What Is Zanamivir?

The chemical name of zanamivir is 5-acetylamino-4-[(aminoiminomethyl) -amino] -2,6-anhydro-3,4,5-trideoxy-D-glycerol -D-Galactose-2-enolate, a colorless crystalline solid, with molecular formula C ₁₂ H ₂₀ N ₄ O ₇ , molecular weight 332.31000, density 1.75 g / cm, melting point 256ºC (dec.).

Chinese name: Zanamivir
Foreign name: zanamivir

CAS: 139110-80-8
Molecular formula: C12H20N4O7

Introduction to Zanamivir compounds

Zanamivir Basic Information

Chinese name: zanamivir

English name: zanamivir

English alias: GG167; ZanamivirHydrate; 4-Guanidino-2, 4-dideoxy-2, 3-dehydro-N-acetylneuraminic acid; 4-Guanidino-Neu5Ac2en; Zanamir; Unii-L6o3xi777i;

CAS number: 139110-80-8

Molecular formula: C ₁₂ H ₂₀ N ₄ O ₇

Molecular weight: 332.31000

Structural formula:

Exact mass: 332.13300

PSA: 198.22000 ^[1]

Zanamivir physical and chemical properties

Appearance and properties: colorless crystalline solid

Density: 1.75 g / cm

Melting point: 256ºC (dec.) ^[1]

Zanamivir molecular structure data

1. Molar refractive index: 71.55

2. Molar volume (cm / mol): 189.6

3. Isotonic specific volume (90.2K): 562.3

4. Surface tension (dyne / cm): 77.3

5. Polarizability (10-24cm3): 28.36 ^[2]

Zanamivir production method

Dissolve 5-acetamido-4,7,8,9-tetra-O-acetyl-2,3,5-trideoxy-D-glyceryl-D-galactosenon-2-enylpyranitol In benzene and methanol, BF3Et2O was added dropwise at room temperature with stirring, ethyl acetate was added, and then saturated sodium bicarbonate, water were washed, concentrated, water and acetic acid were added, and stirred. Ethyl acetate was added, washed with 5% sodium bicarbonate, water, and concentrated. The obtained material was subjected to silica gel column chromatography to obtain an O-acetyl hydrolyzate at the 4-position. The compound was dissolved in anhydrous dichloromethane and pyridine, and a dichloromethane solution containing triflic anhydride was added dropwise and stirred. It was concentrated to dryness under reduced pressure, and the obtained material was dissolved in a dimethylformamide solution containing sodium azide and tetrabutylammonium hydrogen sulfate, and stirred at room temperature. Concentrated to dryness under reduced pressure. The obtained material was added with ethyl acetate and water, and the organic layer was separated, washed with water, dried, and concentrated. The obtained substance was subjected to silica gel column chromatography to obtain a 4-position azide product. The compound was dissolved in pyridine, bubbling with hydrogen sulfide at room temperature, and introducing nitrogen gas. Pyridine was distilled off under reduced pressure, and the obtained substance was subjected to silica gel column chromatography to obtain a product reduced to the amino group at the 4-position. Under ice-cooling, the compound was added to water containing thallium-methylthiourea, and after the reaction, it was placed in an ion exchange resin column, washed with cold water, and then developed with ammonia. The obtained effluent was concentrated to dryness under reduced pressure, and the obtained material was subjected to silica gel column chromatography to obtain zanamivir. ^[1]

Zanamivir uses

For the treatment of influenza A and B. Neuraminidase inhibitor. The product changes the aggregation and release of influenza virus in infected cells by inhibiting the neuraminidase of the influenza virus. It is suitable for the treatment of uncomplicated urgent infections caused by influenza A or B virus in adults or adolescents over 12 years old with symptoms of flu less than 2 days. ^[1]

Zanamivir Compound Related Drugs

Zanamivir drug name:

[General name] Zanamivir inhalation powder

[Product Name] Yilewei

[English name] Zanamivir Powder for Inhalation

[Chinese Pinyin] Zha Na Mi Wei Xi Ru Fen Wu Ji ^[3]

Zanamivir Ingredients:

