TY - JOUR T1 - Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection. AU - Ando,Yoshinori, AU - Noshi,Takeshi, AU - Sato,Kenji, AU - Ishibashi,Toru, AU - Yoshida,Yuki, AU - Hasegawa,Takahiro, AU - Onishi,Motoyasu, AU - Kitano,Mitsutaka, AU - Oka,Ryoko, AU - Kawai,Makoto, AU - Yoshida,Ryu, AU - Sato,Akihiko, AU - Shishido,Takao, AU - Naito,Akira, PY - 2020/02/10/received PY - 2020/08/11/accepted PY - 2020/10/10/pubmed PY - 2021/6/25/medline PY - 2020/10/9/entrez SP - 189 EP - 198 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 76 IS - 1 N2 - 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. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/33035324/Pharmacokinetic_and_pharmacodynamic_analysis_of_baloxavir_marboxil_a_novel_cap_dependent_endonuclease_inhibitor_in_a_murine_model_of_influenza_virus_infection_ DB - PRIME DP - Unbound Medicine ER -