Lopinavir
When ATH: J05AE06
Pharmacological action
Antiviral agent, HIV protease inhibitor-1 and HIV-2. Inhibition of HIV protease prevents the synthesis of viral proteins, resulting in immature and incapable of infection.
Pharmacokinetics
EC50 лопинавира in vitro примерно в 10 times lower than that of ritonavir.
When Css plasma lopinavir approximately 98-99% It binds to proteins. Lopinavir binds to both the α1-acid glycoprotein, and albumin, but has a higher affinity for the α1-acidic glycoprotein.
Lopinavir primarily undergoes extensive oxidative metabolism involving the cytochrome P450 isoenzyme hepatocytes almost exclusively under the influence of CYP3A4. The plasma is found not less than 13 lopinavir oxidative metabolites. The main metabolites, has antiviral activity, is 4-Hydroxy- and 4 gidroksimetabolitnye isomeric pair.
Displayed predominantly in the feces (neizmenennыy lopinavir – 19.8%) , minority – urine (neizmenennыy lopinavir – 2.2%).
The clearance of lopinavir ingestion of 5.98 ± 5.75 l / h.
Testimony
AIDS (in a combination therapy with ritonavir).
Dosage regimen
Individual, depending on the age of the patient, the dosage form and regimen.
Side effect
Adverse Reactions, observed with the combination of lopinavir and ritonavir.
From the digestive system: abdominal pain, diarrhea, dysphagia, dyspepsia, flatulence, vomiting, nausea.
From the central and peripheral nervous system: insomnia, headache, depression, paresthesia.
Cardio-vascular system: arterial hypertension, vascular disorders.
Metabolism: anorexia, weight loss.
On the part of the reproductive system: male hypogonadism, amenorrhea, decreased libido.
Skin and subcutaneous fat: lipodystrophy, skin rash.
Other: asthenia, fever, chills, bronchitis, myalgia.
Contraindications
Hepatic failure, severe, simultaneous use with astemizole, terfenadine, midazolamom, triazolamom, cizapridom, pimozidom, ergot alkaloids (incl. ergotamin, digidroergotamin, ergometrine, methylergometrine), lovastatin, simvastatin, Hypericum perforatum, rifampicin, vorikonazolom; hypersensitivity to lopinavir.
Pregnancy and lactation
Pregnancy may only, when the intended benefits to the mother outweighs the potential risk to the fetus.
If necessary, use during lactation should decide the issue of termination of breastfeeding.
Cautions
Be wary of viral hepatitis B and C, cirrhosis, mild to moderate hepatic insufficiency, increase in liver enzymes, hemophilia A and B, dyslipidaemia (incl. hypercholesterolemia, gipertrigliceridemii), in elderly patients (senior 65 years).
During postmarketing surveillance in HIV-infected patients, receiving protease inhibitors, We have reported cases of decompensation of diabetes mellitus and hyperglycemia. In some cases, it had to appoint insulin or oral hypoglycemic agents (or increase their dose). Sometimes developing diabetic ketoacidosis. In some patients, hyperglycemia persisted after the abolition of the protease inhibitor. Reports of these incidents have been reported on a voluntary basis, therefore estimate their frequency and communication with protease inhibitors is not possible.
In patients with advanced HIV infection increased the risk of developing hypertriglyceridemia and pancreatitis.
In the study of protease inhibitors has been fixed cross-resistance of varying severity. Currently, we study the effect on the effectiveness of lopinavir subsequent therapy with other protease inhibitors.
Patients with hemophilia A and B in the treatment of protease inhibitors described cases of bleeding, including spontaneous formation of subcutaneous hematoma and hemarthrosis development. Some patients received an additional dose of factor VIII. More than half the cases, treatment with protease inhibitors was continued. The causal relationship, or the mechanism of development of such adverse events in the treatment of protease inhibitors have not been established.
Against the background of antiretroviral therapy was observed redistribution / accumulation of body fat deposition in the central parts of his body, in the back area, Neck, appearance “gorʙa ʙujvola”, a decrease in body fat in the face and extremities, breast enlargement and kushingoidom. The mechanism and long-term consequences of these adverse effects are unknown. Their connection with therapy is not installed.
