Pharmacology: Mechanism of Action: Baloxavir marboxil is an antiviral drug with activity against influenza virus [see Microbiology as follows].
Pharmacodynamics: Cardiac Electrophysiology: At twice the expected exposure from recommended dosing, XOFLUZA did not prolong the QTc interval.
Exposure-Response Relationships: No change in the baloxavir exposure-response (time to alleviation of symptoms) relationship was observed at the recommended dosing.
Clinical Studies: Two randomized controlled double-blinded clinical trials conducted in two different influenza seasons evaluated efficacy and safety of XOFLUZA in otherwise healthy subjects with acute uncomplicated influenza.
In Trial 1, a placebo-controlled phase 2 dose-finding trial, a single oral dose of XOFLUZA was compared with placebo in 400 adult subjects 20 to 64 years of age in Japan. All subjects in Trial 1 were Asian, the majority of subjects were male (62%), and the mean age was 38 years. In this trial, among subjects who received XOFLUZA and had influenza virus typed, influenza A/H1N1 was the predominant strain (63%), followed by influenza B (25%), and influenza A/H3N2 (12%).
In Trial 2 (NCT02954354), a phase 3 active- and placebo-controlled trial, XOFLUZA was studied in 1,436 adult and adolescent subjects 12 to 64 years of age weighing at least 40 kg in the U.S. and Japan. Adults ages 20 to 64 years received XOFLUZA or placebo as a single oral dose on Day 1 or oseltamivir twice a day for 5 days. Subjects in the XOFLUZA and placebo arms received a placebo for the duration of oseltamivir dosing after XOFLUZA or placebo dosing in that arm. Adolescent subjects 12 to less than 20 years of age received XOFLUZA or placebo as a single oral dose.
In Trial 2, subjects weighing less than 80 kg received XOFLUZA at a dose of 40 mg and subjects weighing 80 kg or more received an 80 mg dose. Seventy-eight percent of subjects in Trial 2 were Asian, 17% were White, and 4% were Black or African American. The mean age was 34 years, and 11% of subjects were less than 20 years of age; 54% of subjects were male and 46% female. In Trial 2, among subjects who received XOFLUZA and had influenza virus typed, influenza A/H3N2 was the predominant strain (90%), followed by influenza B (9%), and influenza A/H1N1 (2%).
In both trials, eligible subjects had an axillary temperature of at least 38°C, at least one moderate or severe respiratory symptom (cough, nasal congestion, or sore throat), and at least one moderate or severe systemic symptom (headache, feverishness or chills, muscle or joint pain, or fatigue) and all were treated within 48 hours of symptom onset. Subjects participating in the trial were required to self-assess their influenza symptoms as "none", "mild", "moderate" or "severe" twice daily. The primary efficacy population was defined as those with a positive rapid influenza diagnostic test (Trial 1) or positive influenza RT-PCR (Trial 2) at trial entry.
The primary endpoint of both trials, time to alleviation of symptoms, was defined as the time when all seven symptoms (cough, sore throat, nasal congestion, headache, feverishness, myalgia, and fatigue) had been assessed by the subject as none or mild for a duration of at least 21.5 hours.
In both trials, XOFLUZA treatment at the recommended dose resulted in a statistically significant shorter time to alleviation of symptoms compared with placebo in the primary efficacy population (see Tables 1 and 2).
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Click on icon to see table/diagram/image
In Trial 2, there was no difference in the time to alleviation of symptoms between subjects who received XOFLUZA (54 hours) and those who received oseltamivir (54 hours). For adolescent subjects (12 to 17 years of age) in Trial 2, the median time to alleviation of symptoms for subjects who received XOFLUZA (N=63) was 54 hours (95% CI of 43, 81) compared to 93 hours (95% CI of 64, 118) in the placebo arm (N=27).
