Description of the drug LOPINAVIR+RITONAVIR (LOPINAVIR+RITONAVIR)

Pharmacodynamics and pharmacokinetics

Pharmacodynamics

In a combination of two substances , Lopinavir acts as an inhibitor of HIV-2 and HIV-1 protease. It is the main antiviral component in this combination. Synthesis of viral proteins becomes no longer possible, resulting in the formation of an extremely immature virus that cannot infect living cells.

Ritonavir is an inhibitor of viral aspartyl proteases and a fairly active peptidomimetic. Inhibition of specific HIV proteases prevents the cleavage of the bond between the group-specific antigen and the polyprotein polymerase. This leads to the development of immature and harmless viruses. The substance is very active in relation to HIV protease and practically inactive in relation to this enzyme in humans.

Ritonavir also inhibits the metabolism of Lopinavir in the liver tissue and this leads to an increase in the plasma concentration of the latter.

The processes of development of addiction (resistance) of the virus to this drug combination were carefully studied. Data were taken into account both from patients who had previously received antiretroviral therapy and those undergoing treatment for the first time, including from the group of human immunodeficiency virus protease inhibitors.

In children and adults undergoing antiretroviral therapy for the first time, no mutations, development of resistance or reduced sensitivity to treatment were identified. In the second phase of research, a certain percentage of mutations were discovered that increase the viral load and reduce the body’s sensitivity to the drug. The number of such patients was higher among those who had previously been treated for a retrovirus .

Pharmacokinetics

The metabolism of Ritonavir and Lopinavir was studied in HIV-infected and healthy patients, but no differences were found between the different groups. After penetration into the body, Lopinavir is completely metabolized by the CYP3A isoenzyme. Ritonavir, in turn, suppresses this process and increases the plasma concentration of Lopinavir.

After using the drug at a dosage of 0.4 g of Lopinavir per 0.1 g of Ritonavir twice a day, the concentrations of the first in the blood plasma were 15 times higher in patients with HIV than the concentration of the second substance. The concentration of Ritonavir in the blood was less than 7% compared to taking 0.6 g twice a day. It was concluded that the main antiviral activity in this combination of lek. remedies exhibited by Lopinavir.

In patients receiving 400 mg of Lopinavir and 100 mg of Ritonavir, the steady-state plasma concentration was reached after 3 weeks and was 11 mcg per ml, the maximum concentration was achieved after 4 hours. The average plasma concentration is 7.1±2.9 μg per cell observed in the morning before taking the medicine.

Food intake has virtually no effect on the pharmacokinetic parameters of the drug. Fatty foods slightly slow down absorption from the digestive tract, but this is not significant. Lopinavir is almost completely, 99% bound to plasma proteins, albumin and alpha1-acid glycoprotein .

First, Lopinavir undergoes oxidation processes using the hepatocyte cytochrome P450 system and the CYP3A isoenzyme. Ritonavir, in turn, interferes with this process, which leads to a significant increase in the concentration of Lopinavir in the blood. The substance has about 13 oxidative metabolites, mainly 4-hydroxy metabolite isomeric pairs and 4-oxometabolites . After 10-14 days of taking the drug, its equilibrium concentration stabilizes and decreases.

After using the combination of Ritonavir and Lopinavir (100 to 400 mg) once, after a week, about 10% of the dose taken can be detected in the urine and about 85% in the feces. With constant use of medication. less than 3% of the drug is excreted unchanged by the kidneys.

Pharmacological properties of the drug Ritonavir

Ritonavir is an antiviral agent, a peptide inhibitor of HIV-1 and HIV-2 proteases. Enzymatic cleavage of proteases makes it impossible to activate the protein precursor and leads to the synthesis of immature HIV particles that are unable to initiate further development of the infection. Proteolysis of HIV polypeptides stops the life cycle of its replication. It binds the C2-symmetric part of the active zone of HIV protease, has a high selective affinity for it and has a weak inhibitory effect on human proteases. Increases the number of CD-4 cells in the blood and reduces the concentration of viral RNA. Leads to an increase in the total number of leukocytes, lymphocytes and platelets. The time to reach maximum concentration in blood plasma after oral administration is 2–4 hours. The apparent volume of distribution is 0.41 l/kg. Bioavailability - 94%. 98–99% binds to blood plasma proteins. Metabolized by the cytochrome P450 system to hydroxylated inactive metabolites, followed by their glucuronidation. The main isoenzymes responsible for metabolism are CYP 2B6 and CYP 3A. Smoking, body weight, age, gender, CYP 2D6 phenotype do not affect the clearance of ritonavir. The half-life in children 2–14 years of age is 1.5 times shorter than in adults, while the maximum concentration values ​​are the same. Excreted in feces (20–40% unchanged).

Contraindications

Lopinavir and Ritonavir should not be prescribed:

• if allergic to these substances individually or in combination;
• patients with severe liver failure ;
• when combined with drugs whose metabolism depends on the SURZA isoenzyme;
• in tablet form - up to 3 years.