Before beginning treatment and at regular intervals during treatment should control the levels of triglycerides and cholesterol. In the presence of lipid disorders shows the corresponding therapy.
Patients, treated with combination antiretroviral therapy, incl. using a combination of lopinavir and ritonavir, observed the development of immune reconstitution syndrome. Against the background of recovery of immune function at the beginning of combined therapy may increase asymptomatic or residual opportunistic infections (incl. Mycobacterium avium, Mycobacterium tuberculosis, Pneumocystis carinii, Cytomegalovirus), which may require additional examination and treatment.
Increased ALT and AST were observed with the combination of lopinavir / ritonavir at higher doses in combination with rifampicin. In the period of treatment should be carefully monitor liver function.
Known, Many factors play a role in the etiology of osteonecrosis (incl. GCS, alcohol abuse, High BMI, severe immunosuppression). In particular, reported cases of osteonecrosis in patients with advanced HIV infection and / or long-term use of combination antiretroviral therapy. Therefore, such patients should be advised to appeal to the doctor if you have pain, stiffness in the joints and impaired motor function.
In applying the lopinavir / ritonavir in the elderly should be careful, given the increased frequency of decreased hepatic, kidney or heart, comorbidities and concomitant therapy.
The safety and pharmacokinetics of lopinavir / ritonavir in children under the age of 6 months have not been established. In HIV-infected children aged 6 Months before 12 age profile of adverse events in clinical trials was similar to that in adults. The use of lopinavir / ritonavir 1 time / has not been studied in children.
Drug Interactions
Лопинавир ингибирует изофермент CYP3A4 . Concomitant use of lopinavir and drugs, метаболизирующихся изоферментами CYP3A (incl. calcium channel blockers of the dihydropyridine derivatives, HMG-CoA reductase, immunosuppressants and sildenafil) It can lead to an increase in their concentration in the plasma and enhance or prolong the therapeutic actions and side effects.
The risk of a significant increase in AUC (≥3 times) during treatment with lopinavir / ritonavir is highest, while the use of drugs, It is extensively metabolized by the action of isoenzymes CYP3A and is metabolized in the “first pass” through the liver.
Lopinavir / ritonavir in vivo to induce its own metabolism and causes an increase in the biotransformation of some drugs, metabolized by the action of isoenzymes under the influence of cytochrome P450 isoenzymes, and by glyukuronirovaniya.
Lopinavir / ritonavir metaboliziruetsya under deystviem izofermentov CYP3A. Concomitant use of lopinavir / ritonavir with inducers of this isoenzyme may reduce plasma concentrations of lopinavir and its therapeutic effect. Other drugs, inhibiting isoenzymes CYRZA, can cause an increase in plasma concentrations of lopinavir, although these changes were not observed while applying ketoconazole.
In an application with the use of ritonavir or lopinavir / ritonavir in combination with stavudine and lamivudine was not observed changes in the pharmacokinetics of lopinavir.
Lopinavir / ritonavir causes an increase in concentrations of tenofovir in the blood plasma (mechanism of interaction is unknown).
In the treatment of protease inhibitors, particularly in combination with nucleoside reverse transcriptase inhibitors have been observed increased activity of CPK, mialgii, myositis, rarely – raʙdomioliz.
In HIV-infected children showed decreased concentrations of lopinavir, while the use of nevirapine. The effect of nevirapine in HIV-positive adults may be similar to that in children, which may lead to decrease in the concentration of lopinavir. The clinical significance of the pharmacokinetic interaction is unknown.
Increasing the dose of lopinavir / ritonavir to 600/150 mg 2 in combination with evafirenzom leads to increased concentrations of lopinavir in the blood plasma 36% and ritonavir 56-92% compared with dosing lopinavir / ritonavir dose 400/100 mg 2 without evafirenza.
Evafirenz and nevirapine can induce the activity of CYP3A and isoenzymes, respectively, lower concentrations of other protease inhibitors.
Delavirdine may cause an increase in the concentration of lopinavir plasma.
Lopinavir / ritonavir may cause a rise in the concentration of amprenavir. With the combination of lopinavir / ritonavir with amprenavir causes a decrease in the concentration of lopinavir.
