What Is Abacavir?

Abacavir is a yellow to light brown transparent liquid with a odor of mercaptan. The molecular formula is C14H18N6O, the molecular weight is 286.33200, the density is 1.7g / cm3, the boiling point is 636ºC at 760 mmHg, the flash point is 338.4ºC, the refractive index is 1.864, and the storage conditions are 0-6 ° C.

Chinese name: Abakawe
Foreign name: abacavir

CAS number: 136470-78-5
Molecular formula: C14H18N6O

Introduction to Abacavir Compounds

Abacawe Basic Information

Chinese name: abacavir

Chinese alias: abacavir; (1S, 4R) -4- [2-amino-6- (cyclopropylamino) -9H-purine-9-yl] -2-cyclopentene-1-methanol; abba Carve sulfate; (1S, 4R) -4- [2-amino-6- (cyclopropylamino) -9H-purine-9-yl] -2-cyclopentene-1-methanol;

English name: abacavir

English alias: Abacavir; (1S, 4R) -4- [2-Amino-6- (cyclopropylamino) -9H-purin-9-yl] -2-cyclopentene-1-methanol;

CAS number: 136470-78-5

Molecular formula: C ₁₄ H ₁₈ N ₆ O

Molecular weight: 286.33200

Structural formula:

Exact mass: 286.15400

PSA: 101.88000

LogP: 1.74650 ^[1]

Abacavir physical and chemical properties

Appearance and properties: yellow to light brown transparent liquid with odor of thiol.

Density: 1.7g / cm

Boiling point: 636ºC at 760 mmHg

Flash point: 338.4ºC

Refractive index: 1.864

Storage conditions: 0-6 ° C

Vapor pressure: 4.77E-17mmHg at 25 ° C ^[1]

Abacavir molecular structure data

1. Molar refractive index: 75.80

2. Molar volume (cm / mol): 167.6

3. Isotonic specific volume (90.2K): 501.7

4. Surface tension (dyne / cm): 80.1

5. Polarizability (10-24cm3): 30.05 ^[2]

Abacavir production method

Acetaminocyclohex-2-enemethanol acetate and barium hydroxide octahydrate were dissolved in water, the reaction was stirred under the protection of nitrogen, the reaction solution was neutralized with carbon dioxide, filtered, and the filtrate was concentrated. The obtained material was reacted with 2-amino4,6-dichloropyrimidine and triethylamine in n-butanol with stirring, hydrochloric acid was added, and concentrated to dryness. The obtained material was dissolved in chloroform. Unreacted 2-amino-4,6-dichloropyrimidine was removed by filtration and washed with chloroform. The chloroform layers were combined and concentrated. After column chromatography, the product separated from the column chromatography and sodium acetate trihydrate was dissolved in an aqueous acetic acid solution, and 4-chlorobenzenediazohydrochloride, concentrated hydrochloric acid, water, and nitric acid were slowly added. Cold solution formed by sodium, stirred, filtered to collect the precipitate, washed with water to give the product 4- [2-amino-6-chloro-5- (4,5- (4-chlorophenyl) azo-4-pyrimidinyl ] Amino-2-cyclohexene-1-methanol. This product was suspended in ethanol, an acetic acid aqueous solution was added, and refluxed under nitrogen, and zinc powder was added in portions for reaction. Unreacted zinc was removed by filtration, and the filtrate was concentrated to obtain Purification by column chromatography gave 4-[(2,5-diamino-4-chloro-6-pyrimidinyl) amino] -2-cyclohexene-1-methanol. It was dissolved in diethoxymethyl acetate Medium, reflux. The solvent was distilled off under vacuum, dioxane and hydrochloric acid were added, stirred at room temperature, cooled, neutralized with sodium hydroxide to pH = 7, and then extracted with 3: 1 chloroform / methanol. The organic layer was sulfuric acid The magnesium was dried, filtered, and concentrated. The obtained material was subjected to column chromatography to obtain 4- (2-amino-6-chloro-9-N-purine-9-yl) -2-cyclohexene-1-methanol. The product was dissolved In ethanol, add cyclopropylamine and react under nitrogen for 6h. Concentrate, add chloroform and saturated carbonic acid Sodium hydrogen solution. The aqueous layer was extracted with chloroform, concentrated, and separated by column chromatography to obtain the product. ^[1]

