No data are currently in the public domain regarding preclinical safety or maternal–fetal and juvenile toxicology.
Formulations in development include tablets for oral administration and a solution for intravenous administration (NCT02659735). Oral pimodivir demonstrates dose proportional pharmacokinetics (Table 2) with a mean terminal plasma T1/2elim of about 24 h [24,30], such that steady-state levels are reached between days 3–4 of dosing [31▪▪]. It is metabolized by CYP 3A4, but has no effect on cytochrome P450 activity. The low renal elimination (∼5%) suggests that pimodivir does not require dose adjustments for renal insufficiency. No meaningful pharmacokinetic differences were found in hospitalized influenza patients between younger (aged 18–64 years) and elderly (65–85 years) adults . In a drug–drug interaction study, oseltamivir increased pimodivir Cmax by 31% with no change in Cmin or AUC12 h; pimodivir had no effect on oseltamivir [24,30].
Among those administered a single dose up to 3200 mg, and patients given multiple doses of 600 mg, the most common adverse event has been dose-related diarrhea, usually characterized as ‘loose stools’ and mild in severity . The self-limited diarrhea has occurred in 27% of outpatients dosed at 600 mg BID. The mechanism remains to be determined. Other adverse events possibly related to pimodivir include nausea, emesis, elevations in transaminases, and decreased neutrophil counts [31▪▪].
Testing of passaged laboratory strains or clinical isolates from treated patients has identified isoleucine-to-threonine, methionine, and phenylalanine substitutions at amino acid position 38 in the polymerase acidic protein (PA/I38T/F/M) that confer at least 10-fold reduced susceptibility to baloxavir acid in influenza A viruses [33,34▪]; for influenza A(H3N2) and A(H1N1) the PA/I38T substitution confers approximately 60 and 30-fold reductions in susceptibility, respectively. Influenza a viruses harboring the PA/I38T substitution show reduced endonuclease activity and impaired replicative fitness in cell culture [34▪]. Another study found that the PA/I38T substitution was stably maintained during cell culture passage without drug pressure and that variants with only the PA/I38T substitution maintained high levels of replication . Replication and transmission fitness studies with PA/I38X variants are in progress in animal models.
Monkeys showed elevations in liver function tests, including alanine aminotransferase, at doses of 20 mg/kg/day or higher. Baloxavir has not shown maternal or juvenile toxicity or adverse effects on reproduction or embryo-fetal development in animal models at exposure levels that exceed those observed with the maximally recommended human dose . No effects on the central nervous, cardiovascular, and respiratory systems have been detected in preclinical studies to date at exposure levels well above those anticipated in humans.
Emergence of PA/I38T/F/M variants conferring reduced susceptibility occurred in 2.3% and 9.7% of baloxavir recipients in the phase 2 [all A(H1N1)] and phase 3 [all A(H3N2)] RCTs, respectively [41▪▪]. Baloxavir recipients developing such variants showed transient rebounds in virus titers, prolonged virus positivity, and compared with recipients without variants, early delay in illness resolution. In a pediatric study, 23% of baloxavir-treated children had PA/I38X variants detected at day 6 or 9 . The possible transmissibility of such variants requires careful study and monitoring, and household-based trials examining baloxavir's effects on transmission of wild-type and variant viruses are planned. Other non-I38X polymerase acidic protein substitutions were also noted in the clinical trials, but their significance remains to be determined.
Papers of particular interest, published within the annual period of review, have been highlighted as:
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18. Avigan Tablets 200 mg, PMDA, 5th Version, August 2018
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Study characterizing clinical isolates from patients receiving favipiravir that shows genetic changes in polymerase genes consistent with favipiravir's induction of genetic errors but no significant loss of susceptibility.
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Publication detailing pimodivir's antiviral spectrum and activities in preclinical models including enhancement of antiviral effects when combined with neuraminidase inhibitors.
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First demonstration of pimodivir's dose-related antiviral activity and tolerability in outpatients with uncomplicated influenza A virus infection. The combination of pimodivir 600 mg and oseltamivir 75 mg, both administered twice daily, showed greater antiviral effect than pimodivir monotherapy and markedly reduced the frequency of PB2 variants with reduced pimodivir susceptibility.
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Key study detailing structure-based mechanism of action of baloxavir and characterization of variants with polymerase acidic protein/I38T substitutions, including effects on in-vitro susceptibility, polymerase activity, and impact on replication fitness in cell culture.
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38. FDA Prescribing Information: XOFLUZATM
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41▪▪. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir
marboxil for uncomplicated influenza
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Pivotal placebo-controlled phase 2 dose-ranging and phase 3 randomized controlled trials of single-dose baloxavir in uncomplicated influenza that show excellent tolerability and decreased times to symptom alleviation of approximately 1 day compared with placebo, similar to oseltamivir's effect. Baloxavir was associated with significantly more rapid inhibition of influenza virus replication than both placebo and oseltamivir but also with emergence of polymerase acidic protein/I38X variants showing reduced baloxavir susceptibility.
42. Ison M, Portsmouth S, Yoshida Y, Shishido T, et al. Phase 3 trial of baloxavir
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