Caution is recommended:

• with viral hepatitis C and B ;
• patients with liver cirrhosis ;
• with moderate and mild liver failure;
• in patients with high activity of liver enzymes;
• with pancreatitis ;
• patients with hemophilia B and A ;
• for dyslipidemia , hypertriglyceridemia , hypercholesterolemia .

Side effects

The combination of drugs Lopinavir + Ritonavir in adult patients can cause:

• nausea, diarrhea , hypercholesterolemia , vomiting, hypertriglyceridemia , allergic reactions, urticaria and angioedema ;
• pain in the epigastric region, hepatomegaly , flatulence , hemorrhoids , hepatitis and bloating, cholangitis , hepatic steatosis ;
• asthenia and weakness;
• menorrhagia , erectile dysfunction , amenorrhea , leukopenia , anemia ;
• arterial hypertension , night sweats , skin rash, itching;
• visual disturbances, dizziness , tinnitus;
• headaches up to migraines , peripheral neuropathy , neuropathy , insomnia , dizziness , high anxiety;
• hypercholesterolemia , weight loss, lack of appetite, diabetes , lymphadenopathy ;
• renal failure , nephritis and hematuria ;
• infections of the lower and upper respiratory tract, fatty tissue and skin, furunculosis , cellulitis , folliculitis , osteonecrosis (very rare);
• increase in the level of uric acid , amylase , glucose , triglycerides , bilirubin , lipase .

In patients starting therapy with severe severe immunodeficiency, at the beginning of treatment, inflammatory reactions to infections that have been in the body for a long time, but the immune system has not fought them, may occur. This phenomenon is called immune reconstitution syndrome .

Side effects of the drug Ritonavir

Nausea, vomiting, diarrhea, anorexia, abdominal pain, dry mouth, dyspepsia, belching, flatulence, laryngeal irritation, loss of taste, fever, allergic reactions, anxiety, insomnia, paresthesia, asthenic syndrome, headache, dizziness, drowsiness, weight loss, myalgia, cough, pharyngitis; papular rash, itching, sweating, hyperglycemia, anemia, decreased hematocrit, erythropenia, leukopenia, neutropenia, eosinophilia, hyperuricemia, hypokalemia, increased activity of liver transaminases, hypertriglyceridemia.

Overdose

To date, cases of drug overdose have been rare. The drug does not have a specific antidote.

Treatment usually consists of maintaining the body's functioning, monitoring vital signs and monitoring the patient's condition. If the medicine has not yet dissolved in the digestive tract, it is recommended to rinse the stomach and drink activated carbon . This drug combination has a high degree of binding to blood proteins, so dialysis is not used.

Interaction

The combination of Ritonavir and Lopinavir is a strong inhibitor of CYP3A and this should be taken into account when combining the drug with other drugs. means. Caution must be observed when taking dihydropyridine blockers of “slow” calcium channels, immunosuppressants, phosphodiesterase 5 (PDE-5) inhibitors simultaneously, the plasma concentration of such drugs will increase significantly, and the side and therapeutic effects will intensify and last.

The medicine cannot be combined with triazolam , blonanserin , astemizole , midazolam , terfenadine , cisapride , sildenafil and salmeterol .

Also included in the list of contraindicated combinations are: voriconazole , ergotamine , methylergometrine , ergot alkaloids , vardenafil , fosamprenavir , HMG-CoA reductase inhibitors, Simvastatin , Lovastatin , alfuzosin , Amiodarone and fusidic acid .

The drug is not used together with boceprevir , St. John's wort, or Rifampicin .

The medicine should not be taken once a day if you are also taking Carbamazepine , phenytoin , Phenobarbital , efavirenz , amprenavir , nevirapine or nelfinavir .

HIV drugs

It is recommended to take tablets one hour before or 2 hours after meals when treating with a combination of didanosine , Ritonavir and Lopinavir.

Use extreme caution when combining this combination of drugs with tenofovir . There is a risk of adverse reactions from tenofovir.

When combined with other NRTIs, the likelihood of myalgia , myositis , and rhabdomyolysis .

should not be taken once daily when combined with nevirapine It may also be necessary to increase the dosage of Ritonavir and Lopinavir to 125 and 500 mg, respectively.

It is contraindicated to take a combination medication. the drug in combination with efavirenz , amprenavir or nevirapine once a day.

Delavirdine increases plasma concentrations of Lopinavir.

Lopinavir/Ritonavir, when combined with indinavir or saquinavir , is recommended to be taken twice a day, 400 and 100 mg, while the dosage of indinavir or saquinavir should be reduced.

The combination agent cannot be combined with nelfinavir when administered once a day.

tipranavir is contraindicated .

Medicines for hepatitis C

Boceprevir is contraindicated .

When taking drugs simultaneously with telaprevir, the equilibrium concentration of the latter decreases.

Other drugs

The medicine may cause an increase in the concentration of Fentanyl in the blood plasma. The patient's respiratory function must be closely monitored.

The drug increases the concentration of Lidocaine , bepridil and Quinidine , it is best to avoid such combinations.

Use extreme caution when combining medications with the antiarrhythmic Digoxin .

Concentrations of Quinidine , Erythromycin , Pheniramine and Clarithromycin may increase and lead to QT prolongation and adverse cardiac reactions.

