What Is Lopinavir?

Lopinavir ritonavir tablets, this product is suitable for combination with other antiretroviral drugs to treat human immunodeficiency virus-1 (HIV-1) infection in adults and children over 2 years old. The experience with lopinavir and ritonavir mainly comes from patients who have not received antiretroviral therapy. Data on patients who have been treated with protease inhibitors are very limited. There is also very limited data on remedial treatment in the case of failure of lopinavir and ritonavir. The choice of HIV-1 infected patients who have been treated with protease inhibitors depends on two factors, that is, the individual drug resistance test results and the history of treatment.

Drug Name: Lopinaviritonavir
Whether prescription drugs: prescription

Dosage form: tablet
Drug type: Essential medicines
Hanyu Pinyin: LPNWLTNWP

Signs of lopinaviritonavir

Warning: Please pay attention to the drugs prohibited for use with this product. Please read the section "Drugs prohibited for use with this product and precautions".

Lopinaviltonavir Tablets Ingredients

This product is a compound preparation, each tablet contains 200 mg of lopinavir and 50 mg of ritonavir.

Lopinaviritonavir tablets traits

This product is an oval red film-coated tablet that appears white or off-white after removing the coating.

Indications for lopinaviritonavir tablets

This product is suitable for combination with other antiretroviral drugs to treat human immunodeficiency virus-1 (HIV-1) infection in adults and children over 2 years old.
The experience with lopinavir and ritonavir mainly comes from patients who have not received antiretroviral therapy. Data on patients who have been treated with protease inhibitors are very limited. There is also very limited data on remedial treatment in the case of failure of lopinavir and ritonavir.
The choice of HIV-1 infected patients who have been treated with protease inhibitors depends on two factors, that is, the individual drug resistance test results and the history of treatment.

Lopinaviltonavir Tablet Specifications

Each tablet contains 200 mg of lopinavir and 50 mg of ritonavir.

Dosage of lopinavirlitonavir tablets

This product should be prescribed by a doctor with clinical experience in treating HIV infection.
This product should be swallowed whole, not chewed, cracked or crushed.
Adults and adolescents < br The recommended dose of this product is 400 / 100mg (2 tablets) twice daily. May be taken with or without food. For adult patients, due to the consideration of patient management, when the medicine needs to be taken once a day, the dosage of this product can be 800 / 200mg (4 tablets), once a day, and can be taken with or without food. Take the same food. The once-daily administration method should be limited to adult patients with very few protease inhibitor (PI) -related mutations (ie, less than 3 PI mutations and consistent with clinical trial results. For a detailed description of the population, see [Pharmacology and Toxicology] []], And should also consider that compared with the twice-daily recommended standard medication method, once-daily medication has a weaker inhibitory effect on the virus (see [Pharmacology and Toxicology]), and the risk of diarrhea will increase (see Adverse reactions).
Children (2 years and older)
The recommended dose of this product is 400 / 100mg (2 tablets), twice a day. It can be used for children weighing 40kg or more or body surface area.

Children over 1.4m2. For children who weigh less than 40 kg or whose BSA is between 0.6 and 1.4 m2 and can swallow tablets, please refer to the dosage of 100 / 25mg of this product. The once-daily dosing method has not been validated in pediatric patients.

Children (under 2 years)
Due to insufficient safety and efficacy data, this product is not recommended for children under 2 years of age.
Concomitant treatment: efavirenz or nevirapine <br The table below contains a BSA-based dosing regimen for children when this product is combined with efavirenz or nevirapine.

Hepatic insufficiency < br In patients with mild to moderate hepatic insufficiency, the exposure dose of lopinavir increased by about 30%, but the increase was not clearly related to clinical treatment. There are no data on patients with severe liver dysfunction, and these patients should not use this product.
Renal insufficiency < br Because the clearance of lopinavir and ritonavir through the kidneys is minimal, patients with renal insufficiency do not experience elevated blood levels. Because both lopinavir and ritonavir have strong protein-binding capacity, hemodialysis or peritoneal dialysis does not significantly affect their clearance.

