Chemical formula: C₂₇H₂₃F₂N₃O₇S Molecular mass: 571.55 g/mol
Baloxavir marboxil is a prodrug that is converted by hydrolysis to baloxavir, the active form that exerts anti-influenza activity. Baloxavir acts on the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acidic (PA) subunit of the viral RNA polymerase complex and thereby inhibits the transcription of influenza virus genomes resulting in inhibition of influenza virus replication.
The 50% inhibition concentration (IC50) of baloxavir was 1.4 to 3.1 nmol/L for influenza A viruses and 4.5 to 8.9 nmol/L for influenza B viruses in an enzyme inhibition assay.
In a MDCK cell culture assay, the median 50% effective concentration (EC50) values of baloxavir were 0.73 nmol/L (n=31; range: 0.20-1.85 nmol/L) for subtype A/H1N1 strains, 0.83 nmol/L (n=33; range: 0.35-2.63 nmol/L) for subtype A/H3N2 strains, and 5.97 nmol/L (n=30; range: 2.67-14.23 nmol/L) for type B strains.
In an MDCK cell-based virus titre reduction assay, the 90% effective concentration (EC90) values of baloxavir were in the range of 0.46 to 0.98 nmol/L for subtype A/H1N1 and A/H3N2 viruses, 0.80 to 3.16 nmol/L for avian subtype A/H5N1 and A/H7N9 viruses, and 2.21 to 6.48 nmol/L for type B viruses.
Viruses bearing PA/I38T/F/M/N/S mutations or the PA/T20K mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir. PA/I38T/F/M/N/S mutations led to an increase in EC50 values ranging from 11 to 57-fold for influenza A viruses and 2 to 8-fold for influenza B viruses. The PA/T20K mutation led to a 7-fold increase in the EC50 value for influenza B virus.
In the four phase 3 studies of treatment of uncomplicated influenza (see below) no resistance to baloxavir was detected in baseline isolates. In the two adult and adolescent studies, treatment-emergent mutations PA/I38T/M/N were detected in 36/370 (9.7%) and in 15/290 (5.2%) patients treated with baloxavir marboxil but were not detected in any patients treated with placebo.
In the phase 3 study in paediatric patients aged 1 to <12 years (Ministone-2 (CP40563)), treatment-emergent mutations, PA/I38T/M/S were found in 11 of 57 (19.3%) influenza-infected subjects in the baloxavir marboxil treatment group.
In the phase 3 study in paediatric patients aged <1 year (Ministone-1 (CP40559)), PA/I38T and PA/T20K were detected in 2 of 13 (15.4%) influenza-infected subjects treated with baloxavir marboxil.
In the phase 3 study of post-exposure prophylaxis (see below), PA/I38T/M were found in 10 of 374 (2.7%) baloxavir marboxil-treated subjects. PA/I38 substitutions were not detected in placebo-treated subjects, with the exception of 2 subjects who received baloxavir marboxil as rescue medication.
Baloxavir is active in vitro against influenza viruses that are considered resistant to neuraminidase inhibitors, including strains with the following mutations: H274Y in A/H1N1, E119V and R292K in A/H3N2, R152K and D198E in type B virus, H274Y in A/H5N1, R292K in A/H7N9.
After oral administration, baloxavir marboxil is extensively converted to its active metabolite, baloxavir. The plasma concentration of baloxavir marboxil is very low or below the limit of quantitation (<0.100 ng/mL).
Pharmacokinetic (PK) parameters of baloxavir have been characterised in healthy adult subjects and in patients with influenza-like symptoms. Baloxavir's PK was best described by a population PK model with a two-compartment disposition model with first-order absorption and elimination processes, including a sigmoid Emax model to quantify the clearance maturation with age in infants. Body weight and race were found to have a significant effect on the PK.
In adults after single administration of baloxavir marboxil at the therapeutic doses, the estimated mean baloxavir AUC0-inf were 9580 and 4750 ng.hr/mL, and the estimated mean Cmax were 95.2 and 62.4 ng/mL in the Asian and non-Asian populations, respectively.
Following a single oral administration of 80 mg of baloxavir marboxil, the time to achieve peak plasma concentration (Tmax) is approximately 4 hours in the fasted state. The absolute bioavailability of baloxavir after oral dosing with baloxavir marboxil has not been established.
In a food-effect study, after administration of baloxavir marboxil at a 40 mg dose to healthy volunteers Cmax and AUC0-inf of baloxavir were decreased by 48% (geometric mean (CV %) of 67.6 (40.0) vs 130 (24.1) ng/mL) and 36% (geometric mean (SD) of 4540 (38.8) vs 7090 (19. 6) ng.hr/mL), in fed (with a meal of approximately 400 to 500 kcal including 150 kcal from fat) relative to fasting conditions, respectively. Tmax was unchanged in the presence of food. In clinical studies there were no clinically relevant differences in efficacy when baloxavir was taken with versus without food.
In an in vitro study, the binding of baloxavir to human serum proteins, primarily albumin, is 92.9% to 93.9%. The apparent volume of distribution of baloxavir during the terminal elimination phase (Vz/F) following a single oral administration of baloxavir marboxil is approximately 1180 L in Caucasian subjects and 647 L in Japanese subjects. The population PK parameter estimates were 260 L for the apparent peripheral volume of distribution, and 489 L and 735 L for the apparent central volume of distribution in the Asian and non-Asian populations, respectively.
Baloxavir is primarily metabolised by UGT1A3 to form a glucuronide with a minor contribution from CYP3A4 to form a sulfoxide.
Based on in vitro and in vivo drug-drug interaction (DDI) studies, baloxavir marboxil and baloxavir are not expected to inhibit isozymes of the CYP or UGT families or cause relevant induction of CYP enzymes.
Based on in vitro transporter studies and in vivo DDI studies, no relevant pharmacokinetic interaction is anticipated between baloxavir marboxil or baloxavir and medicines which are substrates of the following transporters: OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.
Following a single oral administration of 40 mg of [14C]-labeled baloxavir marboxil, the proportion of total radioactivity excreted in faeces was 80.1% of the administered dose, with the urine accounting for 14.7% (3.3% and 48.7% of the administered dose was excreted as baloxavir in urine and faeces respectively).
Population PK analyses estimated an apparent oral clearance (CL/F) of 5.47 L/h and 11.02 L/h for baloxavir in the Asian and non-Asian populations, respectively. The apparent terminal elimination half-life (t1/2,z) of baloxavir after a single oral administration of baloxavir marboxil is 79.1, 50.3 and 29.4 hours in Caucasian adults, adolescent and paediatric subjects, respectively.
Following single oral administration of baloxavir marboxil, baloxavir exhibits linear pharmacokinetics within the dose range of 6 mg to 80 mg.
Body weight is a significant covariate for baloxavir pharmacokinetics based on the population pharmacokinetic analysis, independently of age. Dosing recommendations for baloxavir marboxil are based on body weight in both adult and paediatric patients.
A population pharmacokinetic analysis did not identify a clinically meaningful effect of gender on the pharmacokinetics of baloxavir. No dose adjustment based on gender is required.
Based on a population pharmacokinetic analysis, race is an age-independent covariate on oral clearance (CL/F) of baloxavir in addition to body weight; however, no dose adjustment of baloxavir marboxil based on race is required.
A population pharmacokinetic analysis using plasma baloxavir concentrations from clinical studies in subjects aged 1 to 64 years did not identify age as a relevant covariate on the pharmacokinetics of baloxavir. In a population PK analysis including 57 paediatric patients under 1 year of age, age significantly influenced baloxavir CL/F; a maturation half-life of 38.3 weeks was estimated. However, no dose adjustment of baloxavir marboxil based on age is required.
Pharmacokinetic data of baloxavir were collected in patients aged 3 weeks to <12 years. The body weight-adjusted dosing regimen (2 mg/kg up to 20 kg and 40 mg for ≥20 kg) provides similar baloxavir exposures to the therapeutic doses of baloxavir marboxil in adults (40 mg for adult patients <80 kg and 80 mg for adult patients ≥80 kg) in both Asian and non-Asian populations (see table).The pharmacokinetics of baloxavir in paediatric patients below 3 weeks of age have not been established.
Mean (5th – 95th percentile) pharmacokinetic parameters of baloxavir in non-Asian patients aged 3 weeks and above receiving a single oral baloxavir marboxil administration:
| Age group | Dose group* | N | AUC0-inf (ng.hr/mL) | Cmax (ng/mL) | C72 (ng/mL) | Tmax (hr) | T1/2 (hr) |
|---|---|---|---|---|---|---|---|
| 22 - <28 days | 1 mg/kg** | 1 | 2640 [NA,NA] | 66.9 [NA,NA] | 8.71 [NA,NA] | 5 [NA,NA] | 23.4 [NA,NA] |
| 28 days - <3 months | 1 mg/kg** | 8 | 2580 [864,4880] | 57.1 [37.1,80.4] | 9.53 [1.3,20.3] | 6.5 [2,13] | 25.2 [13,32.8] |
| 3 months - <1 year | 2 mg/kg | 37 | 5670 [1800,11900] | 144 [48.8,294] | 18.4 [4.43,41.5] | 5.09 [2,13] | 22.9 [15.5,30.3] |
| 1 - <2 years | 2 mg/kg | 8 | 3260 [1670,5970] | 95.5 [33.1,215] | 10.0 [2.02,14.2] | 3.56 [1.5,7] | 23 [11.6,38.8] |
| 2 - <12 years | 2 mg/kg | 32 | 4490 [765,9070] | 116 [21.4,272] | 15.0 [3.06,32.2] | 3.94 [1.5,7.5] | 24.2 [17.4,35.3] |
| 40 mg | 64 | 4650 [1770,9130] | 87.1 [31.1,147] | 19.1 [7.36,39.2] | 5.51 [2.5,10.5] | 33.8 [21.7,52.4] | |
| 12 - <18 years | 40 mg | 44 | 3520 [1230,7470] | 52.7 [17.5,94.3] | 15.5 [5.76,31.2] | 4.32 [1.5,7.5] | 42.9 [32,69] |
| 80 mg | 13 | 6600 [2730,11600] | 83.7 [43.9,147] | 29.6 [12.1,51.7] | 5.19 [1,13] | 50.7 [34.2,64.5] | |
| 18 years and above | 40 mg | 310 | 3470 [1440,6350] | 47.4 [20.6,86.2] | 15.4 [6.36,27.8] | 4.67 [1.5,10] | 47.7 [31.2,67.5] |
| 80 mg | 338 | 5880 [2270,11200] | 73.4 [27.5,141] | 26.2 [10.7,49.4] | 5.19 [2,11] | 52.8 [33.6,76.2] |
* Dose groups are based on bodyweight: <20 kg: 2 mg/kg; ≥20 kg - <80 kg: 40 mg; ≥80 kg: 80 mg;
** For age categories with no PK observations at the recommended dose of baloxavir marboxil, population-PK modeling predicts that a dose of 2 mg/kg in children 22 days to 3 months of age produces a similar exposure as adults and older children.
Pharmacokinetic data collected in 181 patients aged ≥65 years show that exposure to baloxavir in the plasma was similar to that in patients aged ≥12 to 64 years.
No clinically meaningful differences in the pharmacokinetics of baloxavir were observed in patients with mild or moderate hepatic impairment (Child-Pugh class A and B) compared with healthy controls with normal hepatic function.
The pharmacokinetics in patients with severe hepatic impairment have not been evaluated.
The effects of renal impairment on the pharmacokinetics of baloxavir marboxil or baloxavir have not been evaluated. Renal impairment is not expected to alter the elimination of baloxavir marboxil or baloxavir.
Nonclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity.
Prolongation of PT and APTT were observed in rats at exposures at least equal to the human exposure based on AUC0-24hr under specific experimental conditions, i.e. when fasted and when the food was either autoclaved or radiation-treated, resulting in vitamin K limiting/deficient conditions. These effects were not observed in monkey studies up to 4 weeks duration at the highest tested dose equivalent to 8-times the human exposure based on AUC0-24hr. They are considered to be of limited clinical relevance.
Carcinogenicity studies have not been performed with baloxavir marboxil.
The pro-drug baloxavir marboxil, and its active form, baloxavir, were not considered genotoxic as they tested negative in bacterial reverse mutation tests, micronucleus tests with cultured mammalian cells, and as baloxavir marboxil was negative in an in vivo rodent micronucleus test.
Baloxavir marboxil had no effects on fertility when given orally to male and female rats at doses providing exposure equivalent to 5-times the human exposure based on AUC0-24hr.
Baloxavir marboxil did not cause malformations in rats or rabbits.
The oral embryo-foetal development study of baloxavir marboxil in rats with daily doses from gestation day 6 to 17 revealed no signs of maternal or foetal toxicity up to the highest tested dose providing exposure equivalent to 5-times the human exposure based on AUC0-24hr.
In rabbits, a dose providing exposure equivalent to 14-times the human exposure based on AUC0-24hr following the MHRD caused maternal toxicity resulting in miscarriages and significant increase in incidence of foetuses with a skeletal variation (cervical rib). The skeletal variations were reabsorbed during the growing process of adjacent cervical vertebra. A dose providing exposure equivalent to 6- times the human exposure based on AUC0-24hr in rabbits was without adverse effects.
The pre- and postnatal study in rats did not show drug-related adverse findings in dams and pups up to the highest tested dose providing exposure equivalent to 5-times the human exposure based on AUC0-24hr.
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