When combining the drug with antitumor drugs, nilotinib , dasatinib , vinblastine and Vincristine , an increase in their concentration and side effects from antitumor drugs may be observed.

Medicines affect the concentration of the anticoagulants Warfarin and rivaroxaban in the blood.

It is strongly recommended to adjust the dosage or completely replace the antidepressants trazodone and bupropion when treated with Lopinavir + Ritonavir.

Anticonvulsants are also known to induce CYP3A4. In this regard, it is contraindicated to combine Lopinavir with Phenobarbital , Carbamazepine and phenytoin .

The combination of the substances Lopinavir and Ritonavir can reduce the concentration of Lamotrigine and valproic acid by half.

You cannot combine medications with antifungal agents - Ketoconazole and Itraconazole , especially in a dosage of more than 0.2 g per day.

The medicine affects the dosage of Colchicine , Clarithromycin , Maraviroc , Rifabutin .

If it is necessary to combine Lopinavir, Ritonavir and Rifampicin , then taking antiviral drugs begins with a dosage of 400, 100 mg twice a day for 10 days, while gradually increasing the dosage. It is recommended to monitor liver function.

Your atovaquone dosage may need to be increased during treatment .

The drug is combined with systemic glucocorticosteroids with caution. The drug increases the serum concentration of Nifedipine , Felodipine , nicardipine and other calcium channel blockers.

The combined use of a drug combination with Sildenafil and tadalafil will lead to the development of unwanted side reactions, prolonged erection and low blood pressure. with vardenafil .

Use caution when combining the medicine with Lovastatin and Simvastatin .

When concurrently treating a patient with immunosuppressants, such as Tacrolimus , Cyclosporine and Sirolimus , it is recommended to monitor the concentrations of these drugs more often until they stabilize.

Lopinavir/Ritonavir strongly reduces plasma concentrations of methadone .

The medicine may affect the concentration of ethinyl estradiol in tablet form, which will reduce the contraceptive effect. Alternative methods of contraception should be used.

Description of the drug LOPINAVIR+RITONAVIR (LOPINAVIR+RITONAVIR)

Co-administration of the combination of lopinavir/ritonavir and drugs that are predominantly metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could enhance its therapeutic and adverse reactions.

The combination of lopinavir/ritonavir in vivo induces its own metabolism and increases the biotransformation of some drugs metabolized with the participation of cytochrome P450 (including isoenzymes CYP2C9 and CYP2C19), and glucuronidation. This may lead to a decrease in plasma concentrations and a decrease in the effectiveness of concomitantly used drugs.

Lopinavir/ritonavir inhibits the CYP3A isoenzyme in vitro and in vivo. The simultaneous use of a combination of lopinavir/ritonavir and drugs metabolized by CYP3A isoenzymes (including dihydropyridine calcium antagonists, HMG-CoA reductase inhibitors, immunosuppressants and PDE-5 inhibitors may lead to an increase in their plasma concentrations and an increase or prolongation of the therapeutic effect and side effects.

A significant increase in AUC (≥3-fold) during treatment with lopinavir/ritonavir is observed with simultaneous use of drugs that are actively metabolized by CYP3A isoenzymes and undergo first-pass metabolism.

Lopinavir/ritonavir is metabolized by CYP3A isoenzymes. Concomitant use of lopinavir/ritonavir with inducers of this isoenzyme may lead to a decrease in plasma concentrations of lopinavir and its therapeutic effect. Other drugs that inhibit CYP3A isoenzymes may cause an increase in plasma concentrations of lopinavir, although these changes were not observed when used concomitantly with ketoconazole.

Lopinavir/ritonavir has been shown to increase tenofovir concentrations. The mechanism of interaction is unknown. Patients receiving lopinavir/ritonavir concomitantly with tenofovir should be monitored for the possibility of tenofovir-related side effects.

Cases of increased CPK activity, myalgia, myositis and rhabdomyolysis (rare) have been reported when taking HIV protease inhibitors, especially in combination with NRTIs.

Efavirenz and nevirapine

induce the CYP3A isoenzyme and thus may reduce plasma concentrations of other HIV protease inhibitors when used in combination with lopinavir/ritonavir.

Delavirdine

may cause an increase in plasma concentrations of lopinavir.

Concomitant therapy with lopinavir/ritonavir and amprenavir

causes a decrease in the concentration of lopinavir.

A study showed that concomitant use of lopinavir/ritonavir with fosamprenavir

reduces concentrations of fosamprenavir and lopinavir. Adequate doses of fosamprenavir and lopinavir/ritonavir in combination with respect to safety and effectiveness have not been established. Concomitant use of fosamprenavir and lopinavir/ritonavir is not recommended.

When using lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, a dose reduction of indinavir may be required.

The use of lopinavir/ritonavir in combination with indinavir once a day has not been studied.

Concomitant use of lopinavir/ritonavir with nelfinavir

leads to a decrease in the concentration of lopinavir.

