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Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza.
J Pharm Sci. 2019 05; 108(5):1896-1904.JP

Abstract

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.

Authors+Show Affiliations

Project Management Department, Shionogi & Co., Ltd, Osaka, Japan.Project Management Department, Shionogi & Co., Ltd, Osaka, Japan.Project Management Department, Shionogi & Co., Ltd, Osaka, Japan. Electronic address: toru.ishibashi@shionogi.co.jp.Project Management Department, Shionogi & Co., Ltd, Osaka, Japan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30557562

Citation

Koshimichi, Hiroki, et al. "Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza." Journal of Pharmaceutical Sciences, vol. 108, no. 5, 2019, pp. 1896-1904.
Koshimichi H, Tsuda Y, Ishibashi T, et al. Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza. J Pharm Sci. 2019;108(5):1896-1904.
Koshimichi, H., Tsuda, Y., Ishibashi, T., & Wajima, T. (2019). Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza. Journal of Pharmaceutical Sciences, 108(5), 1896-1904. https://doi.org/10.1016/j.xphs.2018.12.005
Koshimichi H, et al. Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza. J Pharm Sci. 2019;108(5):1896-1904. PubMed PMID: 30557562.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza. AU - Koshimichi,Hiroki, AU - Tsuda,Yoshiyuki, AU - Ishibashi,Toru, AU - Wajima,Toshihiro, Y1 - 2018/12/15/ PY - 2018/10/25/received PY - 2018/11/30/revised PY - 2018/12/07/accepted PY - 2018/12/18/pubmed PY - 2020/6/25/medline PY - 2018/12/18/entrez KW - S-033188 KW - baloxavir marboxil KW - cap-dependent endonuclease inhibitor KW - influenza KW - population pharmacokinetics SP - 1896 EP - 1904 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 108 IS - 5 N2 - Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/30557562/Population_Pharmacokinetic_and_Exposure_Response_Analyses_of_Baloxavir_Marboxil_in_Adults_and_Adolescents_Including_Patients_With_Influenza_ DB - PRIME DP - Unbound Medicine ER -