The main ingredient of this product is zanamivir. Chemical name: 5-acetylamino-4-[(aminoiminomethyl) -amino] -2,6-anhydro-3,4,5-trideoxy-D-glycerol-D-galactose- 2-enolic acid. Molecular formula: C ₁₂ H ₂₀ N ₄ O ₇ , molecular weight: 332.3 ^[3]

Zanamivir category:

Chemical Drugs and Biological Products >> Antimicrobials >> Antivirals >> Other antivirals ^[3]

Zanamivir traits:

This product is a vesicle-type inhalation powder, and the content is white or off-white powder. ^[3]

Zanamivir indications:

Influenza A and B treatment for adults and children aged 7 years and over. Treatment should be started as early as possible and not later than 48 hours after the initial symptoms of the infection appear (see [Precautions]). Antiviral drugs are not necessary for the treatment of influenza A and B. Therefore, the necessity of this product should be carefully considered when using this product to treat influenza. ^[3]

Zanamivir specifications:

5mg / bubble (based on zanamivir) ^[3]

Zanamivir dosage:

Take 2 inhalations (2 x 5 mg) twice a day for 5 consecutive days with a total inhaled dose of 20 mg per day. In order to achieve the maximum therapeutic effect, treatment should be started as soon as possible after the symptoms appear (there is no data to support the application of this product when the flu symptoms appear 48 hours later). This product is administered by oral inhalation. Use the provided disc-shaped inhaler-Xuanda to inhale the lungs for oral administration. If the patient is using other inhaled drugs while using this product, such as fast-acting bronchodilators, please use other drugs before using this product (see [Precautions]). ^[3]
No dose adjustment is necessary for patients with renal insufficiency (see [Pharmacokinetics]).
In patients with hepatic insufficiency, zanamivir is not metabolized in the liver, so no dose adjustment is required (see [Pharmacokinetics]).
Elderly patients Elderly patients (65 years of age) have limited experience with zanamivir. However, based on the pharmacokinetic properties of zanamivir, there is no need to adjust the dosage (see [Pharmacokinetics]).
No dose adjustment is necessary for children (see [Pharmacokinetics]). When zanamivir is used by children, it should be used under adult supervision. ^[3]

Zanamivir adverse reactions:

Although this product is only approved for the treatment of influenza A and B, but it has not provided more safety information for clinical use, to ensure the safety of clinical drug considerations, this content includes the preventive research of this product in foreign countries. Security Information.
The incidence of adverse reactions in drug clinical trials may not reflect the incidence of adverse reactions in actual situations. The blank control used in the clinical trial of this product consists of inhaled lactose powder and is also the vehicle for the active drug; therefore, the frequency of similar adverse reactions in different treatment groups may be related to the inhalation of the lactose vehicle.
Clinical trials of influenza treatment in adults and adolescents: adverse events with a incidence of 1.5% are detailed in Table 1. This table shows the incidence of adverse events in people 12 years of age and older who received zanamivir 10 mg twice daily, and received all zanamivir dosing regimens and blank controls (placebo and zanamivir used the same Lactose carrier).

The incidence of other adverse reactions was <1.5% in patients receiving zanamivir, including discomfort, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria.
The most common laboratory abnormalities in phase III trials include elevated liver enzymes, elevated CPK, decreased lymphocytes, and decreased neutrophils. The proportion of laboratory abnormalities was similar in the zanamivir group and the blank control group.
Clinical trials in pediatric patients: The adverse events that occurred at a rate of 1.5% in two phase III trials are shown in Table 2. This table shows 5-12 years old receiving zanamivir 10 mg twice daily and receiving placebo Adverse events in children (same placebo and zanamivir used the same lactose carrier).

In one of the two studies described in Table 2, some additional information was obtained from children (aged 5 to 12 years) who did not have an acute influenza-like illness and received the research preventive regimen zanamivir: 132 children Zanamivir was received and 145 patients received placebo. In these children, the zanamivir group reported nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat than the placebo group. / Tonsillar discomfort and pain (11% for zanamivir, 6% for placebo) are more frequent. Among Yi patients with chronic lung disease, 7 of 7 patients receiving zanamivir and 5 of 12 patients receiving placebo reported adverse respiratory events (described as asthma, cough, or viral respiratory infection, Including flu-like symptoms).
Influenza prevention home / post-exposure prevention studies: A list of adverse events with a incidence of 1.5% in 2 prevention studies is shown in Table 3. This table lists those who received zanamivir 10 mg once daily for 10 consecutive days, aged 5 years Of adverse events in patients.