When lopinavir/ritonavir was co-administered with an additional dose of ritonavir (100 mg 2 times / day), an increase in lopinavir AUC by 33% and Cmin by 64% was observed compared with those when using only lopinavir/ritonavir at a dose of 400/100 mg 2 times / day .

Lopinavir/ritonavir increases the concentration of saquinavir (use of saquinavir at a dose of 800 mg 2 times/day in combination with lopinavir/ritonavir leads to an increase in AUC, Cmax and Cmin compared to taking saquinavir at a dose of 1200 mg 3 times/day). When using lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, a dose reduction of saquinavir may be required. The use of lopinavir/ritonavir in combination with saquinavir once a day has not been studied.

With simultaneous use of tipranavir (500 mg 2 times / day) with ritonavir (200 mg 2 times / day) and lopinavir / ritonavir (400/100 mg 2 times / day), AUC and Cmin decrease by 55% and 70%, respectively. Concomitant use of lopinavir/ritonavir and tipranavir with low dose ritonavir is contraindicated.

Concomitant use of lopinavir/ritonavir with telaprevir

leads to a decrease in the Css of telaprevir without changing the Css of lopinavir. Simultaneous use is not recommended.

Concomitant use of lopinavir/ritonavir with boceprevir

leads to a decrease in Css of boceprevir and lopinavir in blood plasma. Concomitant use of lopinavir/ritonavir with boceprevir is contraindicated.

Concomitant use of simeprevir

with lopinavir/ritonavir may cause an increase in plasma concentrations of simeprevir. Concomitant use of lopinavir/ritonavir and simeprevir is contraindicated.

Concomitant use of maraviroc

with lopinavir/ritonavir leads to an increase in the concentration of maraviroc in the blood plasma. When used simultaneously with lopinavir/ritonavir at a dose of 400/100 mg 2 times a day, the dose of maraviroc should be reduced.

Because lopinavir/ritonavir inhibits the CYP3A4 isoenzyme, possibly increasing fentanyl

in blood plasma. If lopinavir/ritonavir and fentanyl are used concomitantly, closely monitor for therapeutic and adverse effects (including respiratory depression).

When administered concomitantly with lopinavir/ritonavir, the concentrations of bepridil, lidocaine and quinidine may increase.

Caution is required when using these drugs; their therapeutic plasma concentrations should be monitored if possible.

There is evidence in the literature that the simultaneous use of ritonavir (300 mg every 12 hours) and digoxin

led to a significant increase in the concentration of digoxin in the blood. Caution should be exercised when using lopinavir/ritonavir concomitantly with digoxin and monitor digoxin serum concentrations.

Under the influence of lopinavir/ritonavir, the concentrations of pheniramine, quinidine, erythromycin, clarithromycin

may increase with subsequent prolongation of the QT interval and the development of cardiac side effects. Particular caution should be exercised when coadministering lopinavir/ritonavir with drugs that prolong the QT interval.

Possible increase in serum concentrations of dasatinib, nilotinib, vincristine, vinblastine

when used simultaneously with lopinavir/ritonavir, which may lead to side effects characteristic of these anticancer drugs. The dose of nilotinib and dasatinib should be adjusted in accordance with the instructions for use of these drugs.

Possible effect on warfarin

when used simultaneously with lopinavir/ritonavir.

Concomitant use of rivaroxaban

with lopinavir/ritonavir may cause an increase in the plasma concentration of rivaroxaban, which may lead to an increased risk of bleeding. Simultaneous use is not recommended.

In addition, concomitant use of phenytoin

and lopinavir/ritonavir leads to a moderate decrease in phenytoin Css. When phenytoin is used concomitantly with lopinavir/ritonavir, phenytoin plasma concentrations should be monitored.

Decreased concentrations of lamotrigine and valproic acid

observed when combined with lopinavir/ritonavir; the reduction in lamotrigine concentrations reached 50%. These drug combinations should be used with caution. When these drugs are used concomitantly with lopinavir/ritonavir, especially during dose selection, it may be necessary to increase the dose of lamotrigine or valproic acid, as well as monitor their plasma concentrations.

Concomitant use of bupropion

with lopinavir/ritonavir reduces plasma concentrations of bupropion and its active metabolite (hydroxybupropion). If concomitant use of lopinavir/ritonavir with bupropion is necessary, it should be done under close clinical monitoring for the effectiveness of bupropion without exceeding the recommended dose, despite the observed increase in metabolism.

Concomitant use of ritonavir and trazodone

may result in increased trazodone concentrations. Side effects observed:

• nausea, dizziness, decreased blood pressure and fainting. Use trazodone with a CYP3A4 inhibitor, such as lopinavir/ritonavir, with caution, reducing the dose of trazodone if necessary.

This combination and midazolam for parenteral administration

. Midazolam therapy should be administered in an intensive care unit or similar setting that can provide clinical supervision and appropriate medical equipment in the event of respiratory depression and/or prolonged sedation. Midazolam dose adjustment is necessary if more than one injection is used.

With simultaneous use of colchicine

with lopinavir/ritonavir, it is possible to increase the concentration of colchicine in the blood plasma. The prescription and dose selection of colchicine should be made in accordance with its instructions for use. Concomitant use is not recommended due to the adverse effects of colchicine associated with neuromuscular toxicity (including rhabdomyolysis), especially in patients with renal and hepatic impairment.

