Xoflusa, 40 mg 2 pcs

Pharmacotherapeutic group

Antiviral agent.

ATX code

J05AX25

Pharmacological properties

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Pharmacodynamics

Mechanism of action

Baloxavir marboxil is a prodrug that is converted by hydrolysis to the active metabolite baloxavir, which has action against the influenza virus. Baloxavir affects the cap-dependent endonuclease (CEN), an influenza virus-specific enzyme in the polymerase acid subunit of the viral RNA polymerase complex. Thus, baloxavir inhibits the transcription of the influenza virus genome, leading to suppression of viral replication.

Viruses with the PA/I38T/M/F/N mutation selected in in vitro studies or in clinical trials have shown reduced sensitivity to baloxavir. Baloxavir has activity against strains resistant to the neuraminidase inhibitor, including the following mutations: H274Y for subtype A/H1N1 virus; E119V and R292K for subtype A/H3N2 virus; R152K and D198E for type B virus; H274Y for subtype A/H5N1 virus and R292K for subtype A/H7N9 virus.

The relationship between antiviral activity in cell culture and inhibition of influenza virus replication in humans has not been established.

Other

Ksoflusa^® does not cause an increase in the QTc interval.

Doclinical safety data

Preclinical studies based on results of standard pharmacological safety studies and acute toxicity and repeated administration toxicity studies have not shown any particular risk to humans.

Carcinogenicity

Carcinogenicity studies of baloxavir marboxil have not been conducted.

Resistance

. Influenza A virus isolates with amino acid substitutions of the RA protein (enzyme in the polymerase acid subunit of the viral RNA polymerase complex) at the I38T/F/M/N position developed during therapy were associated with more than a 10-fold decrease in sensitivity to baloxavir. Influenza B virus isolates with amino acid substitutions at the I38T position were associated with more than a 5-fold decrease in sensitivity to baloxavir. The clinical significance of this reduced sensitivity is unknown.

In clinical trials, no virus isolates with baseline (non-therapy-related) amino acid substitutions were found to be associated with reduced sensitivity to baloxavir. In controlled clinical trials, influenza virus with the RA/I38T/M mutation was detected in 9.7% of patients without comorbidities; influenza virus with the RA/I38T/M/N mutation was detected in 5.2% of patients at high risk for complications receiving Xoflusa^®.

Cross Resistance

. Amino acid substitutions that could provide cross-resistance between baloxavir and neuraminidase inhibitors (e.g., peramivir, oseltamivir, zanamivir) have not been detected. However, the virus may carry amino acid substitutions in PA protein associated with reduced sensitivity to baloxavir as well as amino acid substitutions in neuraminidase associated with reduced sensitivity to neuraminidase inhibitors. Thus, the virus may exhibit reduced sensitivity to both classes of inhibitors. The clinical significance of assessing phenotypic cross-resistance has not been established.

immunogenicity

There have been no interaction studies of influenza vaccines and baloxavir marboxil. Xoflusa^® had no effect on the normal humoral antibody response in studies following infection of patients by natural and experimental routes.

Pharmacokinetics

. After oral administration, baloxavir marboxil is extensively converted to its active metabolite baloxavir, primarily under the action of arilacetamide deacetylase in the GI tract, intestinal epithelium and liver. Plasma concentrations of baloxavir marboxyl were very low or below the limit of quantification (<0.100 ng/ml).

absorption

After a single oral administration of baloxavir marboxil at a dose of 80 mg, the time to reach maximum plasma concentration (T_max) of baloxavir in the fasting state was ~4 hours. The absolute bioavailability of baloxavir marboxil has not been established.

Effects of food intake

A study of baloxavir marboxil administration in healthy volunteers on an empty stomach and after a meal (approximately 400-500 kcal, including 150 kcal as fat) found that after a meal, C_max and AUC of baloxavir were reduced by 48% and 36%, respectively. The T_max did not change in the presence of food. In clinical trials, no clinically significant differences in efficacy were observed in patients with influenza when Xoflusa^® was administered on an empty stomach or after a meal.