* In preventive studies, symptoms related to influenza-like illness were recorded as adverse events, and subjects were selected during the winter prone respiratory season, and any symptoms that occurred during this period were recorded as adverse events.
Community prevention studies: Adverse events with a incidence of 1.5% in the two prevention studies are listed in Table 4. This table lists adverse events that occurred in patients 5 years old who received zanamivir 10 mg once daily for 28 consecutive days.

Clinical trial data: Zanamivir is well tolerated after oral administration. In clinical studies, including those in high-risk patients (the elderly and patients with certain chronic diseases), adverse reactions occurred similarly in the zanamivir and placebo groups.
Post-marketing experience Existing clinical medication experience has found the following adverse events in the following areas, including immune system symptoms (immunity or immune-like reactions, including oropharyngeal edema), neuropsychiatric symptoms (delirium, including changes in the level of consciousness, Symptoms such as confusion, abnormal behavior, paranoia, hallucinations, agitation, anxiety, nightmares, etc.), heart (arrhythmia, syncope), nerves (epilepsy), breathing (bronchial spasm, dyspnea), and skin (facial edema; net Measles; rash, including severe skin reactions).
The following incidents were found during use after the approval of zanamivir inhalation powder (Rotadisk), and these events were also related to zanamivir inhalation powder (Rotacaps) preparations. Zanamivir injection has not produced post-marketing data; however, the following events may also be relevant to the formulation.
Very common: 1 / 10; common: 1 / 100 and <1/10; uncommon: 1 / 1000 and <1/100; rare: 1 / 10000 and <1/1000; very rare: <1 / 10000.
Immune system abnormalities are rare: allergic reactions, including allergic and allergic reactions, facial and oropharyngeal edema.
Nervous system abnormalities are rare: In patients with flu symptoms, there have been reports of vasovagal reactions such as fever and dehydration immediately after inhalation of zanamivir.
Respiratory, thoracic, and mediastinal abnormalities are rare: bronchospasm, dyspnea, abnormal skin and subcutaneous tissue are rare: rash, urticaria are rare: severe skin reactions, including erythema polymorphic, Stevens-Johnson syndrome, toxic epidermal necrosis Dissolve ^[3]

Zanamivir contraindications:

This product is contraindicated in patients with allergy to zanamivir or lactose. ^[3]

Notes on Zanamivir :