Lopinavir/ritonavir may cause a moderate increase in clarithromycin

. In patients with impaired renal function (with creatinine clearance <30 ml/min) or liver function, a reduction in the dose of clarithromycin should be considered when used concomitantly with lopinavir/ritonavir.

With simultaneous use of rifabutin

and lopinavir/ritonavir for 10 days, the Cmax and AUC of rifabutin (unchanged drug and active 25-O-desacetyl metabolite) increased by 3.5 and 5.7 times, respectively.

In studies with higher doses of lopinavir/ritonavir when coadministered with rifampicin

an increase in the activity of ALT and AST was noted; this phenomenon may depend on the dosage sequence.

In a study in healthy volunteers, bedaquiline 400 mg administered once and lopinavir/ritonavir 400/100 mg twice daily for 24 days resulted in a 22% increase in bedaquiline AUC.

Delamanid interaction studies

only with ritonavir were not carried out. In studies in healthy volunteers, delamanid 100 mg twice daily and lopinavir/ritonavir 400/100 mg twice daily for 14 days were used and a slight increase in concentrations of delamanid and delamanid metabolite (DM-6705) was observed. If use of delamanid and ritonavir is truly necessary, ECG monitoring should be performed throughout delamanid treatment due to the risk of QTc prolongation associated with the metabolite DM-6705.

The therapeutic concentration of atovaquone may be reduced when used concomitantly with lopinavir/ritonavir. The dose of atovaquone may need to be increased.

Dexamethasone

may cause an increase in the activity of the CYP3A isoenzyme and a decrease in the concentration of lopinavir. It is necessary to monitor antiviral activity.

Concomitant use of lopinavir/ritonavir and fluticasone

may significantly increase plasma concentrations of fluticasone and decrease serum cortisol concentrations. Should be used with caution. It is recommended that alternatives to fluticasone be considered, especially if long-term use is required.

With simultaneous use of ritonavir with intranasal and inhaled forms of fluticasone and budesonide, systemic effects of GCS

, including Cushing's syndrome and adrenal suppression. Concomitant use of lopinavir/ritonavir and fluticasone, as well as other corticosteroids that are metabolized by CYP3A4, such as budesonide, is not recommended unless the potential benefits of such therapy outweigh the risk of systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression. .

With the simultaneous use of lopinavir/ritonavir and any corticosteroids for inhalation and intranasal use, special caution should be exercised.

The possibility of reducing the dose of GCS should be considered with careful monitoring of local and general reactions or switching to GCS that is not a substrate for the CYP3A4 isoenzyme (for example, beclomethasone). If GCS therapy is discontinued, a gradual dose reduction should be carried out over a long period.

There may be an increase in serological concentrations of felodipine, nifedipine, nicardipine

when taking lopinavir/ritonavir. Clinical monitoring is required when co-administered with lopinavir/ritonavir.

Particular caution should be exercised when using sildenafil and tadalafil

for the treatment of erectile dysfunction in patients taking lopinavir/ritonavir. Concomitant use of lopinavir/ritonavir with these drugs may significantly increase their concentrations, which may lead to an increased incidence of side effects such as hypotension and prolonged erection.

In patients receiving treatment with lopinavir/ritonavir, simultaneous use of drugs containing St. John's wort is contraindicated, because this combination may help reduce lopinavir/ritonavir plasma concentrations. This effect may occur due to induction of the CYP3A4 isoenzyme and may lead to loss of therapeutic effect and the development of resistance.

If the patient is already taking St. John's wort

and he is prescribed lopinavir/ritonavir, then it is necessary to discontinue St. John's wort preparations and check the level of viral load. When drugs containing St. John's wort are discontinued, the concentration of lopinavir/ritonavir in the blood plasma may increase. A dose adjustment of lopinavir/ritonavir may be required. The inducing effect may persist for at least 2 weeks after cessation of treatment with St. John's wort. Lopinavir/ritonavir is recommended to be prescribed 2 weeks after stopping the use of St. John's wort.

There were no signs of clinically significant interaction between lopinavir/ritonavir and pravastatin. Metabolism of pravastatin and fluvastatin

does not depend on the CYP3A4 isoenzyme, so interaction with lopinavir/ritonavir is not expected. If treatment with HMG-CoA reductase inhibitors is indicated during the use of lopinavir/ritonavir, it is recommended to use pravastatin or fluvastatin.

Concentrations of these drugs (eg, cyclosporine, tacrolimus, and sirolimus

) may increase when used concomitantly with lopinavir/ritonavir. More frequent monitoring of therapeutic concentrations is recommended until blood concentrations of these drugs are stabilized.

Lopinavir/ritonavir is known to reduce plasma concentrations of methadone

. It is recommended to monitor plasma concentrations of methadone.

Because ethinyl estradiol concentrations

plasma levels may be reduced when lopinavir/ritonavir is co-administered with estrogen-containing oral contraceptives or patch contraceptives; alternative or additional methods of contraception should be used.