Adverse reactions to lopinaviritonavir tablets

a. Safety Overview < br The safety of this product was evaluated in phase II and IV clinical trials involving more than 2,600 patients, of which more than 700 patients used 800/200 mg (4 tablets) once daily Therapeutic dose. In the case of using nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, this product is combined with efavirenz or nevirapine.
The most common adverse reactions associated with the treatment of this product during clinical trials were diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia. Patients taking this product once daily may be at greater risk of developing diarrhea. Diarrhea, nausea, and vomiting may occur at the beginning of treatment, and hypertriglyceridemia and hypercholesterolemia may occur later. In phase II-IV trials, 7% of subjects withdrew from the study early due to adverse events during treatment.
It is worth noting that pancreatitis has been reported in patients receiving this product, including those who have developed hypertriglyceridemia. In addition, reports of prolonged PR intervals during the treatment of this product are extremely rare (see [Notes] Pancreatitis and elevated lipids).
b. List of adverse reactions < br Adverse reactions in adult and pediatric patients in clinical trials and post-marketing use:
Phase II and IV clinical trials involving more than 2,600 patients were evaluated for its safety. More than 700 patients were treated with 800/200 mg (4 tablets) once daily. In the case of using nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, this product is combined with efavirenz or nevirapine.
The following events have been identified as adverse reactions. The frequency classification includes all reported moderate to severe events, whether or not causal. The adverse reactions are listed according to the body system and organ classification. In each frequency group, the frequency of adverse reactions is listed in descending order: very common 1 / 10; common 1 / 100, <1/10; uncommon 1 / 1000 , <1/100.
Incidents given a frequency of "unknown" were identified in post-market monitoring.

c. Description of some adverse reactions

Cushing's syndrome has been reported in patients receiving ritonavir and inhaled or intranasal fluticasone propionate; this may also occur with other corticosteroids (budenaide) metabolized by P450 3A (see [Precautions] and [Drug Interactions]).
Increased creatine phosphokinase (CPK), myalgia, myositis, and rhabdomyolysis (rare) have been reported when protease inhibitors are used, especially in combination with nucleoside reverse transcriptase inhibitors.
Redistribution of body fat (lipotrophy) in HIV patients treated with antiretroviral drugs, including reduced peripheral and facial subcutaneous fat, increased abdominal and visceral fat, breast hypertrophy and fat accumulation on the back of the neck (buffalo back) .
Metabolic abnormalities such as hypertriglyceridemia, hypercholesterolemia, insulin resistance, hyperglycemia, and hyperlactic acidemia may occur in combination with antiretroviral drugs (see [Precautions]).
AIDS patients who have been severely immunocompromised at the start of combined antiretroviral drug therapy (CART) may experience asymptomatic or residual opportunistic inflammatory reactions (see [Precautions]).
Cases of osteonecrosis have been reported, especially in patients with recognized risk factors, in patients with advanced AIDS, or in patients receiving long-term combined antiretroviral therapy (CART). Its frequency is unknown (see [Precautions]).
d. Children < br The safety characteristics of this product in children 2 years and older are similar to those observed in adults (see table in subsection b above).

Lopinaviritonavir taboo

This product is contraindicated in patients known to be allergic to lopinavir, ritonavir, or any excipient.
This product is contraindicated in patients with severe liver dysfunction.
This product contains lopinavir and ritonavir, both of which are inhibitors of the cytochrome P450 isomer CYP3A. This product should not be taken at the same time as those drugs that rely primarily on CYP3A for clearance and whose elevated plasma concentrations can cause serious and / or fatal adverse events. These drugs include

