In‐host modeling of dengue virus and non‐structural protein 1 and the effects of ivermectin in patients with acute dengue fever
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<sub>50</sub> 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.
Authors
- Nattaya Tangthawornchaikul (ORCID: https://orcid.org/0009-0005-2055-8217)
- Kulkanya Chokephaibulkit (ORCID: https://orcid.org/0000-0002-0140-4600)
- Sansanee Noisakran (ORCID: https://orcid.org/0000-0002-9336-3331)
- Panisadee Avirutnan (ORCID: https://orcid.org/0000-0003-0053-3045)
- Adisak Songjaeng (ORCID: https://orcid.org/0009-0009-6157-0377)
- Tanapan Prommool (ORCID: https://orcid.org/0000-0002-1967-2670)
- Nasikarn Angkasekwinai (ORCID: https://orcid.org/0000-0001-5723-4877)
- Dumrong Mairiang (ORCID: https://orcid.org/0000-0002-2743-0145)
- Chunya Puttikhunt (ORCID: https://orcid.org/0000-0003-1611-2667)
- Keswadee Lapphra (ORCID: https://orcid.org/0000-0002-4513-5924)
- Nicholas John White (ORCID: https://orcid.org/0000-0002-1897-1978)
- Joel Tärning (ORCID: https://orcid.org/0000-0003-4566-4030)
- Junjie Ding (ORCID: https://orcid.org/0000-0002-6429-3178)
- Nattapong Kaewjiw
- Dararat Prayongkul
- Yupin Suputtamongkol (ORCID: https://orcid.org/0000-0002-4918-9604)
Institutions
- National Science and Technology Development Agency (TH)
- Siriraj Hospital (TH)
- Mahidol University (TH)
- University of Oxford (GB)
- Mahidol Oxford Tropical Medicine Research Unit (TH)
- Infectious Diseases Data Observatory (GB)
- National Center for Genetic Engineering and Biotechnology (TH)
Publication Details
- Journal
- CPT Pharmacometrics & Systems Pharmacology
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1002/psp4.13233
- Citations
- 2
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 1.09
Funders
- Wellcome Trust
- Mahidol University
- Thailand Research Fund
- Health Systems Research Institute
- Faculty of Medicine Siriraj Hospital, Mahidol University