Abacavir uses

Abacavir API functions as an anti-AIDS adjuvant. ^[1]

Abacavir Compound Related Drugs

Abacavir drug name:

[General name] Abacavir Sifodine

[Product Name] Trizivir

[English name] Compound Abacavir Sulfate, Lamivudine and Zidovudine Tablets

[Pinyin] A Ba Ka Wei Shuang Fu Ding Pian ^[3]

Abacavir Ingredients:

Each tablet contains 300 mg zidovudine, 150 mg lamivudine, and 300 mg abacavir. ^[3]

Abacavir traits:

This product is a blue-green capsule film-coated tablet with "GXLL1" engraved on one side. ^[3]

Abacavir indications:

This product is used to treat adults with human immunodeficiency virus (HIV) infection. The three components (abacavir, lamivudine, and zidovudine) fixed in this product are used to replace three single-agent preparations with similar doses. It is recommended to treat abacavir, lamivudine, and zidovudine alone for 6-8 weeks at the beginning of treatment. The choice of this fixed combination should be based primarily on its expected benefits and the risks associated with the three nucleoside analogs, and not solely on simple applicable criteria.
The efficacy of this product can be confirmed by the results of first-time patients and non-progressive patients who have undergone moderate antiretroviral therapy. Patients with high viral loads (> 100,000 copies / mL) need special consideration when choosing treatment. ^[3]

Abacavir Usage and Dosage:

The reference dose for adults (18 years and older) is 1 tablet 2 times a day.
This product should not be used for adults and adolescents weighing less than 40 kg, because this product is a fixed-dose tablet and cannot be reduced in dosage.
This product can be taken with or without food.
If it is clinically shown that a certain component of this product needs to be reduced or discontinued, a single dose of abacavir, lamivudine, and zidovudine can be used.
Renal damage: Although it is not necessary to adjust the dose of abacavir for patients with renal insufficiency, the blood concentration of lamivudine and zidovudine is increased due to the decline of the kidneys' ability to clear drugs. Therefore, for patients with impaired renal function (creatinine clearance (smaller than or equal to) 50 mL / min), it is necessary to adjust the dose of these two drugs. Zidovudine, lamivudine, and abaca are recommended. Wei's single preparation. Doctors should consider the product characteristics of each of the three drugs separately. This product should not be used in patients with advanced kidney disease (see Contraindications and Pharmacology and Toxicology).
Liver damage This product is contraindicated in patients with liver damage.
Patients with adverse blood reactions should adjust the dose: if the patient's hemoglobin level is <9 g / dL or 5.59 mmol / L or the neutrophil count is <1.0x10 / L, the dose of zidovudine may be adjusted. Since this product is a mixture, the dosage of a single drug cannot be adjusted, so if the above situation occurs, a single preparation of abacavir, lamivudine and zidovudine should be used. Doctors should consider the characteristics of each of the three drugs separately. ^[3]

Abacavir adverse reactions:

In treating HIV infection, side effects of lamivudine, abacavir, and zidovudine alone or in combination have been reported. This product contains abacavir, lamivudine, and zidovudine. Side effects related to these compounds can be foreseen (listed in the table below).