Precautions for lopinaviritonavir tablets

Patients with complications

Hepatic insufficiency: The safety and effectiveness of this product in patients with severe liver disease have not been determined. This product is contraindicated in patients with severe liver dysfunction. Patients with chronic hepatitis B or C who are concurrently treated with antiretroviral drugs will have an increased risk of serious and potentially fatal liver adverse reactions. If patients with hepatitis B or C are concurrently treated with antiviral drugs, refer to the product information of these drugs when using them.
Patients with original liver damage (including chronic hepatitis) have an increased risk of abnormal liver function during the combined antiretroviral therapy. Hepatic function of these patients should be based on experience during medication Condition monitoring. If there is evidence of worsening liver disease in such patients, interruption or termination of treatment should be considered.
Individuals who have been infected with HIV-1 alone and who have undergone post-exposure prophylaxis following exposure to the virus have increased transaminase levels 7 days after they started receiving lopinavir / ritonavir combined with other antiretroviral drugs, Reports with or without elevated bilirubin levels. In some cases, liver damage is severe. Appropriate laboratory tests should be performed before starting lopinavir / ritonavir treatment, and close monitoring should be performed during treatment.
Renal insufficiency: Because the clearance of lopinavir and ritonavir via the kidneys is minimal, patients with renal insufficiency do not experience elevated blood levels. Because both lopinavir and ritonavir have strong protein-binding capacity, hemodialysis or peritoneal dialysis does not significantly affect their clearance.
Hemophilia: Increased bleeding has been reported in patients with type A or B hemophilia when treated with protease inhibitors, including spontaneous skin hematomas and joint hemorrhages. Some patients received additional factor treatment. More than half of the reported cases continued or were retreated with protease inhibitors. Although the mechanism of action that causes bleeding has not been elucidated, the causal relationship between protease inhibitor treatment and bleeding has attracted attention. Therefore, it should be recognized that the use of protease inhibitors in patients with hemophilia has the potential to increase bleeding.
Lipid elevation < br The application of this product can sometimes cause a large increase in total cholesterol and triglyceride concentrations. Triglyceride and cholesterol levels should be checked regularly before and during treatment with this product. Patients with high levels of triglycerides and cholesterol and a history of dyslipidemia should be treated with extreme caution. Dyslipidemia can be managed through appropriate clinical measures.
Pancreatitis < br Pancreatitis has been reported in patients receiving this product, and some patients have developed hypertriglyceridemia. In the vast majority of reported cases, the patient has a previous history of pancreatitis and / or is co-administered with other drugs that can cause pancreatitis. A significant increase in triglycerides is a risk factor for pancreatitis. Patients with advanced AIDS may be at risk for elevated triglycerides and pancreatitis.
If there are clinical symptoms (nausea, vomiting, and abdominal pain) or laboratory tests (such as elevated serum lipase or amylase), the possibility of pancreatitis should be considered. Patients with these symptoms or signs should be evaluated, and if pancreatitis is diagnosed, treatment with this product should be temporarily stopped.
Hyperglycemia < br In patients receiving protease inhibitor therapy, there have been cases of newly diagnosed diabetes, hyperglycemia, or exacerbation of pre-existing diabetes. Some of these patients are severely ill and may even have ketoacidosis. Most patients have complex clinical conditions, and some of them also need to be treated with drugs, and these drugs are also related to the occurrence of diabetes or hyperglycemia.
Fat Redistribution and Metabolic Disorders < br HIV patients receiving combined antiretroviral medications will experience redistribution of body fat (lipid metabolism disorders). The long-term consequences of these adverse events are currently unknown. The understanding of the mechanism of action is not comprehensive. It is hypothesized that visceral lipoma-like changes are associated with protease inhibitors (PIs), dyslipidemia, and nucleoside reverse transcriptase inhibitors (NRTIs). The high risk of dyslipidemia mainly depends on individual factors such as older age, drug-related factors such as long-term antiretroviral treatment and metabolic disorders. Redistribution of fat should be assessed during clinical examinations. Consideration should be given to measuring fasting lipids and blood glucose. Dyslipidemia can be managed through appropriate clinical measures.
