Preclinical pharmacokinetics and first-in-human pharmacokinetics, safety, and tolerability of velpatasvir, a pangenotypic hepatitis C virus NS5A inhibitor, in healthy subjects

Antimicrobial Agents and Chemotherapy

Volumn 61, Issue 5, 2017, Pages

  Mogalian, Erik ^a   German, Polina ^a   Kearney, Brian P ^a   Yang, Cheng Yong ^a   Brainard, Diana ^a   Link, John ^a   McNally, John ^a   Han, LingLing ^a   Ling, John ^a   Mathias, Anita ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

Clinical trials; HCV NS5A inhibitor; Pharmacokinetics; Safety; Velpatasvir

Indexed keywords

LOW DENSITY LIPOPROTEIN; PLACEBO; TRIACYLGLYCEROL LIPASE; VELPATASVIR; ANTIVIRUS AGENT; CARBAMIC ACID DERIVATIVE; FUSED HETEROCYCLIC RINGS; NS-5 PROTEIN, HEPATITIS C VIRUS; VIRAL PROTEIN;

ADULT; AREA UNDER THE CURVE; ARTICLE; COHORT ANALYSIS; CONSTIPATION; CONTROLLED STUDY; DERMATITIS; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG CLEARANCE; DRUG DISPOSITION; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG HALF LIFE; DRUG POTENCY; DRUG SAFETY; DRUG TOLERABILITY; EC50; FEMALE; FOOD; FOOD DRUG INTERACTION; HEMATURIA; HEPATITIS C VIRUS GENOTYPE 1; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IN VITRO STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NAUSEA; NONHUMAN; NORMAL HUMAN; ORTHOSTATIC HYPOTENSION; PHARMACOKINETIC PARAMETERS; PHASE 1 CLINICAL TRIAL; PITYRIASIS ROSEA; PRESYNCOPE; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; REPLICON; SIDE EFFECT; SINGLE DRUG DOSE; UPPER RESPIRATORY TRACT INFECTION; VIRUS INFECTION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; DOG; DRUG EFFECTS; HEPACIVIRUS; HEPATITIS C; LIVER MICROSOME; MACACA FASCICULARIS; METABOLISM; MIDDLE AGED; RAT; SPRAGUE DAWLEY RAT; VIROLOGY; VIRUS REPLICATION; YOUNG ADULT;

ADULT; ANIMALS; ANTIVIRAL AGENTS; CARBAMATES; DOGS; FEMALE; HEALTHY VOLUNTEERS; HEPACIVIRUS; HEPATITIS C; HETEROCYCLIC COMPOUNDS, 4 OR MORE RINGS; HUMANS; MACACA FASCICULARIS; MALE; MICROSOMES, LIVER; MIDDLE AGED; RATS; RATS, SPRAGUE-DAWLEY; VIRAL NONSTRUCTURAL PROTEINS; VIRUS REPLICATION; YOUNG ADULT;

EID: 85018182237     PISSN: 00664804     EISSN: 10986596     Source Type: Journal    
DOI: 10.1128/AAC.02084-16     Document Type: Article

References (31)