Lopinavir / ritonavir may cause a rise in the concentration of indinavir in the blood plasma, wherein AUC is not altered. In applying the lopinavir / ritonavir dose 400/100 mg 2 may require dose reduction of indinavir. Lopinavir / ritonavir sleduet primenyaty 1 times / in combination with indinavir.
Lopinavir / ritonavir may cause a rise in the concentration of nelfinavir and its M8 metabolite.
The combination of lopinavir / ritonavir with nelfinavir reduces the concentration of lopinavir.
With simultaneous use of lopinavir / ritonavir, ritonavir at a dose of 100 mg 2 there was an increase in the AUC of lopinavir 33% and Cmin at 64% in comparison with those when using only lopinavir / ritonavir dose 400/100 mg 2
Lopinavir / ritonavir may cause a rise in the concentration of saquinavir. In an application in a dose of saquinavir 800 mg 2 with lopinavir / ritonavir was an increase in AUC, Cmax and Cmin in comparison with those when using a dose of saquinavir 1200 mg 3 In applying the lopinavir / ritonavir dose 400/100 mg 2 may require dose reduction of saquinavir. The use of lopinavir / ritonavir in combination with saquinavir 1 time / has not been studied.
Concentrations of amiodarone, bepridil, lidocaine and quinidine may be increased while the use of lopinavir / ritonavir.
Concentrations pheniramine, xinidina, erythromycin and clarithromycin can increase followed QT prolongation and development of side effects of the cardiovascular system while the use of lopinavir / ritonavir.
While the use of ritonavir / lopinavir may increase plasma concentrations of vincristine and vinblastine followed by a potential increase in the frequency of side effects, are characteristic of these drugs.
Lopinavir / ritonavir may cause a decrease in the concentration of warfarin (INR monitoring is recommended).
Phenobarbital, phenytoin and carbamazepine induce CYP3A isoenzymes and may cause a decrease in the concentration of lopinavir.
Serum concentrations of ketoconazole and itraconazole may be increased while the use of lopinavir / ritonavir.
Lopinavir / ritonavir may cause a moderate increase in AUC of clarithromycin.
With simultaneous use of rifabutin and lopinavir / ritonavir for 10 Cmax and AUC days rifabutin (of the drug and active 25-O-metabolite dezatsetilovogo) increase in 3.5 and 5.7 times, respectively,.
Given the significant reduction in lopinavir concentrations while the use of rifampicin, possible deterioration of virologic response and the potential development of resistance to lopinavir / ritonavir, the entire class of protease inhibitors or other anti-retroviral drugs.
Dexamethasone may cause an increase in the activity of isoenzymes CYP3A and reduced concentrations of lopinavir.
The combination with lopinavir / ritonavir may result in increased concentrations of fluticasone and reduce serum cortisol concentrations.
Serum concentrations of felodipine, nifedipine and nicardipine may increase while the use of lopinavir / ritonavir.
Lopinavir / ritonavir may cause a significant increase in plasma levels of HMG-CoA reductase, metaboliziryuschihsya under the influence of CYP3A isoenzymes, Taki how lovastatin and simvastatin. We do not recommend the combination of lopinavir / ritonavir with statins, because increasing concentrations of statins can lead to the development of myopathies, incl. rhabdomyolysis.
Metabolism Atorvastatin is less dependent on CYP3A isoenzymes. With simultaneous use of atorvastatin with lopinavir / ritonavir experienced higher Cmax and AUC of atorvastatin 4.7 and 5.9 times, respectively,. In combination with lopinavir / ritonavir atorvastatin should be used in minimal doses.
No evidence of clinically significant interaction between lopinavir / ritonavir with pravastatin were found. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A isoenzyme, therefore they should not engage in the lopinavir / ritonavir.
The concentrations of cyclosporine, tacrolimus and sirolimus may increase while the use of lopinavir / ritonavir.
Lopinavir / ritonavir is a decrease in plasma concentrations of methadone.
Given the possibility of reducing the concentration of ethinyl estradiol in the plasma, while the use of lopinavir / ritonavir with oral contraceptives or patch, containing estrogens, suitable other or additional contraceptive measures.
