In-host modeling of dengue virus and non-structural protein 1 and the effects of ivermectin in patients with acute dengue fever.
Journal
CPT: pharmacometrics & systems pharmacology
ISSN: 2163-8306
Titre abrégé: CPT Pharmacometrics Syst Pharmacol
Pays: United States
ID NLM: 101580011
Informations de publication
Date de publication:
23 Sep 2024
23 Sep 2024
Historique:
revised:
19
08
2024
received:
13
06
2024
accepted:
21
08
2024
medline:
23
9
2024
pubmed:
23
9
2024
entrez:
23
9
2024
Statut:
aheadofprint
Résumé
The increased incidence of dengue poses a substantially global public health challenge. There are no approved antiviral drugs to treat dengue infections. Ivermectin, an old anti-parasitic drug, had no effect on dengue viremia, but reduced the dengue non-structural protein 1 (NS1) in a clinical trial. This is potentially important, as NS1 may play a causal role in the pathogenesis of severe dengue. This study established an in-host model to characterize the plasma kinetics of dengue virus and NS1 with host immunity and evaluated the effects of ivermectin, using a population pharmacokinetic-pharmacodynamic (PK-PD) modeling approach, based on two studies in acute dengue fever: a placebo-controlled ivermectin study in 250 adult patients and an ivermectin PK-PD study in 24 pediatric patients. The proposed model described adequately the observed ivermectin pharmacokinetics, viral load, and NS1 data. Bodyweight was a significant covariate on ivermectin pharmacokinetics. We found that ivermectin reduced NS1 with an EC
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Department of Disease Control, Ministry of Public Health
ID : R015745005
Organisme : Department of Disease Control, Ministry of Public Health
ID : R015845009
Organisme : Higher Education Commission
Organisme : Mahidol University under the National Research Universities Initiative, Thailand Research Fund
ID : RDG59D0011
Organisme : Health Systems Research Institute
ID : R016141025
Organisme : Faculty of Medicine Siriraj Hospital
ID : R015936007
Organisme : Faculty of Medicine Siriraj Hospital
ID : R016136003
Organisme : Wellcome Trust
ID : 220211
Pays : United Kingdom
Informations de copyright
© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Références
Control ECfDPa. 2‐Month Dengue Virus Disease Case Notification Rate per 100 000 Population. November 2022–October 2023. 2023. https://www.ecdc.europa.eu/en/publications‐data/12‐month‐dengue‐virus‐disease‐case‐notification‐rate‐100‐000‐population‐0
World Health Organization. WHO Position Paper on Dengue. 2018.
Tricou V, Yu D, Reynales H, et al. Long‐term efficacy and safety of a tetravalent dengue vaccine (TAK‐003): 4.5‐year results from a phase 3, randomised, double‐blind, placebo‐controlled trial. lancet glob. Health. 2024;12:e257‐e270.
WHO. Summary of WHO Position Paper on Dengue Vaccines (2018). World Health Organization; 2018.
Hadinegoro SR, Arredondo‐García JL, Capeding MR, et al. Efficacy and long‐term safety of a dengue vaccine in regions of endemic disease. N Engl J Med. 2015;373:1195‐1206.
Tricou V, Minh NN, Van TP, et al. A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults. PLoS Negl Trop Dis. 2010;4:e785.
Nguyen NM, Tran CNB, Phung LK, et al. A randomized, double‐blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J Infect Dis. 2013;207:1442‐1450.
Low JG, Sung C, Wijaya L, et al. Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double‐blind, placebo‐controlled, proof‐of‐concept trial. Lancet Infect Dis. 2014;14:706‐715.
Sung C, Wei Y, Watanabe S, et al. Extended evaluation of virological, immunological and pharmacokinetic endpoints of CELADEN: a randomized, placebo‐controlled trial of Celgosivir in dengue fever patients. PLoS Negl Trop Dis. 2016;10:e0004851.
Whitehorn J, Nguyen CV, Khanh LP, et al. Lovastatin for the treatment of adult patients with dengue: a randomized, double‐blind, placebo‐controlled trial. Clin Infect Dis. 2016;62:468‐476.