1. Ghany MG, Strader DB, Thomas DL, Seeff LB. 2009. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49:1335-1374. https://doi.org/10.1002/hep.22759.
2. Naggie S, Patel K, McHutchison J. 2010. Hepatitis C virus directly acting antivirals: current development with NS3/4A HCV serine protease inhibitors. J Antimicrob Chemother 65:2063-2069. https://doi.org/10.1093/jac/dkq284.
3. Negro F, Alberti A. 2011. The global health burden of hepatitis C virus infection. Liver Int 31(Suppl 2):1-3. https://doi.org/10.1111/j.1478-3231.2011.02537.x.
4. Cornberg M, Razavi HA, Alberti A, Bernasconi E, Buti M, Cooper C, Dalgard O, Dillion JF, Flisiak R, Forns X, Frankova S, Goldis A, Goulis I, Halota W, Hunyady B, Lagging M, Largen A, Makara M, Manolakopoulos S, Marcellin P, Marinho RT, Pol S, Poynard T, Puoti M, Sagalova O, Sibbel S, Simon K, Wallace C, Young K, Yudaydin C, Zuckerman E, Negro F, Zeuzem S. 2011. A systematic review of hepatitis C virus epidemiology in Europe, Canada, and Israel. Liver Int 31(Suppl 2):30-60. https://doi.org/10.1111/j.1478-3231.2011.02539.x.
5. Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, Alomair A, Amarapurkar D, Chen CH, Dou X, Khayat H, Elshazly M, Esmat G, Guan R, Hand KH, Koike K, Largen A, McCaughan G, Mogawer S, Monis A, Nawaz A, Piratvisuth T, Sanai FM, Sharara AI, Sibbel S, Sood A, Suh DJ, Wallace C, Young K, Negro F. 2011. A systematic review of hepatitis C virus epidemiology in Asia, Australia, and Egypt. Liver Int 31(Suppl 2):61-80. https://doi.org/10.1111/j.1478-3231.2011.02540.x.
6. Smith BD, Morgan ML, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, Jewett A, Baack B, Rein DB, Patel N, Alter M, Yartel A, Ward JW, Centers for Disease Control and Prevention. 2012. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 61(RR-4):1-32.
7. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. 2011. A sustained virologic response reduces risk of all-cause mortality in patients with hepatitis C. Clin Gastroenterol Hepatol 9:509-516. https://doi.org/10.1016/j.cgh.2011.03.004.
8. Pietschmann T, Lohmann V, Rutter G, Kurpanek K, Bartenschlager R. 2001. Characterization of cell lines carrying self-replicating hepatitis C virus RNAs. J Virol 75:1252-1264. https://doi.org/10.1128/JVI.75.3.1252-1264.2001.
9. Tellinghuisen TL, Foss KL, Treadaway J. 2008. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLoS Pathog 4:e1000032. https://doi.org/10.1371/journal.ppat.1000032.
10. Gale MJ, Jr, Korth MJ, Tang NM, Tan SL, Hopkins DA, Dever TE, Polyak SJ, Gretch DR, Katze MG. 1997. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology 230:217-227. https://doi.org/10.1006/viro.1997.8493.
11. Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, Romero-Gomez M, Zarski JP, Agarwal K, Buggisch P, Foster GR, Brau N, Buti M, Jacobson IM, Subramanian GM, Ding X, Mo H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Mangia A, Marcellin P. 2014. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 370:1889-1898. https://doi.org/10.1056/NEJMoa1402454.
12. Afdhal N, Reddy R, Nelson DR, Lawitz E, Gordon SC, Schiff E, Nahass R, Ghalib R, Gitlin N, Herring R, Lalezari J, Younes ZH, Pockros PJ, Di Bisceglie AM, Arora S, Subramanian GM, Zhu Y, Dvory-Sobol H, Yang JC, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Sulkowski M, Kwo P. 2014. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 370:1483-1493. https://doi.org/10.1056/NEJMoa1316366.
13. Nelson DR, Cooper JN, Lalezari JP, Lawitz E, Pockros PJ, Gitlin N, Freilich BF, Younes ZH, Harlan W, Ghalib R, Oguchi G, Thuluvath PJ, Ortiz-Lasanta G, Rabinovitz M, Bernstein D, Bennett M, Hawkins T, Ravendhran N, Sheikh AM, Varunok P, Kowdley KV, Hennicken D, McPhee F, Rana K, Hughes EA. 2015. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 61:1127-1135. https://doi.org/10.1002/hep.27726.
14. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, Weiland O, Aguilar H, Xiong J, Pilot-Matias T, Da Silva-Tillmann B, Larsen L, Podsadecki T, Bernstein B. 2014. Treatment of HCV with ABT-450/rombitasvir and dasabuvir with ribavirin. N Engl J Med 370:1594-1603. https://doi.org/10.1056/NEJMoa1315722.
15. Wang C, Jia L, O'Boyle DR, Sun JH, Rigat K, Valera L, Nower P, Huang X, Kienzle B, Roberts S, Gao M, Fridell RA. 2014. Comparison of daclatasvir resistance barriers on NS5A from hepatitis C virus genotypes 1 to 6: implications for cross-genotype activity. Antimicrob Agents Chemother 58:5155-5163. https://doi.org/10.1128/AAC.02788-14.