Warnings and important precautions Influenza infections may be accompanied by increased hyperresponsiveness of the airways. Among patients treated for influenza, extremely rare reports of bronchospasm and / or decreased respiratory function after zanamivir use have been reported, and some patients have no previous history of respiratory disease. Zanamivir should be discontinued in any patient who has such a reaction and should be examined by a doctor. Patients with potential respiratory diseases should always have a quick-acting bronchodilator when using inhaled zanamivir (see Usage and Dosage).
Zanamivir inhalation powder must not be temporarily formulated into a solution and administered by spray or mechanical ventilation. There have been reports of inpatients with flu receiving zanamivir inhaled powders by spray or mechanical ventilation, including one fatal case, and lactose in this preparation has reportedly impaired proper functioning of the device. Zanamivir inhalation powder must be administered only through the device provided with the drug (see Dosage and Administration).
Flu can be accompanied by a variety of neurological and behavioral symptoms. Post-marketing reports of convulsions, delirium, hallucinations, and behavioral abnormalities have been reported in influenza patients receiving neuraminidase inhibitors, including zanamivir (mostly from Japanese and pediatric subjects). Events are observed primarily in the early stages of the disease, often with sudden onset and rapid resolution. The impact of zanamivir on the incident has not been determined. If neuropsychiatric symptoms occur, each patient should be evaluated for the risks and benefits of continuing treatment.
1. Bronchial spasm Due to the limited number of study cases, zanamivir has not been adequately evaluated for the treatment of influenza patients with severe asthma or other severe chronic respiratory diseases. This product is not recommended for the treatment of influenza in patients with respiratory disease or potential respiratory disease (such as asthma, chronic obstructive pulmonary disease). There have been some reports of severe bronchospasm, including death, in patients with / without underlying respiratory disease following flu treatment with zanamivir. Some cases are reported after marketing and their causality is difficult to evaluate.
Any patient with hyporespiratory symptoms and / or bronchospasm after using zanamivir should be discontinued immediately and treated and hospitalized immediately. Some patients without previous lung disease may also develop respiratory tract abnormalities due to acute respiratory infections, which may be similar to the adverse reactions, or increase the incidence of respiratory adverse reactions in patients.
In a phase I trial, 1/13 of patients with mild or moderate asthma (no acute flu-like illness) developed bronchospasm after using zanamivir. In the phase III trial, 10% (24/244) of patients receiving zanamivir and 9% (22/237) of patients receiving placebo in patients with acute influenza-like illness combined with potential asthma or COPD After a one-day treatment cycle, a decrease in FEV1 of more than 20% occurred.
If zanamivir is used in patients with potential respiratory disease, the possible risks and benefits should be carefully evaluated. If used in such patients, respiratory dysfunction should be considered as a potential risk. Therefore, patients should be reminded to pay attention to bronchospasm and respiratory dysfunction, and there should be available fast-acting bronchodilators. Patients who use bronchodilators who are also receiving zanamivir are advised to use bronchodilators before zanamivir. (See [Usage and dosage]). Any patient with hyporespiratory symptoms and / or bronchospasm after using zanamivir should discontinue administration and seek medical attention in a timely manner.
2. Post-marketing reports of neuropsychiatric events (mainly from Japan). Patients receiving neuraminidase inhibitors including this product have delirium and abnormal behaviors and cause self-harm. Because these events are spontaneous reports in clinical treatment, the frequency of occurrence cannot be estimated, but based on data on the use of this product, these events seem to be rare. These incidents are mainly reported in pediatric patients and often occur suddenly and quickly. The relevance of these events to this product is unclear. During treatment with this drug, signals for abnormal behavior should be closely observed. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment for each patient should be assessed.
3. Allergic reactions Zanamivir has reported allergic reactions, including oropharyngeal edema, severe rash, and allergic reactions. If an allergic reaction occurs or is suspected, the drug should be discontinued immediately and seek medical attention in a timely manner.
Other considerations 1. There is no evidence that zanamivir is effective for diseases other than influenza A and B. The use of this product should be limited to patients with local influenza A and B virus infection records and typical influenza symptoms.
2. The safety and effectiveness of patients with high-risk underlying diseases have not been proven. No data are available on the safety and effectiveness of zanamivir in patients with poor or unstable medical conditions who must be admitted.
3. The safety and effectiveness of zanamivir for children under 7 years of age have not been determined. Although data for children 5-7 years of age have been completed in clinical trials of this product abroad, the estimated therapeutic effect is lower in children 5 and 6 years of age compared to the overall study population. In addition, pharmacokinetic studies show that There is evidence of inadequate inhalation by the population when using this product inhalation device.
4. Including the United States, Europe, Japan, and many other countries approved zanamivir for the prevention of influenza A and B (including post-exposure prevention and community outbreak prevention) for adults and children 5 years and older. Considering that vaccination is still the preferred method for the prevention and control of influenza, and China does not basically use antiviral drugs to prevent seasonal influenza, it is not recommended for the prevention of influenza A and B. Under special circumstances, please refer to the relevant guidelines or schemes issued by the Ministry of Health for the preventive application of this product.
5. Zanamivir administration in elderly patients, patients with chronic metabolic diseases (including diabetes), patients with cardiovascular disease other than hypertension, or immunosuppressed patients has limited experience. The patient's condition should be carefully considered and closely monitored when applying this product.
6. Severe bacterial infections may begin or co-exist with flu-like symptoms or appear as complications during the flu process. This product has not been shown to prevent complications.
7. There have been reports of syncope and shock symptoms in patients after using zanamivir. The inducement may be that the patient inhales excessively and inhales for a long time when using the inhalation device, or may be exacerbated by the fever and dehydration caused by the flu. Please use this product strictly according to the instructions for use, and pay attention to correcting possible causes.
8. There have been no reports of zanamivir affecting driving and mechanical operation capabilities. According to the pharmacology of this product, the impact on these activities cannot be expected. ^[3]

Zanamivir medication for pregnant and lactating women:

