Mechanism Of Action
Baloxavir marboxil is an antiviral drug with activity
against influenza virus [see Microbiology].
At twice the expected exposure from recommended dosing,
XOFLUZA did not prolong the QTc interval.
No change in the baloxavir exposure-response (time to
alleviation of symptoms) relationship was observed at the recommended dosing.
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.
Table 3 : Pharmacokinetic Parameters of Plasma
|Effect of food (relative to fasting)b
||Cmax: ↓48%, AUC0-inf; ↓36%
|% Bound to human serum proteinsc
||92.9 - 93.9
|Ratio of blood cell to blood
||48.5% - 54.4%
|Volume of distribution (V/F, L)d
|Major route of elimination
|Clearance (CL/F, L/hr)d
|t½ (hr) d e
|% of dose excreted in urineg
||14.7 (Total radioactivity), 3.3 (Baloxavir)
|% of dose excreted in fecesg
||80.1 (Total radioactivity)
b Meal: approximately 400 to 500 kcal including 150 kcal from fat
c in vitro
d Geometric mean (geometric CV%)
e Apparent terminal elimination half-life
f Baloxavir is primarily metabolized by UGT1A3 with minor
contribution from CYP3A4
g Ratio of radioactivity to radio-labeled [14C]-baloxavir marboxil
dose in mass balance study
There were no clinically significant differences in the
pharmacokinetics of baloxavir based on age (adolescents as compared to adults),
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 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.
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
Drug Interaction 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
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,
Uridine Diphosphate (UDP)-Glucuronosyl Transferase (UGT)
Baloxavir marboxil and its active metabolite, baloxavir,
did not inhibit UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, or UGT2B15.
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.
Mechanism Of Action
Baloxavir marboxil is a prodrug that is converted by
hydrolysis to baloxavir, the active form that exerts antiinfluenza 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.
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.
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.
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.
Table 4 : Treatment-Emergent Amino Acid Substitutions
in PA Associated with Reduced Susceptibility to Baloxavir
|Amino Acid Substitution
||E23G/K, A37T, I38M/T, E199G
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 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 crossresistance evaluations
has not been established.
Interaction studies with influenza vaccines and baloxavir
marboxil have not been conducted.
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
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
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 (Tables 5 and 6).
Table 5 : Time to Alleviation of Symptoms after Single
Dose in Adult Subjects with Acute Uncomplicated Influenza in Trial 1 (Median
||XOFLUZA 40 mg
N = 100
N = 100
|Adults (20 to 64 Years of Age)
|1CI: Confidence interval
2XOFLUZA treatment resulted in a statistically significant shorter
time to alleviation of symptoms compared to placebo using the Gehan-Breslow’s generalized
Wilcoxon test (p-value: 0.014, adjusted for multiplicity). The primary analysis
using the Cox Proportional Hazards Model did not reach statistical significance
Table 6 : Time to Alleviation of Symptoms after Single
Dose in Subjects 12 Years of Age and Older with Acute Uncomplicated Influenza
in Trial 2 (Median Hours)
||XOFLUZA 40 mg or 80 mg1 (95% CI2)
N = 455
|Placebo (95% CI2)
N = 230
|Subjects (≥ 12 Years of Age)
||54 hours3 (50, 59)
||80 hours (73, 87)
|1Dosing was based on weight. Subjects weighing
< 80 kg received a single 40 mg dose and subjects ≥ 80 kg received a
single 80 mg dose.
2CI: Confidence interval
3XOFLUZA treatment resulted in a statistically significant shorter
time to alleviation of symptoms compared to placebo using the Peto-Prentice’s generalized
Wilcoxon test (p-value: <0.001).
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.