antivir Ther. 2013;18:931–40.
Bertz R. Bristol-Myers Squibb HCV full development portfolio overview. In: Plenary presentation presented at the 14th International Workshop on Clinical Pharmacology; 22–24 Apr 2014; Amsterdam.
Garimella T, Wang R, Luo W, et al. Single-dose pharmacokinetics and safety of daclatasvir in subjects with renal function impairment. Antivir Ther. 2015;20(5):535–43.
Garimella T, Wang R, Luo WL, et al. Assessment of drug–drug interactions between daclatasvir and methadone or buprenorphine-naloxone. Antimicrob Agents Chemother. 2015;59:5503–10.
Bifano M, Adamczyk R, Hwang C, Kandoussi H, Marion A, Bertz RJ. An open-label investigation into drug–drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects. Clin Drug Investig. 2015;35:281–9.
Gandhi Y, Adamczyk R, Wang R, et al. Assessment of drug–drug interactions between daclatasvir and darunavir/ritonavir or lopinavir/ritonavir. In: Presented at the 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy; 26–28 May 2015; Washington, DC.
Garimella T, Adamczyk R, Stonier M, et al. Effect of steady-state daclatasvir plus asunaprevir on the single-dose pharmacokinetics of the P-glycoprotein substrate digoxin in healthy adult subjects. Presented at ID Week 2014, 8–12 Oct 2014; Philadelphia (PA).
Janssen Therapeutics. Olysio™ (simeprevir): summary of product characteristics. 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002777/WC500167867.pdf. Accessed Jun 2016.
Eley T, You X, Huang S, et al. Evaluation of drug interaction potential between daclatasvir and sofosbuvir. Rev Antivir Ther Infect Dis. 2013;6:16.
Chan P, Li H, Zhu L, et al. Population pharmacokinetic analysis of daclatasvir in subjects with chronic hepatitis C virus infection. Clin Pharmacokinet. 2017;56(10):1173–83.
Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology. 2014;59(6):2083–91.
Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009;461:798–801.
Garimella T, You X, Wang R, et al. A review of daclatasvir drug–drug interactions. Adv Ther. 2016;33:1867–84.
Sovaldi (sofosbuvir). Package insert. Foster City, California, USA: Gilead Sciences Inc.; 2017.
Kirby BJ, Symonds WT, Kearney BP, et al. Pharmacokinetic, pharmacodynamic, and drug-interaction profile of the hepatitis C virus NS5B polymerase inhibitor sofosbuvir. Clin Pharmacokinet. 2015;54:677–90.
Eley T, Sevinsky H, Huang SP, He B, Zhu K, Kandoussi H, et al. The pharmacokinetics of daclatasvir and asunaprevir administered in combination in studies in healthy subjects and patients infected with hepatitis C virus. Clin Drug Investig. 2014;34:661–71.
Eley T, Garimella T, Li W, et al. Asunaprevir: a review of preclinical and clinical pharmacokinetics and drug-drug interactions. Clin Pharmacokinet. 2015;54:1205–22.
Eley T, Han Y-H, Huang S-P, He B, Li W, Bedford W, Stonier M, Gardiner D, Sims K, Rodrigues A, Bertz R. Organic anion transporting polypeptide-mediated transport of, and inhibition by, asunaprevir, an inhibitor of hepatitis C virus NS3 protease. Clin Pharmacol Ther. 2015;97:159–66.
Gandhi Y, Adamczyk R, Wang R, et al. Assessment of drug–drug interactions between daclatasvir and darunavir/ritonavir or lopinavir/ritonavir. In: Presented at the 16th international workshop on clinical pharmacology of HIV and hepatitis therapy 015; 26–28 May 2015, Washington, DC.
Smolders EJ, Colbers A, de Kanter CTMM, et al. Metformin and daclatasvir: absence of a pharmacokinetic–pharmacodynamic drug interaction in healthy volunteers. Br J Clin Pharmacol. 2017;83:2225–34.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
All funding for preparation of this article was provided by Bristol-Myers Squibb and all the studies included were sponsored by Bristol-Myers Squibb.
Conflict of interest
Yash Gandhi, Aberra Fura, Wenying Li, and Tushar Garimella are current employees of Bristol-Myers Squibb and are shareholders. Richard Bertz and Timothy Eley were employees of Bristol-Myers Squibb at the time the studies were conducted and are shareholders.
Rights and permissions
About this article
Cite this article
Gandhi, Y., Eley, T., Fura, A. et al. Daclatasvir: A Review of Preclinical and Clinical Pharmacokinetics. Clin Pharmacokinet 57, 911–928 (2018). https://doi.org/10.1007/s40262-017-0624-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40262-017-0624-3