Zanamivir has not been adequately and well controlled in pregnant women. Zanamivir should not be used during pregnancy, especially during the first three months, unless the potential benefit to the patient exceeds any risks that the fetus may face.
No data on zanamivir through human placenta. Zanamivir can penetrate the placenta of rats and rabbits. Radiolabeled zanamivir (10 mg / kg) was injected intravenously to rats at 12 and 19 days of gestation, and there was a small amount of placental metastasis after 30 minutes (0.04% and 0.02%, respectively). Embryo-natal development studies have shown that repeated intravenous doses to 90 mg / kg / day in rats or rabbits, or subcutaneous doses to 80 mg / kg / day in rats, three times a day, with total systemic exposures (AUCs) per day at a later stage The clinical exposure in the study reached 1050 times and there was no evidence of teratogenicity.
Studies in lactating women's rats have shown that zanamivir excreted into milk. However, it should be informed whether zanamivir has entered human milk or not. Because many drugs are excreted into human milk, zanamivir should be used with caution in breastfeeding women. Due to limited experience, the use of zanamivir for nursing mothers should only be considered if the potential benefits of zanamivir to the mother outweigh any risks that the baby may face. ^[3]

Zanamivir medication for children:

No dose adjustment is required (see [Pharmacokinetics]). When zanamivir is used by children, it should be used under adult supervision. ^[3]

Zanamivir medications for the elderly:

Elderly patients (65 years of age) have limited experience with zanamivir. However, based on the pharmacokinetic properties of zanamivir, there is no need to adjust the dosage (see [Pharmacokinetics]). ^[3]

Zanamivir drug interactions:

Zanamivir does not affect the activity of cytochrome P450 isoenzymes (CYP1A1 / 2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) probe substrates in human liver microsomes. Based on data from in vitro studies, no clinically significant pharmacokinetic drug interactions are expected.
The combined use of zanamivir and intranasal attenuated influenza vaccine (LAIV) has not been evaluated. Because antiviral drugs may inhibit the replication of live vaccine viruses, LAIV should not be used within 2 weeks or 48 hours after zanamivir unless medically indicated.
Trivalent inactivated influenza vaccine can be used at any time during the administration of zanamivir. ^[3]

Zanamivir overdose:

No overdose of zanamivir has been reported. Given that zanamivir is administered by inhalation and has low bioavailability (2% for oral administration and 10-20% for inhaled powder), this product is unlikely to have an accidental overdose. It has been confirmed that no adverse reactions occurred when the zanamivir dose was administered nasally to 96 mg / day (approximately 5 times the maximum daily recommended dose). In addition, 1200 mg / day was administered intravenously for 5 consecutive days, and no systemic exposure was achieved. No special treatment is required after an overdose event. ^[3]

Zanamivir clinical trials:

Influenza treatment for adults and adolescents: Placebo-controlled studies have been performed in the respective flu seasons in North America, the Southern Hemisphere and Europe to evaluate the effectiveness of zanamivir 10 mg twice daily inhalation for 5 days. The degree of therapeutic effect varies between studies and may be related to population-related factors, including the amount of medication used to relieve symptoms.
Study population: The main phase III study included 1,588 patients aged 12 years and older (median age 34 years, 49% were male, 91% were white), and within 2 days of developing symptoms of influenza-like illness, No comorbidities occurred. It has been confirmed to be influenza by culture, hemagglutination inhibitory antibody or experimental direct detection. Of the 1,164 patients confirmed to be influenza, 89% were influenza A and 11% were influenza B. These studies serve as the main basis for evaluating effectiveness. Phase II studies are more limited due to the need for supporting information. After randomization to the zanamivir or placebo (inhaled lactose excipient) group, all patients were instructed and the first dose was supervised by a physician.
Main results: Definition of time to improvement of major symptoms of influenza includes absence of fever and self-evaluation of "none" or "mild" headache, myalgia, cough, and sore throat. A Phase II and Phase III study in North America (a total of more than 600 influenza-positive patients) suggested that patients receiving zanamivir received a 1-day improvement in defined symptoms compared to patients receiving placebo. In a study in the Southern Hemisphere (321 flu-positive patients), the median difference in time to symptom improvement was 1.5 days. European studies provide additional evidence of effectiveness.
Other findings: No consistent difference in treatment effect was found between influenza A and influenza B patients; however, these trials included fewer cases of influenza B and therefore provided less evidence in support of influenza B. In general, patients with lower body temperature (for example, 38.2 ° C or lower) at the time of enrollment or patients evaluated by the investigator as having less severe symptoms benefited less from treatment. No therapeutic effect has been demonstrated in patients with basic chronic medical conditions, including respiratory or cardiovascular (see notes). No consistent difference in the incidence of complications was found between the treatment groups. Following the main research focus in both treatment groups, some fluctuations in symptoms were observed.
Pediatric patients: The effectiveness of zanamivir 10mg inhaled twice daily for 5 days in pediatric patients was evaluated in a placebo-controlled study in North America and Europe. The study included 471 patients aged 5 to 12 Age (55% were male, 90% were white), all within 36 hours of symptom onset. Among patients with confirmed influenza, 65% were influenza A and 35% were influenza B. Definitions of time to improvement include no fever and no or mild cough by parental evaluation, no / mild myalgia and joint pain, sore throat, chills / fever, and headache. Patients receiving zanamivir had a median time to improvement of 1 day compared to placebo patients. No consistent difference in the incidence of complications was observed between the treatment groups. Symptoms were observed after the primary study endpoint in both treatment groups.
There are no studies that begin flu treatment 48 hours after the onset of symptoms. ^[3]