Immune Reconstruction Syndrome < br AIDS patients who have been severely immunodeficiency at the beginning of combined antiretroviral drug therapy (CART) may develop asymptomatic infections or residual inflammatory infections and cause severe inflammation Clinical condition may worsen current symptoms. Usually, this response occurs within weeks or months after starting CART. Related cases include cytomegalovirus retinitis, systemic and / or local mycobacterial infections, and pneumocystis pneumonia. All inflammatory symptoms should be evaluated and treated as necessary.
Osteonecrosis < br Although there are many factors for the cause of osteonecrosis (including the use of corticosteroids, alcohol, severe immunosuppressive reactions, high body mass index, etc.), in patients with advanced AIDS and / or long-term combined antireversion Osteonecrosis is particularly common in patients treated with viral drugs (CART). Patients should be advised to see a doctor if they have joint pain, stiffness, or difficulty moving.
Prolonged PR interval < br Some healthy adult subjects have mild asymptomatic PR interval prolongation after taking lopinavirlitonavir. In patients with structural heart disease and pre-existing conduction system abnormalities or receiving drugs that can cause prolonged PR interval (such as verapamil or atazanavir), it is rare after receiving lopinavir ritonavir Atrioventricular block at 2 or 3 degrees was reported. This product should be used with caution in such patients.
Drug Interactions < br This product contains lopinavir and ritonavir, both of which are inhibitors of the cytochrome P450 isoform CYP3A. This product is likely to increase the blood concentration of drugs that are primarily metabolized by CYP3A. During the combined application of this product, the blood concentration of such drugs will be increased or the therapeutic effect will be prolonged and adverse events will occur.
Colchicine cannot be administered concomitantly, especially in patients with impaired renal or liver function.
It is not recommended to co-administer this product with the following drugs:
-Tadalafil (for the treatment of pulmonary hypertension)
-Fusic acid-salmeterol-rivaroxaban is not recommended for patients with bone and joint infections. This product is not recommended in combination with atorvastatin. If atorvastatin must be used, the lowest dose of atorvastatin should be used and safety monitoring performed. Such as lopinavir ritonavir combined with rosuvastatin must be used with caution and the combined dose should be reduced. If the patient has an indication for treatment with an HMG-CoA reductase inhibitor, two drugs, pravastatin or fluvastatin, are recommended.
PDE5 inhibitors: In patients receiving this product, special care should be taken when applying sildenafil and tadalafil in the treatment of erectile dysfunction. The combination of these drugs with this product is believed to cause a continuous increase in the concentration of these drugs, thereby increasing adverse events such as hypotension, syncope, visual changes, and prolonged erectile time. Vardenafil is prohibited from being combined with this product. Sildenafil is not allowed to be used with this product when it is used to treat pulmonary hypertension.
Special care should be taken when combining this product with drugs that can induce QT interval prolongation, such as chlorpheniramine, quinidine, erythromycin, and clarithromycin. This product will increase the blood concentration of the combination drug and may lead to an increase in drug-related adverse cardiac events. Cardioadverse events have been reported in combination with this product in preclinical studies; therefore, this product cannot be ruled out as having potential cardiac effects.
It is not recommended to use this product in combination with rifampicin. The combination of rifampicin and this product will significantly reduce the blood concentration of lopinavir and further affect the therapeutic effect of lopinavir. Increasing the dosage of this product can make lopinavir and ritonavir reach a suitable level of treatment, but it also increases the risk of toxic and side effects of liver and gastrointestinal tract in patients. Therefore, unless absolutely necessary, this product should be avoided in combination with rifampicin.
Others < br This product does not cure HIV infection or AIDS. This product does not reduce the risk of HIV transmission to others through sexual contact or blood. Take appropriate precautions. Patients receiving this product may still be infected or develop other diseases related to HIV and AIDS.
Unless it is determined that the potential therapeutic effect is greater than the risk of systemic glucocorticoid effects, including Cushing's syndrome and adrenal suppression, this product is not recommended in combination with fluticasone or other glucocorticoids metabolized by CYP3A4.
Impact on the ability to drive and operate machines <br /> Although it has not been confirmed that this product has an effect on the ability to drive and operate machines, patients should be informed of reports of nausea during the use of this product.