16. Stirnimann G. 2014. Ombitasvir (ABT-267), a novel NS5A inhibitor for the treatment of hepatitis C. Expert Opin Pharmacother 15:2609-2622. https://doi.org/10.1517/14656566.2014.972364.
17. Cheng G, Yu M, Peng B, Lee Y, Trejo-Martin A, Gong R, Bush C, Worth A, Nash M, Chan K, Yang H, Beran R, Tian Y, Taylor J, Yang C, Paulson M, Delaney W, Link JO. 2013. GS-5816, a second generation HCV HS5A inhibitor with potent antiviral activity, broad genotypic coverage and a high resistance barrier. J Hepatol 58:S484-S485.
18. Clarysse S, Tack J, Lammert F, Duchateau G, Reppas C, Augustijns P. 2009. Postprandial evolution in composition and characteristics of human duodenal fluids in different nutritional states. J Pharm Sci 98: 1177-1192. https://doi.org/10.1002/jps.21502.
19. U.S. Pharmacopeia. 2011. General notices and requirements: applying to standards, tests, assays, and other specifications of the USP. Version 1 May 2011. U.S. Pharmacopeia, Rockville, MD.
20. Davies B, Morris T. 1993. Physiological parameters in laboratory animals and humans. Pharm Res 10:1093-1095. https://doi.org/10.1023/A:1018943613122.
21. Mordenti J. 1986. Man versus beast: pharmacokinetic scaling in mammals. J Pharm Sci 75:1028-1040. https://doi.org/10.1002/jps.2600751104.
22. Kostewicz ES, Wunderlich M, Brauns U, Becker R, Bock T, Dressman JB. 2004. Predicting the precipitation of poorly soluble weak bases upon entry in the small intestine. J Pharm Pharmacol 56:43-51.
23. Craig DQM. 2002. The mechanisms of drug release from solid dispersions in water-soluble polymers. Int J Pharm 231:131-144. https://doi.org/10.1016/S0378-5173(01)00891-2.
24. Carver PL, Fleisher D, Zhou SY, Kaul D, Kazanjian P, Li C. 1999. Meal composition effects on the oral bioavailability of indinavir in HIVinfected patients. Pharm Res 16:718-724. https://doi.org/10.1023/A:1018880726035.
25. Winstanley PA, Orme ML. 1989. The effects of food on drug bioavailability. Br J Clin Pharmacol 28:621-628. https://doi.org/10.1111/j.1365-2125.1989.tb03554.x.
26. Lawitz E, Freilich B, Link J, German P, Mo H, Han L, Brainard DM, McNally J, Marbury T, Rodriguez-Torres M. 2015. A phase 1, randomized, doseranging study of GS-5816, a once-daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat 22:1011-1019. https://doi.org/10.1111/jvh.12435.
27. Pianko S, Flamm SL, Shiffman ML, Kumar S, Strasser SI, Dore GJ, McNally J, Brainard DM, Han L, Doehle B, Mogalian E, McHutchison JG, Rabinovitz M, Towner WJ, Gane EJ, Stedman CAM, Reddy KR, Roberts SK. 2015. Sofosbuvir plus velpatasvir combination therapy for treatment-experienced patients with genotype 1 or 3 hepatitis C virus infection. Ann Intern Med 163: 809-817. https://doi.org/10.7326/M15-1014.
28. Everson GT, Towner WJ, Davis MN, Wyles DL, Nahass RG, Thuluvath PJ, Etzkorn K, Hinestrosa F, Tong M, Rabinovitz M, McNally J, Brainard DM, Han L, Doehle B, McHutchison JG, Morgan T, Chung RT, Tran TT. 2015. Sofosbuvir with velpatasvir in treatment-naïve noncirrhotic patients with genotype 1 to 6 hepatitis C virus infection. Ann Intern Med 163:818-826. https://doi.org/10.7326/M15-1000.
29. Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HLY, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S. 2015. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 373:2599-2607. https://doi.org/10.1056/NEJMoa1512610.
30. Foster GR, Afdahl N, Roberts SK, Brau N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C, Towner WJ, Conway B, Ruane P, Bourliere M, Asselah T, Berg T, Zeuzem S, Rosenberg W, Agarwal K, Stedman CAM, Mo H, Dvory-Sobol H, Han L, Wang J, McNally J, Osinusi A, Brainard DM, McHutchison JG, Mazzotta F, Tran TT, Gordon SC, Patel K, Reau N, Mangia A, Sulkowski M. 2015. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 373:2608-2617. https://doi.org/10.1056/NEJMoa1512612.
31. Curry MP, O'Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, Reddy KR, Lawitz E, Flamm SL, Schiano T, Teperman L, Fontana R, Schiff E, Fried M, Doehle B, An D, McNally J, Osinusi A, Brainard DM, McHutchison JG, Brown RS, Jr, Charlton RSM. 2015. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 373:2618-2628. https://doi.org/10.1056/NEJMoa1512614.