When used concomitantly with bosentan

in combination with lopinavir/ritonavir, an increase in the Cmax and AUC of bosentan was observed by 6 and 5 times, respectively.

special instructions

During treatment with the combination drug Lopinavir + Ritonavir, redistribution of adipose tissue and metabolic . This phenomenon is most often observed in the older age group, with prolonged treatment. It is necessary to determine the serum concentration of glucose and blood lipids in the patient on an empty stomach. Treatment is carried out depending on the clinical picture.

With hemophilia A and B, bleeding may increase, hemarthrosis and subcutaneous hematomas . It is possible to use additional factors VIII.

Sometimes when treated with this combination of lek. means, approximately 20% of patients experience immune reconstitution syndrome . This is the name of the phenomenon in which asymptomatic or residual infections, for example, caused by mycobacteria, CMV, become aggravated. Additional treatment and testing may be required. Autoimmune diseases may also occur.

The safety of treatment in children under six months of age has not been established. In patients infected with HIV for 6 months to a year, side effects from treatment are no more common than in adults. In childhood, this combination of medications should not be used. funds for children once a day.

Drug interactions Ritonavir

Increases the concentration of drugs metabolized with the participation of cytochrome P450 (including amiodarone, astemizole, itraconazole, ketoconazole, bepridil, cisapride, clozapine, dihydroergotamine, ergotamine, encainide, flecainide, piroxicam, propafenone, clonidine, rifabutin, terfenadine). Chlorazepam, diazepam, estazolam, midazolam, trizolam, zolpidem increase the risk of developing respiratory failure and asthenia. Phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampin, rifabutin, and smoking reduce the effectiveness of ritonavir. Ritonavir reduces the effectiveness of oral contraceptives, theophylline, increases the AUC of saquinavir, indinavir, clarithromycin, trimethoprim, rifabutin and its metabolite, reduces the AUC of cidovudine (by 26%), theophylline (by 45%), ethinyl estradiol (by 41%), sulfamethoxazole (by 20). %). Concomitant use (due to possible changes in concentration) with analgesics, antihistamines, antiarrhythmics and sedatives, antidepressants, antipsychotics, calcium antagonists is not recommended.

List of pharmacies where you can buy Ritonavir:

• Moscow
• Saint Petersburg

Treatment of coronavirus

As soon as the COVID-19 , before it developed into a pandemic, various drugs and their combinations began to be considered as candidates for effective treatment of the disease. Great hopes were placed on the combination of drugs Lopinavir and Ritonavir. Moreover, this lek. the drug has already proven itself in the treatment of MERS-CoV in vitro and in experiments on living cells. There have even been practical cases of using the drug to treat those infected with coronavirus. Computer modeling also gave good results. Lopinavir was suitable for inhibiting the activity of the main proteinase of the virus. The use of additional Ritonavir was also considered necessary, since it significantly enhances the effect of the main antiviral agent.

Clinical trials conducted in China showed that the drugs had little effect on treatment efficacy parameters compared to a group of patients who did not take them. Patients with a mild form of the disease had relatively good results.

The graph (presented below) shows that the average time (median) until the onset of improvement was 16 days. It did not matter whether treatment for coronavirus was started in the first 12 days after the onset of symptoms or later. The duration of illness was not reduced in any way. Viral load levels did not change at all.

Results of a randomized trial (n = 199) of treatment with Lopinavir + Ritonavir in adults with SARS-CoV-2 infection

However, in the group of patients receiving treatment with the drug, about 45% experienced improvements after 14 days, and 30% without the drug. The overall mortality rate was reduced (19% and 25% without treatment with the drug). There were fewer patients with complications from coronavirus infection: respiratory failure, acute renal failure , secondary infections, pneumothorax , sepsis and acute heart failure (0% versus 1%).

Additionally, other experiments were conducted to treat the virus in China using this drug combination, but no significant improvements were found. In addition, the studies were not blinded. At the moment, experiments on the treatment of COVID-19 with the help of Lopinavir and Ritonavir are ongoing, but there is no great hope for pharmaceuticals. The industry does not rely on this drug.

At the moment, they are trying to use several drugs that were used in past outbreaks of coronaviruses for treatment. First of all, these are Ribavirin, Ribavirin + Lopinavir + Ritonavir and interferon-based drugs. In the experimental mode, the following treatment regimens are used:

• Ribavirin + Lopinavir + Ritonavir and recombinant interferon ;
• Lopinavir + Ritonavir and interferon beta 1b ;
• There is a regimen of Ribavirin, Lopinavir + Ritonavir, recombinant interferon beta 1b .

Doctors strongly discourage self-medication and taking antiviral drugs with unproven effectiveness.

Finding a cure for COVID-19

Pfizer recently announced a drug it had developed against SARS-CoV-2. This is not the first drug against COVID-19; Merck has been at the forefront of this issue with its development.

And yet, such an event prompted obvious questions. What are the mechanisms of action of drugs against coronavirus infection? How are different drugs fundamentally different from each other? Which existing solutions are more effective? Can vaccines be replaced with drugs?