There have been no safety evaluations of this product in clinical studies.
The reported adverse reactions of abacavir, lamivudine and zidovudine are listed in the table above. For most of these side effects, it is unclear whether they are related to the active ingredients, or to the use of a large number of drugs in the treatment of HIV infection, or are themselves caused by the underlying disease progression.
Abacavir allergic reactions: The signs and symptoms associated with abacavir allergic reactions are summarized below:
Gastrointestinal tract-nausea, vomiting, diarrhea, abdominal pain, mouth ulcers;
Neurology / psychiatry-headache, paresthesia;
Hematology-lymphopenia;
Liver / Pancreas-elevated liver function indicators;
Muscles and bones-myalgia, myolysis, joint pain, elevated creatine phosphatase;
Respiratory tract-dyspnea, sore throat, cough, flu-like syndrome;
Skin-rash (usually maculopapular and urticaria);
Urology-elevated creatinine, renal failure;
Others-fever, drowsiness, discomfort, edema, lymphatic disease, hypotension, conjunctivitis, allergies.
In clinical studies, about 4% of patients treated with abacavir experienced an allergic reaction, although precautionary measures were taken, partly life-threatening and lethal allergic reactions. This allergic reaction is characterized by the involvement of multiple organs.
Fever and / or rash (usually maculopapular and urticaria) are part of the syndrome in all patients with allergic reactions, but allergic reactions without rash and fever have also occurred.
Some patients with an allergic reaction will initially be considered to have gastrointestinal, respiratory (pneumonia, bronchitis, pharyngitis) or flu-like illness. These can delay the diagnosis of an allergic reaction, and continued use or reuse of abacavir can lead to more severe allergic reactions and death. Therefore, patients with symptoms of these diseases should carefully consider whether to diagnose an allergic reaction.
Symptoms usually occur during the first 6 weeks of treatment (on average, on the 11th day after starting treatment), and can also occur at any time during the treatment. Close medical monitoring is necessary during the first two months of treatment, with consultations every two weeks.
The risk factors that predict the seriousness of the abacavir allergic reaction have not been confirmed, but it is likely that intermittent treatment can increase the risk of allergic reactions and produce significant clinical allergic reactions. Therefore, patients should be informed about the importance of taking this product regularly.
Re-taking this product or any other abacavir-containing preparation after an allergic reaction can cause symptoms to develop quickly within hours. This recurring allergic reaction is usually more severe than the onset, and life-threatening hypotension and death can occur.
In order to avoid delay in diagnosis and reduce the occurrence of life-threatening allergic reactions, once an allergic reaction cannot be ruled out, even if it may be another diagnosis (respiratory disease, influenza-like disease, gastrointestinal disease, or response to other drugs), Products must be deactivated.
Rapid allergic reactions, including life-threatening reactions, that occurred before abacavir were discontinued. Only one key allergic reaction symptom (rash, fever, gastrointestinal symptoms, respiratory symptoms, and such as lethargy and discomfort) reappeared Abakawe's patient. Reports of patients with allergic reactions after resuming treatment without previous symptoms of allergic reactions are rare. The decision to resume treatment with this product must be made with medical assistance.
All patients with abacavir must be warned of allergic reactions.
Single-component adverse reactions have been reported: see table above. Once any of these symptoms occur, care must be taken to reduce the possibility of allergic reactions.
Lactic acidosis: Treatment with nucleoside analogs is associated with lactic acidosis, which is sometimes fatal and is usually accompanied by severe hepatomegaly and cirrhosis.
Hematological adverse reactions related to zidovudine: anemia, neutropenia, and leukocytopenia, which are common in high-dose (1200-1500 mg / day) medications and in patients with advanced HIV infection (especially pre-treatment bone marrow hyperplasia Poor patients), especially patients with CD4 cell counts <100 / mm. It may be necessary to reduce the dose or stop treatment. Anemia patients may require blood transfusions.
At the beginning of zidovudine treatment, patients with low neutrophil counts, hemoglobin levels, and serum vitamin B12 levels will have an increased chance of a decrease in neutrophil counts when using zidovudine. ^[3]

Abacavir contraindications:

This product is contraindicated in people known to be allergic to abacavir, lamivudine, zidovudine or any of its excipients.
Disabled in patients with advanced kidney disease and liver damage.
Due to its active ingredient abacavir, this product is contraindicated in patients with severe liver impairment.
Due to its active ingredient zidovudine, this product is contraindicated for patients with abnormal neutrophil counts (<0.75x10 / L) or abnormal hemoglobin levels (<7.5 g / dL or 4.65 mmol / L). ^[3]

