Lopinavir inhibits the isoenzyme CYP3A4. The simultaneous use of lopinavir and drugs metabolized by CYP3A isoenzymes (including calcium antagonists of dihydropyridine derivatives, HMG-CoA reductase inhibitors, immunosuppressants and sildenafil) can lead to an increase in their plasma concentrations and enhance or prolong the therapeutic effect and side effects.
The risk of a significant increase in AUC (≥ 3 times) when treated with lopinavir / ritonavir is highest with the simultaneous use of drugs that are metabolized actively by CYP3A isoenzymes and undergo metabolism during the "first passage" through the liver.
Lopinavir / ritonavir in vivo induces its own metabolism and causes an increase in the biotransformation of some drugs metabolized by isoenzymes of the cytochrome P450 system and by glucuronation.
Lopinavir / ritonavir is metabolized by CYP3A isoenzymes. The simultaneous use of lopinavir / ritonavir with inducers of this isoenzyme may lead to a decrease in plasma lopinavir concentrations and its therapeutic effect. Other drugs that inhibit CYP3A isoenzymes may cause an increase in plasma lopinavir, although these changes were not noted with the simultaneous use of ketoconazole.
Lopinavir / ritonavir causes an increase in the concentration of tenofovir in the blood plasma (the mechanism of interaction is unknown).
In the treatment of protease inhibitors, especially in combination with nucleoside reverse transcriptase inhibitors, there was an increase in activity creatine phosphokinase, myalgia, myositis, rarely - rhabdomyolysis.
In HIV-infected children, there was a decrease in lopinavir concentration with simultaneous use of nevirapine. The effect of nevirapine in HIV-positive adults may be similar to that of children, which may lead to a decrease in the concentration of lopinavir. The clinical significance of pharmacokinetic interaction is unknown.
An increase in the dose of lopinavir / ritonavir up to 600/150 mg twice a day in combination with efavirenz leads to an increase in the concentration of lopinavir in the blood plasma by 36% and ritonavir from 56-92% compared with the dose of lopinavir / ritonavir 400/100 mg 2 once a day without efavirenz.
Efavirenz and nevirapine can induce the activity of CYP3A isoenzymes and, accordingly, reduce the concentrations of other protease inhibitors.
Delavirdine can cause an increase in the concentration of lopinavir in plasma.
Lopinavir / ritonavir may cause an increase in the concentration of amprenavir. When a combination of lopinavir / ritonavir with amprenavir causes a decrease in the concentration of lopinavir.
Lopinavir / ritonavir can cause an increase in the concentration of indinavir in the blood plasma, while the AUC does not change significantly.When using lopinavir / ritonavir in a dose of 400/100 mg 2 times a day, a decrease in the dose of indinavir may be required. Lopinavir / ritonavir should not be used once a day in combination with indinavir.
Lopinavir / ritonavir can cause an increase in the concentration of nelfinavir and its M8 metabolite.
The combination of lopinavir / ritonavir with nelfinavir leads to a decrease in the concentration of lopinavir.
With the simultaneous use of lopinavir / ritonavir with ritonavir at a dose of 100 mg twice a day, an increase in AUC of lopinavir by 33% and Cmin on 64% in comparison with those at application only lopinavir / ritonavir in a dose of 400/100 mg 2 times a day.
Lopinavir / ritonavir may cause an increase in saquinavir concentrations. With simultaneous application of saquinavir in a dose of 800 mg 2 times per day with lopinavir / ritonavir there was an increase in AUC, FROMmax and FROMmin compared with those with saquinavir in a dose of 1200 mg 3 times per day. When using lopinavir / ritonavir in a dose of 400/100 mg 2 times per day a dose reduction of saquinavir may be required. Use of lopinavir / ritonavir in combination with saquinavir 1 time per day not studied.
Concentrations of amiodarone, beprinid, lidocaine and quinidine may increase with simultaneous use with lopinavir / ritonavir.
Concentrations of phenyramine, quinidine, erythromycin and clarithromycin may increase with the subsequent prolongation of the QT interval and the development of cardiovascular side effects with simultaneous use with lopinavir / ritonavir.
When used concomitantly with ritonavir / lopinavir, plasma concentrations of vincristine and vinblastine may increase, followed by a potential increase in the incidence of side effects that are characteristic of these drugs.
Lopinavir / ritonavir may cause a decrease in warfarin concentration (control is recommended international normalized attitude).
Phenobarbital, phenytoin and carbamazepine induce isoenzymes CYP3A and can cause a decrease in the concentration of lopinavir.
Serum concentrations of itraconazole and ketoconazole may increase with simultaneous use with lopinavir / ritonavir.
Lopinavir / ritonavir may cause a moderate increase in clarithromycin AUC.
With the simultaneous use of rifabutin and lopinavir / ritonavir for 10 days FROMmax and AUC rifabutin (the drug itself and the active 25-O-deacetyl metabolite) are increased by 3.5 and 5.7 times, respectively.
Given the significant decrease in lopinavir concentration when used concomitantly with rifampicin, there may be a worsening of the virologic response and the potential development of resistance to lopinavir / ritonavir, the whole class of protease inhibitors or other antiretroviral drugs.
Dexamethasone can cause an increase in the activity of CYP3A isoenzymes and a decrease in the concentration of lopinavir.
The combination with lopinavir / ritonavir can lead to an increase in the concentration of fluticasone and a decrease in serum cortisol concentration.
Serum concentrations of felodipine, nifedipine and nicardipine may increase with simultaneous use with lopinavir / ritonavir.
Lopinavir / ritonavir can cause a significant increase in plasma concentrations of HMG-CoA reductase inhibitors metabolized by CYP3A isoenzymes such as lovastatin and simvastatin. The combination of lopinavir / ritonavir with statins is not recommended, since an increase in the concentrations of statins can lead to the development of myopathy, including rhabdomyolysis.
Atorvastatin metabolism is less dependent on CYP3A isoenzymes. With the simultaneous use of atorvastatin with lopinavir / ritonavir, an increase FROMmax and AUC of atorvastatin in 4.7 and 5.9 times, respectively. In combination with lopinavir / ritonavir atorvastatin should be used in minimal doses.
Signs of clinically significant interaction of lopinavir / ritonavir with pravastatin have not been revealed. Metabolism of pravastatin and fluvastatin does not depend on the isoenzyme CYP3A, so they should not interact with lopinavir / ritonavir.
Concentrations of cyclosporine, tacrolimus and sirolimus may increase with simultaneous use with lopinavir / ritonavir.
Lopinavir / ritonavir causes a decrease in the concentration of methadone in the plasma.
Considering the possibility of reducing the concentration of ethinyl estradiol in plasma with simultaneous use of lopinavir / ritonavir with oral contraceptives or patches containing estrogens, other or additional contraceptive measures are advisable.