Lopinavir and ritonavir tablets for pregnant and lactating women

Safety data on pregnant women taking this product have not been established. Animal experiments prove that this product has reproductive toxicity. The potential danger to humans is unknown. Unless necessary, pregnant women should avoid using this product.
Studies in rats have shown that lopinavir can be secreted through milk. Whether lopinavir can be secreted by human milk is unclear. Women infected with HIV should not breastfeed their babies to avoid HIV transmission after birth.

Lopinavilt tonavir tablets for children

Due to insufficient safety and efficacy data, this product is not recommended for children under 2 years of age.

Lopinaviritonavir tablets for elderly

The test was not performed and there are no reliable references.

Lopinaviritonavir tablets drug interactions

This product contains lopinavir and ritonavir, both of which are in vitro inhibitors of the cytochrome P450 isoform CYP3A. When this product is used in combination with drugs that are mainly metabolized through CYP3A, it may increase the blood concentration of these drugs, and then lead to prolonged drug action time and increase the occurrence of adverse reactions. This product will not inhibit the activity of CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 in the range of clinical drug concentration.
This product has been proven to induce its own metabolism in the body, and can increase the biotransformation of some drugs, which are metabolized by cytochrome P450 enzymes (including CYP2C9 and CYP2C19) and combined with glucuronic acid. This may reduce the blood concentration of such combination drugs and then affect the efficacy of the drugs.
Combination use of drugs known to have significant interactions and to cause serious adverse events is prohibited.
Unless otherwise specified, all studies of drug interactions use lopinavir ritonavir soft capsules, and the exposure of lopinavir soft capsules is about 20% lower than that of 200/50 mg tablets.
The known and theoretical interactions between this product and selected antiretroviral and non-retroviral drugs and other drugs are shown in the table below ("" indicates an increase; "" indicates a decrease ; "" means no change; "QD" means once a day; "BID" means twice a day; "TID" means three times a day).
Unless otherwise specified, the following studies used lopinavir and ritonavir at a dose of 400/100 mg twice daily.

Lopinavirritonavir overdose

To date, acute overdose use of this product has been rare.
Adverse clinical symptoms observed in experimental dogs include drooling, vomiting, and diarrhea / feces abnormalities. Toxic reactions observed in mice, rats, or experimental dogs include reduced activity, ataxia, wasting, dehydration, and tremor.
There is no specific antidote for this product in excess. The overdose of this product should be treated with general supportive measures including monitoring vital signs and observing the clinical symptoms of patients. If indicated, unabsorbed pharmaceutically active ingredients can be removed by vomiting or gastric lavage. Activated charcoal can also be used to help remove unabsorbed drugs. Because this product has a high protein binding rate, dialysis may not help to clear the drug in large quantities.