Abacaway Notes:

The application of this product requires the guidance of a physician with experience in treating HIV infection.
Allergic reactions: Approximately 4% of patients receiving abacavir have developed allergic reactions, some of which are fatal, and deaths have occurred despite attention.
Description of allergic reactions: This allergic reaction is characterized by symptoms involving multiple organs, and almost all allergic reactions will have symptoms such as fever and / or rash.
Other symptoms of allergic reactions include respiratory symptoms such as dyspnea, sore throat and cough; gastrointestinal symptoms such as nausea, vomiting, diarrhea and abdominal pain, which can lead to the misdiagnosis of an allergic reaction as a respiratory disease (pneumonia, bronchial Inflammation, pharyngitis) and gastrointestinal disorders. Other common signs of an allergic reaction include drowsiness, discomfort, and musculoskeletal symptoms (myalgia, rare myolysis, and joint pain).
Continued treatment can worsen the symptoms associated with allergic reactions and can be life threatening. These symptoms are usually relieved after abacavir is discontinued.
Management of allergic reactions: Allergic reactions usually occur within the first 6 weeks of abacavir treatment, although these reactions can occur at any time during the treatment process. Patients should be closely monitored, especially during the first 2 months of treatment with this product, consultations should be conducted every two weeks.
If the patient is diagnosed with an allergic reaction during the treatment, he must stop taking this product immediately.
Patients who have stopped treatment due to an allergic reaction should never use this product or any drug containing abacavir in the future. Re-using abacavir after an allergic reaction can cause symptoms to develop rapidly within a few hours, and recurrent allergic reactions are usually more severe than the initial onset, including life-threatening hypotension and death.
To avoid delays in diagnosis and reduce the risk of life-threatening allergic reactions, when allergic reactions cannot be ruled out, or even other diagnoses (respiratory diseases, flu-like illness, gastroenteritis, and reactions to other drugs), the use of this drug must be stopped Product. If necessary, re-treatment of this product must be performed in the hospital.
Patients who receive this product and other drugs known to cause skin toxicity (such as non-nucleoside reverse transcriptase inhibitors) at the beginning of treatment should pay special attention because it is difficult to distinguish whether the rash is caused by an allergic reaction to abacavir or other drugs caused.
Discontinuation of treatment of this product: Regardless of the reason for stopping the treatment of this product, its re-administration needs to be carefully considered. Before discontinuing the medication, it is necessary to confirm whether the reason for interrupting the treatment is related to the symptoms of allergic reactions.
Rapid allergic reactions, including life-threatening reactions, occurred after only one key allergic reaction symptom (rash, fever, gastrointestinal symptoms, respiratory symptoms, and systemic symptoms such as lethargy and discomfort) before abacavir was discontinued Patients retaking abacavir. Reports of patients with allergic reactions after resuming treatment without previous symptoms of allergic reactions are rare. The decision to resume treatment with this product must be made with medical assistance.
The prescriber must ensure that the patient is fully aware of the following allergic reactions:
Patients must be aware that an allergic reaction to abacavir may cause life-threatening or death.
Patients must contact their doctor immediately when they develop signs and symptoms that may be related to allergic reactions.
To avoid re-administration of this product, patients with allergic reactions should dispose of the remaining abacaviradivudine tablets according to local requirements and consult a doctor or pharmacist.
For any reason, especially patients who may discontinue this product due to adverse reactions or disease, it is recommended to contact their doctor before re-treatment of this product.
It is recommended to inform patients of the importance of taking this product regularly.
Remind the patient to read the instructions in the product box.
Patients should be reminded of the importance of carrying the warning card in the box and always carry it with them.
Lactic acidosis / severe hepatomegaly with fatty liver: Treatment with nucleosides has been reported. Lactic acidosis (hypoxemia) has also been reported with severe hepatomegaly and fatty liver, sometimes death. Taking nucleoside drugs, the rapid rise of transaminase, progressive hepatomegaly, or unexplained metabolic / lactic acidosis should be discontinued. Benign gastrointestinal symptoms, such as nausea, vomiting, and abdominal pain, suggest the possibility of lactic acidosis. Patients with hepatomegaly, hepatitis and other liver diseases with known risk factors (especially obese women) should be careful with nucleosides. These patients should be followed closely.
Hematological adverse reactions: Patients receiving zidovudine treatment may develop anemia, neutropenia, and leukopenia (usually secondary neutropenia). The above conditions are more common with high-dose zidovudine (1200-1500 mg days) and poor bone marrow hyperplasia before treatment, especially in patients with advanced HIV infection. Therefore, hematological parameters of patients receiving this product should be carefully monitored. These hematological effects are usually not observed during the first 4-6 weeks of treatment. For patients with advanced HIV infection, it is generally recommended that blood tests be performed at least every 2 weeks during the first 3 months of treatment and at least monthly thereafter.
In the early stages of HIV infection, people with abnormal blood conditions are rare. Based on the general condition of the patient, it is not necessary to perform routine blood tests so frequently. It can be monitored every 1-3 months. When severe anemia or bone marrow suppression occurs during the treatment of this product, or if there is already low bone marrow hyperplasia before treatment, such as hemoglobin below 9 g / dL (5.59 mmol / L) or neutrophil count below 1.0x10 / L, Qi Dovudine's dose needs to be adjusted. Since it is impossible to meet this requirement by adjusting the dosage of this product, a single formulation of zidovudine, abacavir and lamivudine should be taken. Doctors should follow the prescribing information for the above-mentioned single-agent medications.
Pancreatitis: Pancreatitis rarely occurs in patients treated with abacavir, lamivudine, and zidovudine. It is unclear whether it is due to medication or a potential HIV infection. If clinical symptoms, signs, or The abnormality of the experimental examination indicates that this product should be discontinued immediately if there is pancreatitis.
Patients who are also infected with hepatitis B virus: clinical trials and market use of lamivudine have shown that patients with chronic hepatitis B virus (HBV) infection may have clinical or laboratory indications of recurrence of hepatitis after discontinuation Especially in patients with decompensated liver disease, the consequences are more serious. Once patients with HBV are discontinued, they must regularly monitor liver function and markers of HBV replication.
Opportunistic infection: HIV infection cannot be cured with this product or any other antiretroviral drugs, and patients may still develop opportunistic infections and other complications of HIV infection. Therefore, patients taking this product must have close clinical observations by physicians familiar with treating HIV infection.
Other: As it has not been proven that current antiretroviral treatments, including this product, can block the risk of HIV transmission through sexual contact or blood contamination, patients should be warned to continue to take appropriate precautions.
Information on the effectiveness and safety of this product taken with non-nucleoside reverse transcriptase inhibitors and protease inhibitors is currently insufficient. ^[3]

