Lopinavir & Ritonavir
Lopinavir & Ritonavir
Lopinavir/ritonavir, sold under the brand name Kaletra among others, is a fixed-dose combination antiretroviral medication for the treatment and prevention of HIV/AIDS. It combines lopinavir with a low dose of ritonavir. It is generally recommended for use with other antiretrovirals.
Mechanism of action:
- Lopinavir provides antiviral activity of this tablet. Lopinavir is an inhibitor of HIV-1 and HIV-2 proteases. Inhibition of HIV protease inhibits the cleavage of Gag-Pol polyproteins resulting in the production of immature, non-infectious viruses.
- The pharmacokinetic properties of lopinavir co-administered with ropinavir have been evaluated in healthy adult volunteers and HIV-infected patients; No substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, leading to an increase in plasma levels of lopinavir. According to the Gross Study, twice-daily yields of the tablet 400/100 mg mean HIV-infected patients have 15 to 20 times more stable lopinavir plasma concentrations than ritonavir. The plasma levels of ritonavir are less than 7% of those obtained after the ratanavir dose of 600 mg twice daily. Lopinavir’s in vitro antiviral EC50 is approximately 10 times lower than that of ritonavir. Therefore, the antiviral activity of this medicine is due to lopinavir.
- Absorption: Multiple doses with 400/100 mg tablet twice daily for 2 weeks and without food restriction produced an average +- SD lopinavir peak plasma concentration (Cmax) of 12.3 g 5.4 μg / ml, approximately 4 hours after administration. The average steady state trough concentration before the morning dose was 8.1 g 5.7 μg / ml. Lopinavir AUC averaged 113. +- 60.5 μg.h / ml at an interval of 12 hours. Absolute bioavailability of lopinavir in association with ritonavir has not been established in humans.
- Effects of food on oral absorption: administration of a single 400/100 mg dose of these tablets under fed conditions (high fat, 872 kcal, 56% of fat) compared to fasting conditions. No significant changes in Cmax and AUCinf Was associated with Therefore, this tablet can be taken with or without food. Lopinavir/ritonavir pills have also shown less pharmacokinetic variability in all food conditions than lopinavir/ ritonavir soft capsules.
- Distribution: At steady state, lopinavir is bound to approximately 98 – 99% of serum protein. Although lopinavir binds both alpha-1-acid glycoprotein (AAG) and albumin, it has a high affinity for AAG. In the steady state, lopinavir protein binding remains stable over the range of concentrations observed twice daily after 400/100 mg, and is similar between healthy volunteers and HIV-positive patients.
- Biotransforming: In vitro experiments with the microsomes of human liver indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is largely metabolized by the liver cytochrome P450 system, almost exclusively by the isozyme CYP3A. Ritonavir is a potent CYP3A inhibitor that inhibits the metabolism of lopinavir and, therefore, increases plasma levels of lopinavir. Studies of 14C-lopinavir in humans showed that 89% of plasma radioactivity after a single 400/100 mg dose was due to the original active substance. At least 13 lopinavir oxidative metabolites have been identified in humans. 4-oxo and 4-hydroxymetabite are major metabolites with epimeric pair antiviral activity, but only minute amounts of total plasma radioactivity are included. Ritonavir has been shown to induce metabolic enzymes, resulting in induction of its own metabolism, and is likely to involve lopinavir metabolism. Pre-dose lopinavir concentrations decrease over time during multiple doses, stabilizing after approximately 10 days to 2 weeks.
- Elimination: After a 400/100 mg 14C-lopinavir / ritonavir dose, approximately 10.4 .6 2.3% and 82.6 ± 2.5% in an administered dose of 14C-lopinavir can occur in urine and feces, respectively. Unchanged lopinavir accounted for approximately 2.2% and 19.8% of the dose administered in urine and feces. After multiple doses, less than 3% of lopinavir dose is unchanged in urine. The half-life (peak to effective) of lopinavir for an interval of more than 12 hours is half-averaged 5 – 6 hours, and the apparent oral clearance (CL / F) of lopinavir is 6 to 7 l / h.
- Once-daily dose: Pharmacokinetics of once-daily cholera is evaluated for antiretroviral treatment in HIV-infected subjects. tablet 800/200 mg was administered in combination with amtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily diet. Multiple doses of 800/200 mg tablet once daily for 2 weeks without food restriction (n = 16) produced an average +- SD lopinavir peak plasma concentration (Cmax) 14.8 μ 3.5 μg / ml, approximately after administration. 6 hours. The average steady state trough concentration before the morning dose was 5.5 t 5.4 μg / ml. Lopinavir AUC yielded an average of 206.5 μ 89.7 μg . h / ml at 24-hour intervals.
- Compared to the BID regimen, once-daily dosing is associated with a decrease of approximately 50% Cmin / Ctrough values.