The number of subjects who received XOFLUZA at the recommended dose and who were infected with influenza type B virus was limited, including 24 subjects in Trial 1 and 38 subjects in Trial 2. In the influenza B subset in Trial 1, the median time to alleviation of symptoms in subjects who received 40 mg XOFLUZA was 63 hours (95% CI of 43, 70) compared to 83 hours (95% CI of 58, 93) in subjects who received placebo. In the influenza B subset in Trial 2, the median time to alleviation of symptoms in subjects who received 40 mg or 80 mg XOFLUZA was 93 hours (95% CI of 53, 135) compared to 77 hours (95% CI of 47, 189) in subjects who received placebo.
Pharmacokinetics: Baloxavir marboxil is a prodrug that is almost completely converted to its active metabolite, baloxavir, following oral administration.
In the phase 3 trial, at the recommended dose of 40 mg for subjects weighing less than 80 kg, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 96.4 ng/mL (45.9%) and 6160 ng·hr/mL (39.2%), respectively. At the recommended dose of 80 mg for subjects weighing 80 kg and more, the mean (CV%) values of baloxavir Cmax and AUC0-inf were 107 ng/mL (47.2%) and 8009 ng·hr/mL (42.4%), respectively. Refer to Table 3 for pharmacokinetic parameters of baloxavir in healthy subjects. (See Table 3.)
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Specific Populations: There were no clinically significant differences in the pharmacokinetics of baloxavir based on age (adolescents as compared to adults), or sex.
Patients with Renal Impairment: A population pharmacokinetic analysis did not identify a clinically meaningful effect of renal function on the pharmacokinetics of baloxavir in patients with creatinine clearance (CrCl) 50 mL/min and above. The effects of severe renal impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite, baloxavir, have not been evaluated.
Patients with Hepatic Impairment: In a clinical study comparing pharmacokinetics of baloxavir in subjects with moderate hepatic impairment (Child-Pugh class B) to subjects with normal hepatic function, no clinically meaningful differences in the pharmacokinetics of baloxavir were observed. The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.
Body Weight: Body weight had a significant effect on the pharmacokinetics of baloxavir (as body weight increases, baloxavir exposure decreases). When dosed with the recommended weight-based dosing, no clinically significant difference in exposure was observed between body weight groups.
Race/Ethnicity: Based on a population pharmacokinetic analysis, baloxavir exposure is approximately 35% lower in non-Asians as compared to Asians; this difference is not considered clinically significant when the recommended dose was administered.
Drug Interaction Studies: Clinical Studies: No clinically significant changes in the pharmacokinetics of baloxavir marboxil and its active metabolite, baloxavir, were observed when co-administered with itraconazole (combined strong CYP3A and P-gp inhibitor), probenecid (UGT inhibitor), or oseltamivir.
No clinically significant changes in the pharmacokinetics of the following drugs were observed when coadministered with baloxavir marboxil: midazolam (CYP3A4 substrate), digoxin (P-gp substrate), rosuvastatin (BCRP substrate), or oseltamivir.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Cytochrome P450 (CYP) Enzymes: Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6. Baloxavir marboxil and its active metabolite, baloxavir, did not induce CYP1A2, CYP2B6, or CYP3A4.
Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Baloxavir marboxil and its active metabolite, baloxavir, did not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
Transporter Systems: Both baloxavir marboxil and baloxavir are substrates of P-glycoprotein (P-gp). Baloxavir did not inhibit organic anion transporting polypeptides (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, multidrug and toxin extrusion (MATE) 1, or MATE2K.
Potential for Interactions with Polyvalent Cations: Baloxavir may form a chelate with polyvalent cations such as calcium, aluminum, or magnesium in food or medications. A significant decrease in baloxavir exposure was observed when XOFLUZA was co-administered with calcium, aluminum, magnesium, or iron in monkeys. No study has been conducted in humans.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Carcinogenicity studies have not been performed with baloxavir marboxil.
Mutagenesis: Baloxavir marboxil and the active metabolite, baloxavir, were not mutagenic in in vitro and in in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, micronucleus tests with cultured mammalian cells, and in the rodent micronucleus assay.