Abacavir medication for pregnant and lactating women:

Pregnancy: The safety of this product for human pregnancy has not been established. Animal reproduction tests found results related to abacavir, lamivudine, and zidovudine (see Pharmacology and Toxicology). Therefore, medications for pregnancy are considered only when the benefits to the mother outweigh the potential harm to the fetus.
Lactation: Both lamivudine and zidovudine are secreted into human milk, and the concentration is similar to that in serum. Although unproven, abacavir is also predicted to be secreted into milk. Therefore it is recommended that mothers taking this product do not breastfeed. To avoid transmitting HIV to babies, women who may be infected with HIV are advised not to breastfeed. ^[3]

Abacavir for children:

There is no sufficient information, so this product is not recommended for children and adolescents. It is difficult to confirm the occurrence of allergic reactions in these patients. ^[3]

Abacavir medications for the elderly:

For patients over 65 years of age, no pharmacokinetic data are available. But attention is being given to this group of patients. Because with age, changes such as decreased kidney function and hematology can occur. ^[3]

Abacavir Drug Interactions:

Because this product contains abacavir, lamivudine, and zidovudine, all the interactions that can be performed with these three drugs can also occur in the application of this product. Lamivudine has limited metabolism, limited plasma protein binding, and is completely cleared by the kidneys, so it is unlikely to interact with other drugs. Zidovudine is mainly metabolized in the liver, and is excreted in the liver after being combined into an inactive glucuronidation metabolite. Any drug excreted by the liver, especially eliminated by glucuronidation, may inhibit the metabolism of zidovudine. Based on the results of abacavir in vitro tests and its main metabolic pathways, it is unlikely that P450 mediates its interaction with other drugs. Clinical studies have shown no significant clinical interactions between abacavir, lamivudine, and zidovudine.
The drug interactions listed below are not all, they only represent the types of drugs that must be noted when using them.
Interactions related to abacavir: Based on the results of in vitro abacavir experiments and their main metabolic pathways, it is unlikely that P450 will mediate its interaction with other drugs. The cytochrome P450 enzyme system does not play an important role in the metabolism of abacavir, and abacavir does not inhibit CYP3A4-mediated metabolism. Clinically significant abacavir concentrations did not inhibit the activity of CYP3A4, CYP2C9 or CYP2D6 enzymes in vitro. As a result, there is very little possibility of interaction between abacavir and antiretroviral protease inhibitors or other drugs that are primarily metabolized by P450.
Strong enzyme inducers, such as rifampicin, phenobarbital, and phenytoin, can slightly reduce the plasma concentration of abacavir by acting on UDP-glucuronyltransferase.
When used with ethanol, it causes a 41% increase in the AUC of abacavir, which alters its metabolism. It is not considered clinically significant. Abacavir does not alter the metabolism of ethanol.
Resin-like compounds are eliminated by the action of alcohol dehydrogenase and may interact with abacavir, but this has not been studied.
In a pharmacokinetic study, when methadone was administered with 600 mg of abacavir twice daily, it was found that Cmax of abacavir was reduced by 35% and Tmax was delayed by 1 hour, but AUC was unchanged. . The pharmacokinetic changes of abacavir have no clinical relevance. In this study, abacavir increased the mean clearance of methadone by 22%. Therefore, the induction of drug metabolism enzymes cannot be ruled out. For most patients, this change is not clinically relevant, but it is sometimes necessary to re-titrate the methadone dose.