The answers to all these questions are in our article today. We prepared it together with the authors of the popular science telegram channel BioLogika.

There are two main ways to treat coronavirus infection: symptom relief in severe cases of the disease and targeted therapy aimed at the virus. In this article we will focus on the second approach, but it is worth saying a few words about symptomatic treatment.

COVID-19 begins with the virus multiplying in the human body: symptoms are caused by viral particles. In later and more severe stages, the main danger is hyperinflammation caused by the body's immune system being too active[]. Cytokine storm is the main cause of problems in severe COVID-19: the body’s condition worsens due to a positive feedback mechanism [].

To “pacify” the immune system, various nonspecific immunosuppressants have long been used: dexamethasone and other glucocorticosteroids []. Later, more specific techniques began to appear to prevent cytokine storm. It is possible to block the cells' response to various inflammatory signals. Then cytokines will be released, but the cells will respond less actively to them, and the positive feedback will be weakened. Inhibitors of certain Janus kinases work on this principle. Janus kinases are enzymes involved in many signaling cascades, including inflammatory ones. Janus kinase inhibitors include tofacitinib, ruxolitinib and other drugs [].

There is also a classic, etiotropic method of treatment - affecting the virus itself, and not the immune system. The disadvantage of these drugs for COVID-19 is that their use is effective only at the very beginning of the development of the disease. In later stages, the virus itself is no longer of key importance: the problem lies in the immune system. If you prevent the virus from multiplying, this will allow you to experience a mild or almost asymptomatic coronavirus infection. The coronavirus will not trigger dangerous immune reactions in the body, and as a result, the mortality rate can be significantly reduced.

For these drugs to work, timely and widespread testing of people with any mild symptoms is necessary. Everyone should have access to rapid tests based on the detection of coronavirus antigens in the mucous membrane. In Russia, few such tests are carried out, so the prospects for the use of such drugs in our country are quite vague.

The use of nucleotide analogues is an old proven method of treating viral diseases caused by herpes simplex virus, Ebola virus, HIV and others.

Back in December 2022, a study was published in Nature Microbiology that a substance called MK-4482, chemically resembling the nucleoside cytidine, was effective against COVID-19 []. It has been shown to be administered orally in tablet form, which is simple and convenient. How does the compound prevent the development of the disease? Nucleosides are the main “building blocks” of nucleic acids (DNA and RNA), they are necessary for the virus to replicate, so MK-4482 causes various problems when the virus multiplies.

The active substance penetrates the infected cell. There, the drug turns into an analogue of a nucleotide: after all, the virus uses nucleotides for replication, and nucleosides are their precursors. The virus's RNA polymerase, the protein responsible for replication, takes this molecule for an ordinary nucleotide. Replication is disrupted. How does this affect SARS-CoV-2?

First, inserting the “wrong” nucleotide can cause a mutation. Secondly, RNA polymerase can be inhibited or stopped: the virus cannot replicate. The substance MK-4482 works through the first mechanism: it causes numerous mutations of the virus, preventing its reproduction and evolution. Biologists are deceiving the coronavirus by slipping fake nucleotides into its polymerase.

Figure 1 | The principle of action of drugs similar to nucleotides or nucleosides

Adapted from the article “Identifying mechanism for a new class of antiviral drugs could have approval”, 2022 [].

This is exactly how the drug developed by Merck works: the drug causes mutations in the replicating SARS-CoV-2. According to the company, their drug reduces the risk of hospitalization for coronavirus patients by 50%, but clinical trials have not yet been completed, so final conclusions about the effectiveness and safety of the drug cannot yet be made. A potential risk of such drugs is an increased rate of emergence of new strains if the drug is used incorrectly and mutagenesis is not strong enough to eliminate the virus population[].

The drug from Pfizer has a fundamentally different mechanism of action: the main active ingredient is an inhibitor of viral proteases, preventing the proliferation of coronavirus. How does it work?

When assembling the capsid—the protein shell of the virus—the coronavirus first synthesizes one long polypeptide chain and then cuts it using proteases. It turns out several ready-made proteins []. When proteases are blocked, viral particles are not assembled and the virus stops reproducing. Some HIV drugs work on this principle.

One of the first studies on the use of such drugs was published in August 2022. Remdesivir, EIDD-2801 and others were effective against various coronaviruses, including SARS-CoV-2 [].

The Pfizer drug consists of the viral protease inhibitor PF-07321332 and the excipient ritonavir. Ritonavir was originally discovered as a protease inhibitor, but of another virus - HIV. In this case, ritonavir increases the effectiveness of the main drug: it predominantly inhibits liver cytochrome P450 - CY3A4, which metabolizes the main component of the drug - PF-07321332. Cytochromes P450 are a large group of liver enzymes from the class of monooxygenases involved in the inactivation, as a rule, of foreign substances, including drugs. Ritonavir weakens the work of two isoenzymes of cytochrome P450 - CYP3A4 and CYP2C6, as a result, the effectiveness of the drug increases.

Pfizer says its drug reduces hospitalization rates by 89%, but clinical trials are still ongoing. Merck and Pfizer's announcements refer to different phases of clinical trials, so it's difficult to say which drug is better.