Zanamivir pharmacology and toxicology:

Pharmacology:
Zanamivir is a neuraminidase (influenza virus surface enzyme) inhibitor that interferes with the release of viral particles. Zanamivir's antiviral activity in laboratory and clinical influenza isolates has been demonstrated by cultured cell lines. The concentration of zanamivir required to inhibit influenza viruses varies widely between different analytical methods and test strains. Effective concentrations (EC50 and EC90) of zanamivir 50% and 90% are 0.005 to 16.0 M and 0.05 to> 100 M, respectively. The relationship between zanamivir inhibition of influenza virus cells and influenza virus replication in humans has not yet been established.
Resistance:
By passage of the virus multiple times in an environment of increasing drug concentration, influenza viruses with reduced sensitivity to zanamivir can be selected. Genetic analysis of these cell-cultured viruses revealed a decrease in sensitivity to zanamivir related to amino acid changes in neuraminidase or hemagglutinin or both caused by gene mutation. Resistance mutations selected for neuraminidase amino acid substitution by cell culture include E119G / A / D and R292K. Mutations selected for hemagglutinin replacement by cell culture include K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T. In immunocompromised patients infected with influenza B virus, virus variants appeared after 2 weeks of treatment with a zanamivir investigational spray solution. Analysis of these mutations revealed that a replacement of erythrocyte agglutinin (T198I) caused a decrease in the affinity of human cell receptors, and the replacement of the neuraminidase active site (R152K) reduced the enzyme's activity to zanamivir by a factor of 1,000. . Information that characterizes the risk of drug resistance for zanamivir in clinical use is lacking.
Cross-resistance:
Cross-resistance has been found in certain cell cultured influenza virus mutants resistant to zanamivir and oseltamivir. However, some cell cultured zanamivir resistant mutants such as E119G / A / D and R292K, like the clinical isolates resistant to oseltamivir, mutated at the same amino acid position as neuraminidase, such as E119V and R292K. No studies have evaluated the risk of cross-resistance due to clinical use.
Mutagenic effects:
Zanamivir was negative in bacterial mutation test, mouse lymphocyte human chromosome test, human peripheral blood chromosome test, and mouse bone marrow micronucleus test.
Reproductive toxicity:
Intravenous injection in male rats (10 weeks before mating, mating, pregnancy / lactation and short term after weaning), female rats (3 weeks before mating, until 19 days of pregnancy or 21 days after delivery) / d Zanamivir has no effect on mating and fertility in rats, and has no effect on sperm in rats. There was no effect on the reproductive capacity of F1 female mice. In the study of subacute toxicity in rats, intravenous injection of 90mg / kg / d, AUC was 142-199mcg · hr / mL (greater than 300 times the human clinical exposure). Embryo / fetal development studies (1, 9) in rats (administered from 6 to 15 days of pregnancy) and rabbits (administered from 7 to 19 days of pregnancy) using the same intravenous dose And 90mg / kg / d). Prenatal and postnatal development studies were performed in rats (dosing from 16th day of pregnancy until 21st to 23th day of pups). No abnormalities, maternal toxicity, or embryo toxicity were found in pregnant rats or rabbits and their fetuses.
Another embryo / fetal study was performed in rats using zanamivir subcutaneously from 7 to 17 days of pregnancy, 3 times daily at a dose of 1, 9, or 80 mg / kg. The incidence of various microskeletal changes and changes in the offspring exposed in this study increased. According to AUC measurement, the exposure of 80mg / kg dose exceeds 1000 times of the human clinical dose. But in most cases, the individual incidence of various skeletal changes or mutations is still within the historical background incidence of the germline. Zanamivir passes through the placenta of rats and rabbits. In these animals, the concentration of zanamivir in the fetal blood was significantly lower than that in the maternal blood.
Carcinogenicity:
In a 2-year study of inhaling powder in rats and mice, zanamivir did not have a statistically significant increase in tumor induction compared to the control group. Based on the human clinical dose of AUC, the maximum daily exposure in rats and mice is approximately 23-25 and 20-22 times the human clinical dose. ^[3]