Distribution

In in vitro conditions The binding rate of baloxavir to human plasma proteins, predominantly to albumin, was 92.9-93.9%. After oral administration of baloxavir marboxil at a dose of 80 mg, the distribution volume of baloxavir in Caucasian patients was ~1180 liters.

Metabolism

In in vitro conditions it has been shown that the conversion of baloxavir marboxyl to the metabolite baloxavir is predominantly performed by arylacetamide deacetylase, which is found in the GI lumen, intestinal epithelium and liver. Baloxavir is primarily metabolized by the enzyme UGT1A3 (uridine diphosphate-glucuronosyltransferase 1-3). The CYP3A4 isoenzyme also provides a minimal contribution to this process.

In a mass balance study in humans after a single oral administration of [¹⁴C]isotope-labeled baloxavir marboxil at a dose of 40 mg, baloxavir accounted for 82.2% of the AUC for total plasma radioactivity. Baloxavir glucuronide (16.4% of the AUC for total plasma radioactivity) and (12aR,5R,11S) baloxavir sulfoxide (1.5% of the AUC for total plasma radioactivity) were also detected in plasma. This confirms the realization of the metabolism of baloxavir marboxyl under in vivo conditions through ester hydrolysis to form baloxavir. The latter undergoes subsequent metabolism with the formation of sulfoxides and glucuronide.

Elimation

Baloxavir marboxyl and its metabolite baloxavir are excreted in humans mainly by the intestine. After a single oral administration of [¹⁴C-labeled baloxavir marboxil at a dose of 40 mg, the proportion of total intestinal radioactivity excreted was 80.1% of the administered dose, and for urine the figure was 14.7%. The amount of baloxavir excreted with the kidneys was 3.3% of the administered dose.

After a single oral administration of baloxavir marboxil, the apparent terminal elimination half-life (t_1/2,z) of baloxavir in European patients was 79.1 hours (see Table 1).

After a single oral administration of baloxavir marboxil at doses ranging from 6 mg to 80 mg in the fasting state, linear pharmacokinetics of baloxavir were observed.

Pharmacokinetics in special patient groups

Body weight

Body weight has been identified as an important covariate based on population pharmacokinetic analysis. The recommended dose in adult patients is 40 mg (if body weight is 40 to <80 kg) and 80 mg (if body weight is ≥80 kg).

Gender

Population pharmacokinetics analysis showed no clinically significant effect of gender on baloxavir pharmacokinetics. No dose adjustment is required.

Race

Based on population pharmacokinetics analysis, it was concluded that in addition to body weight, race was also a covariate of the CL/F (apparent total clearance) of baloxavir. Nevertheless, there is no need to adjust the dose of baloxavir marboxil according to race.

Age

. A population pharmacokinetics analysis using plasma concentrations of baloxavir from clinical studies of baloxavir marboxil in patients aged 12 years to 64 years showed no clinically significant effect of age on baloxavir pharmacokinetics.

Patients of pediatric age

The pharmacokinetics of Xoflusa^® in pediatric patients (˂12 years) have not been established.

Elderly patients

Pharmacokinetic data obtained in patients ≥65 years of age showed that exposure to baloxavir was comparable to that in patients aged 12 years (inclusive) to 64 years.

Patients with impaired renal function

Population pharmacokinetics analysis showed no clinically significant effect of renal function on baloxavir pharmacokinetics in patients with a creatinine clearance (CrCl) ≥50 ml/min. The effect of severe renal function impairment on the pharmacokinetics of baloxavir marboxil or its active metabolite baloxavir has not been studied.

Patients with impaired liver function

The ratios of geometric mean (90% confidence interval) of C_max and AUC of baloxavir in patients with moderate hepatic impairment (Child-Pugh class B) and healthy volunteers were 0.80 (0.50-1.28) and 1.12 (0.78-1.61), respectively. Because there were no clinically significant differences in baloxavir pharmacokinetics between patients with mild to moderate hepatic impairment (Child-Pugh class B) and healthy volunteers with normal hepatic function, it can be concluded that no dose adjustment is necessary in patients with mild to moderate hepatic impairment.

In patients with severe hepatic impairment, pharmacokinetics has not been studied.