Suputtamongkol Y, Avirutnan P, Mairiang D, et al. Ivermectin accelerates circulating nonstructural protein 1 (NS1) clearance in adult dengue patients: a combined phase 2/3 randomized double‐blinded placebo controlled trial. Clin Infect Dis. 2021;72:e586‐e593.
Chen HR, Lai YC, Yeh TM. Dengue virus non‐structural protein 1: a pathogenic factor, therapeutic target, and vaccine candidate. J Biomed Sci. 2018;25:58.
Bhatt P, Sabeena SP, Varma M, Arunkumar G. Current understanding of the pathogenesis of dengue virus infection. Curr Microbiol. 2021;78:17‐32.
Modhiran N, Watterson D, Muller DA, et al. Dengue virus NS1 protein activates cells via toll‐like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med. 2015;7:304ra142.
Glasner DR, Puerta‐Guardo H, Beatty PR, Harris E. The good, the bad, and the shocking: the multiple roles of dengue virus nonstructural protein 1 in protection and pathogenesis. Annu Rev Virol. 2018;5:227‐253.
Lin CF, Chiu SC, Hsiao YL, et al. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol. 2005;174:395‐403.
Ghetia C, Bhatt P, Mukhopadhyay C. Association of dengue virus non‐structural‐1 protein with disease severity: a brief review. Trans R Soc Trop Med Hyg. 2022;116:986‐995.
Garcia LL, Padilla L, Castano JC. Inhibitors compounds of the flavivirus replication process. Virol J. 2017;14:95.
Mastrangelo E, Pezzullo M, de Burghgraeve T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67:1884‐1894.
Denolly S, Guo H, Martens M, et al. Dengue virus NS1 secretion is regulated via importin‐subunit beta1 controlling expression of the chaperone GRp78 and targeted by the clinical drug ivermectin. MBio. 2023;14:e0144123.
Clapham HE, Quyen TH, Kien DT, Dorigatti I, Simmons CP, Ferguson NM. Modelling virus and antibody dynamics during dengue virus infection suggests a role for antibody in virus clearance. PLoS Comput Biol. 2016;12:e1004951.
Ben‐Shachar R, Koelle K. Minimal within‐host dengue models highlight the specific roles of the immune response in primary and secondary dengue infections. J R Soc Interface. 2015;12:20140886.
Anam V, Guerrero BV, Srivastav AK, Stollenwerk N, Aguiar M. Within‐host models unravelling the dynamics of dengue reinfections. Infect Dis Model. 2024;9:458‐473.
World Health Organization. Dengue: guidelines for diagnosis, treatment, prevention and control. dengue: guidelines for diagnosis, treatment, prevention and control. World Health Organization; 2009.
Martina BE, Koraka P, Osterhaus AD. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev. 2009;22:564‐581.
Chan M, Johansson MA. The incubation periods of dengue viruses. PLoS One. 2012;7:e50972.
Kobylinski KC, Jittamala P, Hanboonkunupakarn B, et al. Safety, pharmacokinetics, and mosquito‐lethal effects of ivermectin in combination with Dihydroartemisinin‐piperaquine and primaquine in healthy adult Thai subjects. Clin Pharmacol Ther. 2020;107:1221‐1230.
Schilling WHK, Jittamala P, Watson JA, et al. Pharmacometrics of high‐dose ivermectin in early COVID‐19 from an open label, randomized, controlled adaptive platform trial (PLATCOV). elife. 2023;12:e83201.
Tipthara P, Kobylinski KC, Godejohann M, et al. Identification of the metabolites of ivermectin in humans. Pharmacol Res Perspect. 2021;9:e00712.
Duthaler U, Suenderhauf C, Karlsson MO, et al. Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers. Br J Clin Pharmacol. 2019;85:626‐633.
Muñoz J, Ballester MR, Antonijoan RM, et al. Safety and pharmacokinetic profile of fixed‐dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. PLoS Negl Trop Dis. 2018;12:e0006020.