Zanamivir pharmacokinetics:

Absorption and bioavailability: Pharmacokinetic studies of zanamivir via oral inhalation indicate that approximately 4% to 17% of the inhaled volume is absorbed throughout the body. Peak serum concentrations ranged from 17 to 142 ng / mL within 1 to 2 hours after 10 mg administration. The area under the curve (AUC) of serum concentration versus time is 111 to 1364 ng · hr / mL.
Distribution: Zanamivir has a low plasma protein binding rate (<10%).
Metabolism: Zanamivir is excreted from the kidneys in the form of the original drug. No metabolites were detected in the human body.
Elimination: Zanamivir has a serum half-life of 2.5 to 5.1 hours after oral inhalation. A single dose was completely eliminated from the urine in the form of the original drug within 24 hours. The total clearance is 2.5 to 10.9 L / hr. Unabsorbed drugs are excreted in the stool.
Hepatic impairment: Zanamivir's liver injury pharmacokinetics have not been studied in patients.
Renal function impairment: After a single dose of 4 mg or 2 mg of zanamivir administered intravenously to volunteers with mild / moderate or severe renal impairment, renal clearance was significantly reduced (total clearance: normal 5.3L / hr, mild / moderate 2.7L / hr, and severe 0.8L / hr; median) and half-life (normal 3.1hr, mild / moderate 4.7hr and severe 18.5hr; median) and system exposure The amount increased significantly. The safety and effectiveness of patients with severe renal insufficiency are not documented. Due to the low system bioavailability of zanamivir after oral inhalation, dose adjustment is not required for patients with renal impairment. However, the possibility of drug accumulation in the body needs to be considered.
Pediatric patients: The pharmacokinetic evaluation of zanamivir was performed on pediatric patients with symptoms of respiratory disease. Sixteen patients between 6 and 12 years of age received a single dose of 10 mg of zanamivir dry powder via a dish inhaler. After 1.5 hours, five patients did not detect zanamivir drug serum levels or were very low (8.32 to 10.38ng / mL) and could not be detected. The median Cmax of the 11 patients was 43 ng / mL (from 15 to 74) and the median AUC was 167 ng · hr / mL (from 58 to 279). Low or undetectable drug serum concentrations in individual patients are related to the lack of a measurable maximum inspiratory flow rate.
Elderly patients: No pharmacokinetic study of zanamivir was performed in patients older than 65 years. ^[3]

Zanamivir expert review

This product is an influenza virus neuraminidase inhibitor. Inhibition of influenza viruses is performed in a slow-binding manner and is highly specific. The results of a randomized, double-blind, placebo-controlled clinical trial abroad show that this product is safe and effective, and well tolerated. After use, 67% of healthy adults have a preventive effect on influenza virus, and it has the best effect on influenza patients with fever symptoms. It can significantly reduce the incidence of complications in susceptible people, so that the incidence of concurrent bronchitis and pneumonia is increased from 65% Reduced to 14%, and can reduce the amount of antibiotics, 38% to 14%. ^[4]