Interactions related to lamivudine: The possibility of interaction between other drugs when combined with this product should be considered, especially some drugs that are mainly cleared by the kidney through the cation transport system, such as trimethoprim. Nucleoside analogs (e.g. zidovudine, didanosine, zalcitabine) and other drugs (e.g. ranitidine, cimetidine) are only partially cleared through this mechanism, and therefore are related to Fuding has no interaction.
When co-administered with trimethoprim / sulfamethoxazole (compound methoxazole) 160 mg / 800 mg, trimethoprim increases the effect of lamivudine by 40%, while Fuding has no interaction. Unless the patient has kidney damage, there is generally no need to adjust the dose of lamivudine. Lamivudine does not affect the pharmacokinetics of trimethoprim or sulfamethoxazole. Caution should be taken when taking it with the compound Xin Nuo Ming, and clinical monitoring should be paid attention to. This product should be avoided in combination with higher doses of compound sirolimus for the treatment of pneumocystis carinii pneumonia and toxoplasmosis.
Lamivudine is not recommended in combination with intravenous ganciclovir and foscarnet until further information is available.
Lamivudine's metabolism does not involve CYP3A, and it seems impossible to interact with drugs (protease inhibitors and non-nucleosides) that rely on this system for metabolism.
Interactions related to zidovudine: Limited data indicate that zidovudine can reduce the former's AUC by 48 ± 34% when shared with rifampicin. Its clinical significance remains unclear.
Limited data suggest that probenecid and zidovudine reduce glucuronidation when used in combination, reducing renal excretion of glucuronic acid (and possibly zidovudine), thereby extending the half-life of zidovudine and expanding Area under the curve at the time of drug administration.
It has been reported that when receiving zidovudine and phenytoin, some patients have low phenytoin blood levels. However, there is a high blood concentration of phenytoin, which suggests that patients receiving the combination of phenytoin and phenytoin should closely monitor the level of phenytoin.
Pharmacokinetic studies of zidovudine and atovaquone combined showed that the oral clearance of zidovudine decreased to 35% ± 23%, and the AUC of zidovudine in plasma increased. The data are limited and its clinical significance is unclear.
In combination with valproic acid and methadone, zidovudine increases its AUC levels and decreases associated clearance. The data are limited and its clinical significance is unclear.
Other medicines, including acetylsalicylic acid, codeine, morphine, methadone, indomethacin, ketoprofen, naproxen, oxazepam, larazepam, cimetidine, clobetin, ampicillin Sulfone and isoprinosine and other drugs can change the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting liver microsome metabolism. Before using these drugs in combination with this product, especially during long-term treatment, the possibility of drug interaction should be considered.
In in vitro tests, ribavirin and stavudine have an antagonistic effect on zidovudine, and the combination of ribavirin or stavudine with this product should be avoided.
Combination therapy, especially in the acute phase, if the drug contains drugs that may cause nephrotoxicity or bone marrow suppression (such as systemic pentamidine, dapsone, pyrimethamine, compound neonomine, amphotericin B, fluorine Cytosine, propoxyguanosine, interferon, vincristine, vincristine, and doxorubicin) can also increase the risk of side effects with zidovudine. If this product is used in combination with these drugs, special attention should be paid to monitoring the patient's renal function and blood phase changes. If necessary, the dose of one or more of these drugs should be reduced.
Limited clinical trial data does not suggest a combination of zidovudine with compound neonomine (see the interaction of lamivudine and compound neonomine), pentamidine aerosol, ethimethamine and acyclovir. The risk of adverse reactions is significantly increased.
The simultaneous use of lamivudine and high-dose combination sirolimus should be avoided in the treatment of pneumocystis carinii pneumonia and toxoplasmosis. ^[3]

