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Polymerase acidic endonuclease inhibitor20,39
Baloxavir marboxil, a prodrug for baloxavir, is the first-in-class inhibitor of influenza polymerase acidic (PA) endonuclease.22,55 It is commonly classified as a “cap-dependent” endonuclease (CEN) inhibitor.56 Located in the viral RNA polymerase complex, PA endonuclease is required for the critical “cap-snatching” step of viral gene transcription and subsequent virus replication.22,40,55 Baloxavir is a single-dose oral antiviral agent approved for administration as soon as possible, but not more than 48 hours, after symptom development in patients ≥12 years of age with uncomplicated influenza A or B.40 The Centers for Disease Control and Prevention (CDC) does not recommend the use of baloxavir for pregnant women, breastfeeding mothers, or patients at high risk of influenza related complications; oseltamivir is preferred in these settings.56 Oral oseltamivir also remains the CDC-recommended antiviral for patients with severe, complicated, or progressive illness who are not hospitalized, and for hospitalized patients with influenza.56
Resistance to baloxavir after a single dose is well characterized, particularly for influenza A/H3N2.57 Viruses with reduced susceptibility most commonly have amino acid substitutions in their PA protein.57-59 The clinical consequences of treatment-emergent resistance, particularly for infection transmissibility, is unknown.57-59 CDC’s Influenza Division has incorporated baloxavir into its routine virologic surveillance and will be tracking baloxavir susceptibility.56 Eventually, the results of routine baloxavir susceptibility tests will be incorporated into FluView,60 CDC’s weekly influenza communications report.56
Baloxavir marboxil is hydrolyzed to the active moiety, baloxavir.40 Baloxavir has a half-life of ~80 hours and elimination is via the feces following UGT1A3 metabolism to a glucuronic acid conjugate and subsequent CYP3A4 conversion to a sulfoxide.61 Both the prodrug, baloxavir marboxil, and baloxavir are substrates of P-glycoprotein.40 The chemical structure of baloxavir marboxil is shown in Figure P1-1.66 Dosing of baloxavir marboxil is weight-based, with a single 40-mg dose recommended for patients weighing ≤40 kg and 80 mg for all others.40 Baloxavir may chelate polyvalent cations, so co-administration with calcium, iron, magnesium, selenium, or zinc must be avoided. Like other oral antivirals, baloxavir should not be administered in close temporal proximity to the intranasal live attenuated influenza vaccine (FluMist Quadrivalent).40
FDA approval of baloxavir marboxil was made on the basis of two premarket clinical trials in outpatients 12–64 years of age.40,41 Patients with underlying medical conditions and adults ≥65 years of age were excluded.57 The vast majority of study patients were Asian, a population known to achieve 35% higher systemic exposures to baloxavir than non-Asians.40,62 Results of these premarket studies indicate that in patients not at high risk for influenza-related complications, single-dose treatment with baloxavir marboxil is well tolerated with an incidence of adverse effects similar to placebo.40,63 The drug bettered placebo and shortened the duration of viral shedding better than 5 days of oseltamivir therapy (24 hours vs 72 hours), but within the adult population, baloxavir marboxil only matched oseltamivir in the time to self-reported symptom reduction.58,59,63-65 Currently, the clinical evidence for efficacy against influenza B is less robust than for influenza A.40 Additional efficacy and safety studies are underway in high-risk patients and children <2 years of age.61
Chemical structure of baloxavir marboxil66 (PubChem CID: 124081876; IUPAC name: [(3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c]benzothiepin-11-yl]-9,12-dioxo-5-oxa-1,2,8-triazatricyclo[188.8.131.52]tetradeca-10,13-dien-11-yl]oxymethyl methyl carbonate).
Chapter 62. Antiviral Agents (Nonretroviral) > Anti-influenza Agents
eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals