Baloxavir marboxil

Mechanism of action

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.

Pharmacodynamic properties

In vitro activity

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.

Resistance

Viruses bearing the PA/I38T/F/M/N mutation selected in vitro or in clinical studies show reduced susceptibility to baloxavir with changes in EC50 values ranging from 11 to 57-fold for influenza A viruses and 2 to 8-fold for influenza B viruses.

In the two Phase 3 studies of treatment of uncomplicated influenza (see below) no resistance to baloxavir was detected in baseline isolates. 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 of post-exposure prophylaxis (see below), treatment-emergent mutations 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.

Cardiac Electrophysiology

At twice the expected exposure from recommended dosing, baloxavir marboxil did not prolong the QTc interval.

Exposure-Response Relationships

When baloxavir marboxil is dosed by weight, as recommended (40 mg in patients weighing 40-80 kg; and 80 mg in patients weighing at least 80 kg), no difference in baloxavir exposure-response (time to alleviation of influenza symptoms in the Otherwise Healthy population or time to improvement of influenza symptoms in the High Risk population) relationship has been observed.

Pharmacokinetic properties

Absorption

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).

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.

Food effect

A food-effect study involving administration of baloxavir marboxil to healthy volunteers under fasting conditions and with a meal (approximately 400 to 500 kcal including 150 kcal from fat) indicated that the Cmax and AUC of baloxavir were decreased by 48% and 36%, respectively, under fed conditions. Tmax was unchanged in the presence of food. In clinical studies there were no clinically relevant differences in efficacy when baloxavir was taken with vs. without food.

Distribution

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 litres in Caucasian subjects and 647 litres in Japanese subjects.

Biotransformation

Baloxavir is primarily metabolised by UGT1A3 to form a glucuronide with a minor contribution from CYP3A4 to form a sulfoxide.

Drug-drug interaction studies

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 followingtransporters: OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, MATE1, or MATE2K.

Excretion

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).

Elimination

The apparent terminal elimination half-life (t1/2,z) of baloxavir after a single oral administration of baloxavir marboxil is 79.1 hours in Caucasian subjects.

Linearity/non-linearity

Following single oral administration of baloxavir marboxil, baloxavir exhibits linear pharmacokinetics within the dose range of 6 mg to 80 mg.

Special populations

Body weight

Body weight is a significant covariate for baloxavir pharmacokinetics based on the population pharmacokinetic analysis. Dosing recommendations for baloxavir marboxil are based on body weight.

Gender

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.

Race

Based on a population pharmacokinetic analysis, race is a 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.

Age

A population pharmacokinetic analysis using plasma baloxavir concentrations from clinical studies in subjects aged 12 to 64 years did not identify age as a relevant covariate on the pharmacokinetics of baloxavir.

Paediatric population

There are limited data on the pharmacokinetics of baloxavir in paediatric patients (<12 years of age).

Elderly

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.

Renal impairment

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.

Hepatic impairment

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.

Preclinical safety data

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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