tetano
Editor, Senior Moderator
J Antimicrob Chemother
. 2020 Oct 10;dkaa393.
doi: 10.1093/jac/dkaa393. Online ahead of print.
Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection
Yoshinori Ando[SUP] 1 [/SUP], Takeshi Noshi[SUP] 1 [/SUP], Kenji Sato[SUP] 1 [/SUP], Toru Ishibashi[SUP] 2 [/SUP], Yuki Yoshida[SUP] 3 [/SUP], Takahiro Hasegawa[SUP] 4 [/SUP], Motoyasu Onishi[SUP] 1 [/SUP], Mitsutaka Kitano[SUP] 1 [/SUP], Ryoko Oka[SUP] 1 [/SUP], Makoto Kawai[SUP] 1 [/SUP], Ryu Yoshida[SUP] 1 [/SUP], Akihiko Sato[SUP] 1 [/SUP], Takao Shishido[SUP] 1 [/SUP], Akira Naito[SUP] 1 [/SUP]
Affiliations
Abstract
Background: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies.
Objectives: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice.
Methods: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid.
Results: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid.
Conclusions: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.
. 2020 Oct 10;dkaa393.
doi: 10.1093/jac/dkaa393. Online ahead of print.
Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection
Yoshinori Ando[SUP] 1 [/SUP], Takeshi Noshi[SUP] 1 [/SUP], Kenji Sato[SUP] 1 [/SUP], Toru Ishibashi[SUP] 2 [/SUP], Yuki Yoshida[SUP] 3 [/SUP], Takahiro Hasegawa[SUP] 4 [/SUP], Motoyasu Onishi[SUP] 1 [/SUP], Mitsutaka Kitano[SUP] 1 [/SUP], Ryoko Oka[SUP] 1 [/SUP], Makoto Kawai[SUP] 1 [/SUP], Ryu Yoshida[SUP] 1 [/SUP], Akihiko Sato[SUP] 1 [/SUP], Takao Shishido[SUP] 1 [/SUP], Akira Naito[SUP] 1 [/SUP]
Affiliations
- PMID: 33035324
- DOI: 10.1093/jac/dkaa393
Abstract
Background: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies.
Objectives: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice.
Methods: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid.
Results: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid.
Conclusions: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.