Abacavir overdose:

No experience with overdose of this product. Acute overdose of zidovudine or lamivudine, no special symptoms and signs different from the above adverse reactions were found. All patients recovered without death. Abacavir has been used in clinical studies in single doses up to 1200 mg and 1800 mg / day, and no unexpected adverse reactions occurred. The response to higher doses is unclear.
In the event of overdose, patients should be monitored for toxicity and, if necessary, regular supportive therapies. Because lamivudine can be discharged through dialysis, although this method has not been tested, it can be treated by continuous hemodialysis in excess. Hemodialysis and peritoneal dialysis have limited clearance of zidovudine, but can increase glucuronic acid metabolites to accelerate excretion. It is unclear whether this method can be used to clear abacavir. ^[3]

Abacavir clinical trials:

In a double-blind, more than 48-week clinical trial, the combination of abacavir, lamivudine, and zidovudine with indinavir, lamivudine, and zidovudine The untreated patients had the same antiviral effect in the primary efficacy analysis and the secondary efficacy analysis. The efficacy of the indinavir combination therapy group in patients with serum HIV-1 RNA baseline levels exceeding 100,000 copies / mL Better. In patients with serum HIV-1 RNA baseline levels below 100,000 copies / mL, both treatments have the same effect.
In an ongoing clinical study of patients who have never been treated for more than 16 weeks, the antiviral efficacy of abacavir, lamivudine, and zidovudine combined Namivir, lamivudine and zidovudine have similar efficacy.
For patients who have never received antiretroviral therapy, abacavir, lamivudine, and zidovudine combined with a low viral load lasted 48 weeks longer than lamivudine and zidovudine. In a similar patient population, approximately 70% of patients have an antiviral response that lasts up to 120 weeks.
A small, ongoing, open-label trial in patients who have never received antiretroviral therapy was treated with abacavir, lamivudine, zidovudine, and efavirenz after 24 weeks About 90% of patients have undetectable viral load (<400 copies / mL), 80% of which are <50 copies / mL.
Baseline levels of viral load were low (<50,000 copies / mL), and patients treated with general antiretroviral therapy were treated with abacavir in addition to previous lamivudine and zidovudine, 48 A moderate reduction in viral load was observed at weekly.
There is no data on the treatment of this product in patients who have received intensive treatment or other treatment failures or have progressive disease (CD4 cells <50 / mm).
For patients who have undergone intensive treatment, the efficacy of this combination of triple nucleosides depends on the nature and duration of the previous treatment. These factors may cause HIV-1 to produce abacavir, zidovudine, or pull Mivudine produces cross-resistant mutants.
At present, there is no sufficient data to show the efficacy and safety of this product taken simultaneously with non-nucleoside reverse transcriptase or protease inhibitors. ^[3]