Another way to treat Covid is the use of monoclonal antibodies []. Scientists isolate antibodies from people who have recovered from coronavirus, study these antibodies and synthesize new ones based on them.

Antibodies synthesized in the laboratory consist of two fragments. The first part binds to viral antigens (Fab - from the English fragment antigen binding), and the second is recognized by the immune system (Fc - from the English fragment crystallizable region, or crystallizing fragment of immunoglobulin). The antibody interacts with viral particles (opsonization) or virus-infected cells and attracts various components of the immune system: the complement system, natural killer cells. The humoral response is also activated: differentiation of B-lymphocytes into plasmacytes.

In addition, monoclonal antibodies can neutralize the virus directly: they form a “coat” around the viral particles, and they can no longer interact with human cells.

Figure 2 | Mechanisms of action of monoclonal antibodies

Adapted from the review “Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?” [].

As with vaccination, antibodies help the body cope with infection, but in this case these antibodies are artificial and not produced by the body itself []. This is a kind of replacement therapy.

Typically, when treating viruses with monoclonal antibodies, entire cocktails of several types of antibodies are used to increase effectiveness. In the case of coronavirus, this is bamlanivimab + etesivimab or casirivimab + imdevimab. Other antibodies, such as sotrovimab, can be used alone rather than as part of a cocktail [].

The vast majority of monoclonal antibodies to coronavirus bind to the coronavirus spike protein, the very spike through which the virus latch onto cells and infect them. When this spike is covered by antibodies, the reproduction of the coronavirus is greatly slowed down, and the immune system, on the contrary, is activated.

The active ingredient of avifavir, favipiravir, was discovered in Japan more than five years ago. It is a derivative of pyrazine carboxamide and inhibits viral RNA polymerase, blocking the reproduction of various RNA viruses.

The first drug containing favipiravir is Avigan, which was registered in Japan in 2014 as an anti-flu drug. At the same time, the use of Avigan was approved only in “emergency situations” - against new strains, when other means were ineffective.

In a study on the safety of favipiravir, scientists conclude that the substance is generally safe, but there are quite a few problems []. In addition, favipiravir is contraindicated in pregnant women [and] this drug has never been approved in the United States. The effectiveness of favipiravir against coronavirus was low, and the drug was not used for treatment anywhere.

Developed in Russia, Avifavir is essentially a generic version of the Japanese favipiravir - the active substance and mechanism are the same. Clinical trials were conducted in Russia. The use of the drug is recognized as more effective than standard therapy []. However, the significance level of viral clearance rates (p-value) in this study was only 0.155, which is significantly higher than the standard 0.01 or 0.05. This means that the results are statistically unreliable. However, based on these studies, the medicine was registered in Russia and included in the recommendations of the Ministry of Health. Other drugs with the same active substance registered in Russia are Areplivir and Coronavir. The effectiveness and safety of these drugs are also questionable.

One of the ways to combat coronavirus is the use of RNA interference: interaction based on the principle of complementarity of a special small interfering RNA with the messenger RNA of the target protein, the translation of which we want to prevent. The miRNA molecule (from the English microRNA) does not carry information about any proteins, like messenger RNA, but can trigger the cleavage of messenger RNA. This signal can “turn off” the synthesis of certain proteins. This switching off is called RNA interference.

If you make miRNA directed against the proteins of the virus, you can stop its reproduction in the body. Despite the fact that RNA interference was discovered more than 20 years ago, there are quite a few FDA-approved drugs based on it. Only three drugs using siRNA (small interfering RNA), among which there are no antiviral drugs, and none with miRNA []. However, drugs that work on the principle of RNA interference can be really effective, since they work well against the hepatitis C virus, which has a genome similar to the coronavirus [].

Russian scientists from the FMBA are developing similar molecules against coronavirus; the first preclinical trials have already been successfully carried out []. The advantage of such drugs is their high specificity, because the principle of nucleotide complementarity works here. There are many problems to be solved: the degradation of siRNA in a living organism and the delivery of this molecule to cells.

There are various ways to treat coronavirus infection, but so far clinical trials of none of the drugs have been completed. When the drugs are finally tested and can be used, it will significantly reduce hospitalization and mortality rates from coronavirus.

But all drugs have certain disadvantages. Firstly, the drugs need to be used at an early stage of the disease. Secondly, their use must be strictly controlled by specialists, since if the course is interrupted ahead of time in each individual patient, the likelihood of the emergence of resistant strains of the virus increases. This phenomenon is reminiscent of the development of bacterial resistance to antibiotics. Finally, the drugs reviewed are very expensive: one course can cost several thousand dollars. Therefore, universal vaccination remains the main tool for combating the pandemic: medicine cannot replace vaccinations.

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Drugs containing (Lopinavir + Ritonavir analogues)

Level 4 ATC code matches:
Calidavir

Kaletra

Combivir

There are analogues of Lopinavir + Ritonavir registered in the Russian Federation, trade names of the drugs: Kalidavir , Lopirita , Kaletra , Lopinavir + Ritonavir extrudate, 16.7% + 4.2% , Alltera .