In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever
Abstract 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 clini...
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.13233 |
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| author | Junjie Ding Dumrong Mairiang Dararat Prayongkul Chunya Puttikhunt Sansanee Noisakran Nattapong Kaewjiw Adisak Songjaeng Tanapan Prommool Nattaya Tangthawornchaikul Nasikarn Angkasekwinai Yupin Suputtamongkol Keswadee Lapphra Kulkanya Chokephaibulkit Nicholas J. White Panisadee Avirutnan Joel Tarning |
| author_facet | Junjie Ding Dumrong Mairiang Dararat Prayongkul Chunya Puttikhunt Sansanee Noisakran Nattapong Kaewjiw Adisak Songjaeng Tanapan Prommool Nattaya Tangthawornchaikul Nasikarn Angkasekwinai Yupin Suputtamongkol Keswadee Lapphra Kulkanya Chokephaibulkit Nicholas J. White Panisadee Avirutnan Joel Tarning |
| author_sort | Junjie Ding |
| collection | DOAJ |
| description | Abstract 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 EC50 of 67.5 μg/mL. In silico simulations suggested that ivermectin should be dosed within 48 h after fever onset, and that a daily dosage of 800 μg/kg could achieve substantial NS1 reduction. The in‐host dengue model is useful to assess the drug effect in antiviral drug development for dengue fever. |
| format | Article |
| id | doaj-art-7a32ce2e7f4c4d01a0fd5acf44c71a81 |
| institution | Kabale University |
| issn | 2163-8306 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj-art-7a32ce2e7f4c4d01a0fd5acf44c71a812024-12-16T05:57:56ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062024-12-0113122196220910.1002/psp4.13233In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue feverJunjie Ding0Dumrong Mairiang1Dararat Prayongkul2Chunya Puttikhunt3Sansanee Noisakran4Nattapong Kaewjiw5Adisak Songjaeng6Tanapan Prommool7Nattaya Tangthawornchaikul8Nasikarn Angkasekwinai9Yupin Suputtamongkol10Keswadee Lapphra11Kulkanya Chokephaibulkit12Nicholas J. White13Panisadee Avirutnan14Joel Tarning15Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandDepartment of Medicine, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandDepartment of Medicine, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandDepartment of Pediatrics, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandDepartment of Pediatrics, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University Bangkok ThailandSiriraj Center of Research Excellence in Dengue and Emerging Pathogens, Faculty of Medicine Siriraj Hospital Mahidol University Bangkok ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine Mahidol University Bangkok ThailandAbstract 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 EC50 of 67.5 μg/mL. In silico simulations suggested that ivermectin should be dosed within 48 h after fever onset, and that a daily dosage of 800 μg/kg could achieve substantial NS1 reduction. The in‐host dengue model is useful to assess the drug effect in antiviral drug development for dengue fever.https://doi.org/10.1002/psp4.13233 |
| spellingShingle | Junjie Ding Dumrong Mairiang Dararat Prayongkul Chunya Puttikhunt Sansanee Noisakran Nattapong Kaewjiw Adisak Songjaeng Tanapan Prommool Nattaya Tangthawornchaikul Nasikarn Angkasekwinai Yupin Suputtamongkol Keswadee Lapphra Kulkanya Chokephaibulkit Nicholas J. White Panisadee Avirutnan Joel Tarning In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever CPT: Pharmacometrics & Systems Pharmacology |
| title | In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| title_full | In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| title_fullStr | In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| title_full_unstemmed | In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| title_short | In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| title_sort | in host modeling of dengue virus and non structural protein 1 and the effects of ivermectin in patients with acute dengue fever |
| url | https://doi.org/10.1002/psp4.13233 |
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