Lopinaviritonavir tablets pharmacology and toxicology

Pharmacological action < br Mechanism of action This product is a compound preparation composed of lopinavir and ritonavir. Lopinavir is an HIV protease inhibitor that blocks the division of Gag-Pol polyproteins, leading to the production of immature, non-infectious virus particles; ritonavir is a drug that targets HIV-1 and HIV- An active peptidomimetic inhibitor of 2aspartyl proteases prevents the enzyme from processing Gag-Pol polyprotein precursors by inhibiting HIV proteases, resulting in the generation of immature forms of HIV particles, and thus inability to start a new infection cycle. Ritonavir inhibits CYP3A-mediated lopinavir metabolism, resulting in higher lopinavir concentrations.
Antiviral activity Lopinavir was tested against laboratory HIV strains and clinical HIV isolates in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the 50% effective concentration (EC ₅₀ ) of lopinavir on five different laboratory strains of HIV-1 subtype B is 10 ~ 27nM (0.006 ~ 0.017g / mL, 1g /mL=1.6M), 50% effective concentration for several clinical isolates is between 4 ~ 11nM (0.003 ~ 0.007g / mL) (n = 6). When containing 50% human serum, the EC50 of lopinavir on the five laboratory strains averaged 65 to 289 nM (0.04 to 0.18 g / mL), which was equivalent to a 7-11 fold reduction. In vitro antiviral activity studies with lopinavir combined with lopinavir show that combined use of lopinavir and nelfinavir increases antagonism, with ampinavir, atazanavir, indinavir, saquine The combined application of naravir and tiranavir increases synergy. The EC50 values of lopinavir for three different HIV-2 strains ranged from 12 to 180 nM (0.008 to 113 g / mL).
Drug resistance has been screened in vitro for HIV-1 isolates with reduced sensitivity to lopinavir. The presence of ritonavir does not appear to affect the in vitro screening of lopinavir resistant strains.
The selective role of patients who have not received antiretroviral therapy for resistance to this product has not yet been established. In a phase III study involving 653 patients who had not received antiretroviral therapy, patients with plasma HIV loads greater than 400 copies / mL at weeks 24, 32, 40 and / or 48 Plasma virus isolates were analyzed. Of the 37 evaluable patients treated with lopinavir / ritonavir, no evidence of resistance to lopinavir / ritonavir was found (0%). In children who have not received antiretroviral therapy, the selective role of lopinavir / ritonavir resistance appears to be consistent with that in adults.
Resistance to lopinavir / ritonavir has occurred in patients who have been treated with other protease inhibitors before lopinavir / ritonavir treatment. In a phase II trial involving 227 patients who have not received antiretroviral therapy and received a protease inhibitor treatment, the virus in their body was 12 to 100 weeks after treatment with lopinavir / ritonavir Of the 23 patients whose RNA was quantifiable (> 400 copies / mL), the sensitivity of the isolates to lopinavir in 4 patients was significantly reduced compared to the corresponding baseline virus isolates. Three of these patients had previously been treated with a single protease inhibitor (indinavir, nelfinavir, or saquinavir), and one had received multiple protease inhibitors (indinavir, ritonavir) Wei and Shaquinavir). Prior to receiving lopinavir / ritonavir, four patients had more than four mutations related to protease inhibitor resistance. After a virological rebound, mutation points in isolated strains of these patients increased, some of which were related to protease inhibitor resistance. However, insufficient data are currently available to identify lopinavir-associated mutation patterns in isolates of lopinavir / ritonavir-treated patients. These mutation patterns are currently being studied.
Cross-resistance-Preclinical studies have observed varying degrees of cross-resistance in HIV protease inhibitors. Data on cross-resistance to viruses that have decreased sensitivity to lopinavir during lopinavir / ritonavir treatment are limited.
The researchers performed in vitro activity testing of lopinavir in clinical isolates of patients who had previously used a single protease inhibitor. Isolates with a sensitivity that was more than 4 times lower than nelfinavir (n = 13) and saquinavir (n = 4) were less than 4 times less sensitive to lopinavir. Isolates that were more than 4 times less sensitive to indinavir (n = 16) and ritonavir (n = 3) had 5.7 and 8.3 times less sensitivity to lopinavir, respectively. Isolates from patients who have previously been treated with two or more protease inhibitors have a greater decrease in sensitivity to lopinavir, as described below.
Clinical study-Antiviral activity of lopinavir / ritonavir in patients who have been treated with protease inhibitorsAnalysis of lopinavir / ritonavir in patients who have been treated with lopinavir / ritonavir The virological response of neravir compared the baseline virus genotype (three studies) and baseline virus phenotype (one study) to assess the clinical significance of reduced in vitro sensitivity of lopinavir.
The virological response of lopinavir / ritonavir is affected by the following three or more amino acid substitutions occurring in the protease at baseline: L10F / I / R / V, K20M / N / R, L24I, L33F, M36I , I47V, G48V, I54L / T / V, V82A / C / F / S / T and I84V. The table below gives a 48-week virological response based on the number of mutations in the aforementioned protease inhibitor resistance at study 888 and 765 (see [Indications] and [Usage and Dosage]) and at baseline in study 957 (see table below) ( HIV RNA <400 copies / mL). For adult patients with three or more of the above amino acid substitutions, a once-a-day dosage is not recommended.

The virological response of lopinavir / ritonavir treatment in relation to the baseline phenotypic sensitivity of lopinavir was determined in study 957. This study included 56 patients who had not been treated with NNRTI. These patients had previously used at least two protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir). With a load greater than 1000 copies / mL, these patients were randomized to receive one of two doses of lopinavir / ritonavir in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs) dose. The EC50 value of lopinavir to 56 baseline virus isolates was 0.5 to 96 times the EC50 value of the wild-type virus strain. 55% (31/56) of the baseline isolates were more than 4 times less sensitive to lopinavir. The median decrease in sensitivity of these 31 strains to lopinavir was 18-fold. The following table shows the response to treatment based on baseline lopinavir sensitivity.

