Pharmacologic background and clinical issue of anti-influenza drugs

Abstract

Since 2000, rapid antigen detection kits and anti-influenza drugs have been used for the early diagnosis and treatment of influenza in Japan, respectively. The main drugs available in clinical practice are the neuraminidase inhibitors oseltamivir, zanamivir, laninamivir, and peramivir, as well as the cap-dependent endonuclease inhibitor baloxavir marboxil. Antiviral therapy with neuraminidase inhibitors has been practiced for many years, especially in Japan; it can shorten the febrile period and reduce complications. Despite having similar structures, the pharmacologic background of neuraminidase inhibitors differs significantly, as reflected in their varying clinical efficacy. Due to its inhibitory mechanism, baloxavir marboxil can rapidly reduce the viral load than neuraminidase inhibitors. However, the duration of symptoms was similar after the administration of baloxavir marboxil and oseltamivir, and variants with reduced drug susceptibility have been detected in 20%-30% of pediatric patients treated with baloxavir marboxil. Clinical trials of several novel anti-influenza drugs are currently underway. When these drugs are first marketed, the characteristics of the influenza virus and the pharmacologic background of the drugs must be clarified before their administration to patients in clinical practice.

Keywords: anti-influenza drug; antiviral; children; influenza.

Fig. 1.

Life cycle of influenza virus ① adsorption, ② endocytosis, ③ membrane fusion, ④ uncoating, ⑤ RNA replication, ⑥ mRNA transcription, ⑦ protein synthesis, ⑧ budding, and ⑨ release

Fig. 2.

Structure of neuraminidase inhibitors ① carboxyl group, ② glycerol group, ③ N-acetylamino group, ④ hydroxy group, ⑤ guanidino group, ⑥ 3-pentyl group, and ⑦ amino group DANA, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid

Fig. 3.

Binding of drugs to virus neuraminidase Each neuraminidase inhibitor binds to the active site of viral neuraminidase (gray solid) using its side chain. Oseltamivir and peramivir are required to induce the formation of hydrophobic pockets (red circle) on the viral neuraminidase for successful binding. DANA, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid

Fig. 4.

Peramivir concentration after a single intravenous administration After a single administration of peramivir, a maximum concentration of 5000 nM of peramivir in the URT is expected, but in children, this drug may be eliminated from the URT approximately 35 h after administration. URT, upper respiratory tract.

Fig. 5.

Proposal of the selection of anti-influenza drugs in children Peramivir may be administered to outpatients only if these patients have a secure intravenous route (a), but it can be the first choice for inpatients (c). Baloxavir marboxil for outpatients aged <12 years should be administered after careful consideration for the frequent emergence of variants with reduced drug susceptibility (b), but it can be the first drug choice if patients have variants with reduced susceptibility against neuraminidase inhibitors (d). OTV, oseltamivir; ZNV, zanamivir; LNV, laninamivir; PRV, peramivir; BXM, baloxavir marboxil.

Fig. 6.

Landscape of anti-influenza drugs under development HA, hemagglutinin; mAb, monoclonal antibody; NSAID, nonsteroidal anti-inflammatory drug; NA, neuraminidase a, oral drug; b, injection drug; c, muscle injection drug; d, inhalation drug