Jessica D, Schulz AN, Coulibaly JT, Keiser J. Development and validation of a LC‐MS/MS method for ivermectin quantification in dried blood spots: application to a pharmacokinetic study in Trichuris trichiura‐infected adults. Anal Methods. 2018;10:2901‐2.
Edi C, Bjerum CM, Ouattara AF, et al. Pharmacokinetics, safety, and efficacy of a single co‐administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Cote d'Ivoire. PLoS Negl Trop Dis. 2019;13:e0007325.
Pukrittayakamee S, Looareesuwan S, Keeratithakul D, et al. A study of the factors affecting the metabolic clearance of quinine in malaria. Eur J Clin Pharmacol. 1997;52:487‐493.
Wills BA, Oragui EE, Minh Dung N, et al. Size and charge characteristics of the protein leak in dengue shock syndrome. J Infect Dis. 2004;190:810‐818.
Schulz JD, Coulibaly JT, Schindler C, Wimmersberger D, Keiser J. Pharmacokinetics of ascending doses of ivermectin in Trichuris trichiura‐infected children aged 2‐12 years. J Antimicrob Chemother. 2019;74:1642‐1647.
Wimmersberger D, Coulibaly JT, Schulz JD, et al. Efficacy and safety of ivermectin against Trichuris trichiura in preschool‐aged and school‐aged children: a randomized controlled dose‐finding trial. Clin Infect Dis. 2018;67:1247‐1255.
Libraty DH, Endy TP, Houng HSH, et al. Differing influences of virus burden and immune activation on disease severity in secondary dengue‐3 virus infections. J Infect Dis. 2002;185:1213‐1221.
Vaughn DW, Green S, Kalayanarooj S, et al. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis. 2000;181:2‐9.
Smith AM. Host‐pathogen kinetics during influenza infection and coinfection: insights from predictive modeling. Immunol Rev. 2018;285:97‐112.
Killingley B, Mann AJ, Kalinova M, et al. Safety, tolerability and viral kinetics during SARS‐CoV‐2 human challenge in young adults. Nat Med. 2022;28:1031‐1041.
Vuong Nguyen Lam QNTH, Hanh TNT, Hue KDT, et al. Dengue viremia kinetics and effects on platelet count and clinical outcomes: an analysis of 2340 patients from Vietnam. elife. 2024;13:RP92606.
Baccam P, Beauchemin C, Macken CA, Hayden FG, Perelson AS. Kinetics of influenza a virus infection in humans. J Virol. 2006;80:7590‐7599.
Waickman AT, Newell K, Lu JQ, et al. Low‐dose dengue virus 3 human challenge model: a phase 1 open‐label study. Nat Microbiol. 2024;9:1356‐1367.
Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta‐mediated nuclear import able to inhibit replication of HIV‐1 and dengue virus. Biochem J. 2012;443:851‐856.
Fobi G, Gardon J, Kamgno J, et al. A randomized, double‐blind, controlled trial of the effects of ivermectin at normal and high doses, given annually or three‐monthly, against Onchocerca volvulus: ophthalmological results. Trans R Soc Trop Med Hyg. 2005;99:279‐289.
Dembele B, Coulibaly YI, Dolo H, et al. Use of high‐dose, twice‐yearly albendazole and ivermectin to suppress Wuchereria bancrofti microfilarial levels. Clin Infect Dis. 2010;51:1229‐1235.
Perdomo‐Celis F, Salgado DM, Narvaez CF. Magnitude of viremia, antigenemia and infection of circulating monocytes in children with mild and severe dengue. Acta Trop. 2017;167:1‐8.
Tricou V, Minh NN, Farrar J, Tran HT, Simmons CP. Kinetics of viremia and NS1 antigenemia are shaped by immune status and virus serotype in adults with dengue. PLoS Negl Trop Dis. 2011;5:e1309.
Duyen HT, Ngoc TV, Ha Do T, et al. Kinetics of plasma viremia and soluble nonstructural protein 1 concentrations in dengue: differential effects according to serotype and immune status. J Infect Dis. 2011;203:1292‐1300.