Impairment of Fertility: In a fertility and early embryonic development study in rats, doses of baloxavir marboxil at 20, 200, or 1,000 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 7 of pregnancy. Males were dosed for 4 weeks before mating and throughout mating. There were no effects on fertility, mating performance, or early embryonic development at any dose level, resulting in systemic drug exposure (AUC) approximately 5 times the MRHD.
Microbiology: Mechanism of Action: Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza virus activity. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, an influenza virus-specific enzyme in the viral RNA polymerase complex required for viral gene transcription, resulting in inhibition of influenza virus replication. The 50% inhibitory concentration (IC50) of baloxavir was 1.4 to 3.1 nM (n=4) for influenza A viruses and 4.5 to 8.9 nM (n=3) for influenza B viruses in a PA endonuclease assay. Viruses with reduced susceptibility to baloxavir have amino acid substitutions in the PA protein.
Antiviral Activity: The antiviral activity of baloxavir against laboratory strains and clinical isolates of influenza A and B viruses was determined in an MDCK-cell-based plaque reduction assay. The median 50% effective concentration (EC50) values of baloxavir were 0.73 nM (n=19; range: 0.20-1.85 nM) for subtype A/H1N1 strains, 0.68 nM (n=19; range: 0.35-1.87 nM) for subtype A/H3N2 strains, and 5.28 nM (n=21; range: 3.33-13.00 nM) for type B strains. In an MDCK-cell-based virus titer reduction assay, the 90% effective concentration (EC90) values of baloxavir against avian subtypes A/H5N1 and A/H7N9 were 1.64 and 0.80 nM, respectively. The relationship between antiviral activity in cell culture and clinical response to treatment in humans has not been established.
Resistance: Cell culture: Influenza A virus isolates with reduced susceptibility to baloxavir were selected by serial passage of virus in cell culture in the presence of increasing concentrations of baloxavir. Reduced susceptibility of influenza A virus to baloxavir was conferred by amino acid substitutions I38T (A/H1N1 and A/H3N2) and E199G (A/H3N2) in the PA protein of the viral RNA polymerase complex.
Clinical studies: Influenza A and B viruses with treatment-emergent amino acid substitutions at positions associated with reduced susceptibility to baloxavir in cell culture were observed in clinical studies (Table 4). The overall incidence of treatment-emergent amino acid substitutions associated with reduced susceptibility to baloxavir in Trials 1 and 2 was 2.7% (5/182) and 11% (39/370), respectively. (See Table 4.)
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None of the treatment-emergent substitutions associated with reduced susceptibility to baloxavir were identified in virus from pre-treatment respiratory specimens in the clinical studies. Strains containing substitutions known to be associated with reduced susceptibility to baloxavir were identified in approximately 0.05% of PA sequences in the National Center for Biotechnology Information/GenBank database (queried August 2018).
Prescribers should consider currently available surveillance information on influenza virus drug susceptibility patterns and treatment effects when deciding whether to use XOFLUZA.
Cross-Resistance: Cross-resistance between baloxavir and neuraminidase (NA) inhibitors, or between baloxavir and M2 proton pump inhibitors (adamantanes), is not expected, because these drugs target different viral proteins. Baloxavir is active against NA inhibitor-resistant strains, including A/H1N1 and A/H5N1 viruses with the NA substitution H275Y (A/H1N1 numbering), A/H3N2 virus with the NA substitution E119V, A/H7N9 virus with the NA substitution R292K (A/H3N2 numbering), and type B virus with the NA substitution D198E (A/H3N2 numbering). The NA inhibitor oseltamivir is active against viruses with reduced susceptibility to baloxavir, including A/H1N1 virus with PA substitutions E23K or I38F/T, A/H3N2 virus with PA substitutions E23G/K, A37T, I38M/T, or E199G, and type B virus with the PA substitution I38T. Influenza virus may carry amino acid substitutions in PA that reduce susceptibility to baloxavir and at the same time carry resistance-associated substitutions for NA inhibitors and M2 proton pump inhibitors. The clinical relevance of phenotypic cross-resistance evaluations has not been established.
Immune Response: Interaction studies with influenza vaccines and baloxavir marboxil have not been conducted.