Toxicological studies <br The results of genotoxicity lopinavir and ritonavir Ames test, mouse lymphoma cell test, human lymphocyte chromosome aberration test and mouse micronucleus test were negative.
Reproductive toxicity When combined with lopinavir and ritonavir in a 2: 1 ratio, no fertility was seen in male and female rats at doses of 10/5, 30/15, or 100 / 50mg / kg / day. Impact. According to the AUC measurement, the exposure of lopinavir and ritonavir in male and female rats at a dose of 100/50 mg / kg / day is approximately human at the recommended therapeutic dose (400/100 mg, twice daily), respectively. The exposure is 0.7 and 1.8 times.
Lopinavir / ritonavir was administered to pregnant rats or rabbits, and no fetal malformations associated with administration were seen. At maternal toxic doses (100/50 mg / kg / day), embryonic and fetal developmental toxicity (early absorption, decreased fetal movement capacity, decreased fetal weight, increased incidence of skeletal variation, and delayed bone ossification) were observed in rats.
Rabbits did not show embryonic and fetal developmental toxicity at maternal toxic doses (80/40 mg / kg / day). According to the AUC measurement, the exposure of lopinavir and ritonavir in rabbits at a dose of 80/40 mg / kg / day is about the same as that in humans at the recommended therapeutic dose (400/100 mg, twice daily). The amount is 0.6 times and 1.0 times.
In a rat perinatal toxicity test, lopinavir / ritonavir has developmental toxicity at doses of 40/20 mg / kg / day and greater (in neonatal pups during delivery and within 21 days after delivery). Reduced survival rate).
Carcinogenic mice and rats were orally given lopinavir / ritonavir for 104 weeks, and the results showed that when the dose was approximately the recommended human dose (400 / 100mg, twice daily) AUC _0-24hr measurement) 1.6-2.2 times (mouse), 0.5 times (rat), the incidence of benign hepatocellular adenoma in male and female mice and male rats and the combined occurrence of hepatocellular adenoma and cancer The rate goes up.
The carcinogenic effects of ritonavir have been studied in mice and rats. In male mice, the incidence of adenoma, the combined incidence of adenoma and liver cancer showed a dose-dependent increase. Based on the AUC measurement results, the exposure of male mice at high doses in the test is approximately four times that of humans at the recommended therapeutic dose (400 / 100mg of this product, twice daily). At this dose, no increase in tumor incidence was seen in female mice. The exposure of female mice at high doses is equivalent to 9 times that of humans. There was no increase in tumor incidence in rats, and the exposure of rats at high doses was approximately 0.7 times that of humans at the recommended dose (400 / 100mg, twice daily). Based on exposure data obtained from animal experiments, the significance of the effects observed is unclear.