- The effect of lopinavir and ratanavir on the QTcF interval was evaluated in a crossover study in a healthy and 39 healthy adults with a placebo and active (moxifloxacin 400 mg once daily). Maximum mean time-matched (95% upper confidence bound) difference in QTcF interval from placebo to 5.3 and 15.2 mseconds (msec) 400/100 mg twice daily and supratherapeutic 800/200 after baseline-correction. Is milligrams. Twice daily lopinavir and ratanavir, respectively. Lopinavir and ritonavir 800/200 mg twice daily a day 3 Resulting Cmax observed with approximately 2-fold mean Cmax once daily and twice daily dose with lopinavir and ritonavir steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction was 24.9 and 31.9, twice the msec for 400/100 mg, and supratherapy 800/200. Mg twice. Daily lopinavir and ratanavir, respectively.
- Before taking this product, tell your doctor or pharmacist if you are allergic to lopinavir or ratanavir; Or if you have any other allergies. This product may contain inactive ingredients, which may cause allergies or other problems. Talk to your pharmacist for more details.
- Before using this medicine, tell your doctor or pharmacist your medical history, specifically: liver disease, diabetes, pancreatitis, high blood fat levels (cholesterol / triglycerides), heart problems (coronary artery disease, heart attack), Bleeding problems (such as hemophilia), and previous infections with certain diseases (eg hepatitis B infection, hepatitis C infection, and tuberculosis).
- Lopinavir / ritonavir can cause a condition that affects the heart rhythm (prolonged QT). Prolonged QT can rarely cause severe (rarely fatal) rapid / irregular heartbeats and other symptoms (such as severe dizziness, fainting) that require immediate therapy.
- There may be diarrhea, nausea, vomiting, upset stomach, gas, headache and trouble sleeping. If any of these effects persist or worsen, tell your doctor or pharmacist immediately.
- Remember that your doctor has prescribed this medicine because he or she has decided that the benefit to you outweighs the risk of side effects. Many people using this medicine do not have serious side effects.
- Human experience of acute overdose with lopinavir/ ritonavir is limited. Treatment of overdose with lopinavir/ ritonavir should consist of common supportive measures, including monitoring vital signs and observing the patient’s clinical condition. There is no specific antidote for overdose. If indicated, the elimination of unspecified medication should be achieved by emission or gastric lavage. The administration of activated charcoal can also be used to aid in the removal of unprocessed medicine. Since lopinavir/ ritonavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
- Tell your doctor about all of your current medications and start or stop using any. Many medicines can interact, and some medicines should not be used together.
- Lopinavir and ritonavir can cause serious heart problems. Call your doctor once if you have a fast or rapid heartbeat, fluttering in your chest, shortness of breath and sudden dizziness (as you may pass out).
- Tell your doctor if you have signs of liver or pancreas problems: loss of appetite, pain in the upper abdomen (which may spread to your back), nausea or vomiting, itching, dark urine, clay colored stool. , Jaundice (yellowing of the skin or eyes).
Drug- drug interactions:
- Co-administration of lopinavir and ratanavir may change plasma concentrations of other drugs and other drugs may alter plasma concentrations of lopinavir. The potential for drug – drug interactions should be considered before and during therapy.
- Adverse reactions that are commonly reported to lopinavir and ritonavir included diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia.
- As a general rule, when it is decided to use antiretroviral agents for the treatment of HIV infection in pregnant women and as a result to reduce the risk of HIV vertical transmission to the newborn, animal data as well as pregnant Clinical experience should be taken in women. Account to mark protection for the fetus.
- Lopinavir / ratanavir has been evaluated in more than 3000 women during pregnancy, including more than 1000 during the first trimester.
- In Post-marketing surveillance through the antiretroviral pregnancy registry established since January 1989, among more than 1000 women exposed during the first trimester, did not indicate an increased risk of birth defect risk with periodontal disease. The prevalence of birth defects after any trimester risk of lopinavir is comparable to the prevalence observed in the general population. No pattern of suggestive birth defects of a common etiology was observed. Reproductive toxicity has been detected in studies in animals. Based on the data outlined, pathological risk in humans is unlikely. Lopinavir can be used during pregnancy if necessary.
- No human data are available on the effect of lopinavir / ritonavir on fertility.
- Lopinavir and ritonavir (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiform, urticaria, angioedema) or hypersensitivity to any of its components, including ranovir. Co-administration with CYP3A-dependent drugs for withdrawal and for which elevated plasma levels may result in severe and / or life-threatening events. Co-administration with potent CYP3A inducers where significantly lower lopinavir plasma concentrations may be associated with loss of virologic response and possible resistance and cross resistance.
- Lopinavir / ritonavir is recommended to be stored at 2–8 ° C before delivery, and may be kept at <or = 25 ° C for <or = 2 months afterwards.
- It is not known whether this medicinal product is excreted in human milk. As a general rule, it is recommended that HIV-infected mothers do not breastfeed their children under any circumstances so as to avoid transmission of HIV.