Pharmacokinetics of lopinavirlitonavir tablets

The pharmacokinetics of lopinavir and ritonavir combined in healthy adult volunteers and HIV-infected patients have been studied; there are no significant differences between the two groups. Lopinavir is metabolized almost entirely by the liver CYP3A. Ritonavir inhibits liver CYP3A metabolism to lopinavir, thereby increasing lopinavir's plasma concentration. In different trials, the average steady-state plasma concentration of lopinavir obtained by HIV-infected patients taking this product 400/100 mg twice daily was 15-20 times higher than that of ritonavir. The plasma concentration of ritonavir is lower than 7% of the concentration of ritonavir administered at 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is about 10 times lower than that of ritonavir. Therefore, the antiviral activity of this product is produced by lopinavir.
absorb:
This product was given multiple times (400 / 100mg twice daily, no dietary restrictions, continued medication for 2 weeks), the blood concentration of lopinavir reached a peak about 4 hours after the medication, and its peak value (Cmax) was 12.3 ± 5.4 g / mL. The average steady-state trough concentration before morning administration was 8.1 ± 5.7 g / mL. The AUC of lopinavir over a 12-hour dosing interval was 113.2 ± 60.5 g · h / mL. The absolute bioavailability of lopinavir and ritonavir in the human body has not been determined.
Effect of food on oral absorption: Compared with the fasting state, a single dose of 400 / 100mg of this product is taken with food (high-fat diet, 872 kcal, 56% of calories from fat), and its AUC _inf and C _max changes No significant clinical significance. Therefore, this product can be taken with or without food. Compared with Kelizhi soft capsule, under the condition of serving with food, the pharmacokinetic variation of this product is less.
distributed:
At steady state, about 98-99% of lopinavir binds to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. In steady state, after 400/100 mg of this product was administered twice daily, the protein binding of lopinavir remained constant over the observed concentration range, and the situation was similar between healthy volunteers and HIV-positive patients.
metabolism:
In vitro experiments with human liver microsomes have shown that lopinavir is primarily oxidatively metabolized. Lopinavir is extensively metabolized by the liver cytochrome P450 system and is almost exclusively metabolized by the CYP3A isomer. Ritonavir is a potent CYP3A inhibitor that inhibits the metabolism of lopinavir and therefore increases the plasma concentration of lopinavir. A human 14C-lopinavir study showed that after a single administration of 400/100 mg of this product, 89% of the plasma radioactivity came from the parent compound. At least 13 oxidative metabolites of lopinavir have been identified in humans. The 4-oxo and 4-hydroxide metabolite isomers are the main metabolites with antiviral activity, but their plasma radioactivity exists for a short time, only a few minutes. Experiments show that ritonavir can induce metabolic enzymes, thereby inducing its own metabolism, and may also induce lopinavir metabolism. In the course of multiple administrations, the concentration of lopinavir before the administration decreased with time, and stabilized after about 10 days to 2 weeks.
eliminate:
After single-dose administration of 14C lopinavir ritonavir 400 / 100mg, 14C-lopinavir detected in urine and feces accounted for 10.4 ± 2.3% and 82.6 ± 2.5% of the administered dose, respectively. Prototype lopinavir detected in urine and feces accounted for approximately 2.2% and 19.8% of the administered dose, respectively. After multiple administrations, lopinavir excreted from the urine in its original form is less than 3% of the administered dose. The average half-life (from peak to trough) of lopinavir over 12 hours dosing interval is 5-6 hours, and the apparent clearance of lopinavir is 6-7 l / h.
Dosing once daily:
The pharmacokinetic study of the once-daily administration method of this product has been performed in patients who have not been treated with antiretroviral drugs. Each patient took 800 / 200mg of this product while taking emtricitabine 200mg and tenofovir DF 300mg once daily. This product was given multiple times (800 / 200mg once daily, no dietary restrictions, continued medication for 2 weeks), the blood concentration of lopinavir reached a peak about 6 hours after the medication, and its peak value (C _max ) was 14.8 ± 3.5 g / mL. The average steady-state trough concentration before morning administration was 5.5 ± 5.4 g / mL. The AUC of lopinavir over a 24-hour dosing interval was 206.5 ± 89.7 g · h / mL.
Compared with the twice-daily administration method, the once-daily administration method will reduce the C _min / C _trough value by about 50%.
Special groups < br Children :
Limited pharmacokinetic data for children under 2 years of age. 53 pediatric patients aged 6 months to 12 years participated in the pharmacokinetics of lopinavirlitonavir oral solution 300/75 mg / m2 twice daily and 230 / 57.5 mg / m2 twice daily Study. After giving this product 230 / 57.5 mg / m2 twice daily (without nevirapine) (n = 12) or 300/75 mg / m2 twice daily (with nevirapine) (n = 12), lopinavir The average steady-state AUC values, Cmax, and Cmin were 72.6 ± 31.1 gh / mL, 8.2 ± 2.9 g / mL, 3.4 ± 2.1 g / mL and 85.8 ± 36.9 gh / mL, 10.0 ± 3.3 g / mL, respectively. , 3.6 ± 5.5 g / mL. The plasma concentration of lopinavir obtained at 230 / 57.5 mg / m2 twice daily (without nevirapine) and 300/75 mg / m2 twice daily (with nevirapine) compared with 400/100 mg daily Adult patients in the subprogramme (without nevirapine) received similar plasma concentrations. The once-daily dosing of lopinavir and ritonavir has not been evaluated in pediatric patients.
Gender, race and age:
The pharmacokinetics of this product have not been studied in elderly patients. There were no age- or sex-related pharmacokinetic differences in adult patients. Ethnic differences in pharmacokinetics have not been determined.
Renal insufficiency:
The pharmacokinetics of lopinavir in patients with renal insufficiency have not yet been studied; however, because lopinavir clearance through the kidneys is minimal, patients with renal insufficiency do not experience a decline in overall clearance.
Liver insufficiency:
In a multidose study of lopinavir and ritonavir (400 / 100mg twice daily), the steady-state pharmacokinetics of HIV-infected patients with mild to moderate liver dysfunction compared with normal liver function was compared. parameter. A small increase of approximately 30% in total lopinavir concentration is not clinically relevant.

Lopinaviltonavir Tablets Storage

Store at room temperature (below 30 ° C).

Lopinaviritonavir tablet packaging

High density plastic bottle, 120 tablets / bottle.

Expiry of lopinavirlitonavir tablets

Within 48 months, this product should be distributed in its original packaging. Patients are not advised to take the product if its original packaging is exposed to excessive humidity for more than 2 weeks.

Lopinaviritonavir

JX20070132

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