Abacavir Pharmacology and Toxicology:

Pharmacological effects Abacavir, lamivudine, and zidovudine are reverse transcriptase nucleoside inhibitors and are effective selective inhibitors against HIV-1 and HIV-2.
All three drugs can be gradually metabolized to 5'-triphosphate (TP) by intracellular kinases. Lamivudine-TP, carbovir-TP (the active triphosphate moiety of abacavir) and zidovudine-TP are substrate competitive inhibitors of HIV reverse transcriptase. However, its main antiviral activity is incorporated into the viral DNA strand through the form of a monophosphate, resulting in termination of the viral DNA strand. The triphosphates of abacavir, lamivudine, and zidovudine have much less affinity for host cell DNA polymerase than viral DNA.
Lamivudine and zidovudine have a high synergistic effect and inhibit HIV replication in cell culture. In the combination test in vitro, abacavir has a synergistic effect with nevirapine and zidovudine, and has an additive effect with didanosine, zalcitabine, stavudine, and lamivudine.
Abacavir-resistant HIV isolates have been screened in vitro, and the development of this drug resistance is related to its special genes in the reverse transcriptase (RT) coding regions (encoding M184V, K65R, L74V and Y115F) Type change. In vitro and in vivo tests, the process of virus resistance to abacavir is relatively slow, multiple mutations must occur, and its IC50 can be 8 times higher than wild type, which may be a clinically significant level. Abacavir-resistant isolates may also have reduced sensitivity to lamivudine, zalcitabine, and / or didanosine, but zidovudine and stavudine remain sensitive.
Cross-resistance between abacavir, lamivudine, and zidovudine and protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely. Clinical isolates with reduced susceptibility to abacavir were isolated from patients who had uncontrolled viral replication, had been treated with other nucleoside inhibitors, and developed resistance to these drugs . Clinical isolates that develop three or more mutations associated with nucleoside reverse transcriptase inhibitors are unlikely to be susceptible to abacavir. ^[3]
Preclinical safety data on toxicology studies do not have preclinical data on the combination of abacavir, lamivudine, and zidovudine in animals. The clinically relevant toxicities of the three drugs are anemia, neutropenia, and leukocytopenia.
General toxicity: The clinically significant side effects of the combination of these three drugs are anemia, neutropenia, and leukopenia. Toxicology studies have shown that abacavir does not increase liver weight in rats and monkeys. Its clinical relevance is unknown. Abacavir has not been shown to have liver toxicity in clinical studies. In addition, abacavir has not been found to have its own metabolism-inducing effect in the human body or to induce metabolism in other drugs metabolized in the liver.
Mutagenicity and carcinogenicity: In bacterial experiments, lamivudine, abacavir or zidovudine have no mutagenic effect. Tested in vitro in mammals, they are as active as other nucleoside analogs, such as the mouse lymphoma assay. This is consistent with the known activity of other nucleoside drugs.
In vivo studies have confirmed that there is no genetic toxicity when lamivudine has a blood concentration of 40-50 times the clinical blood concentration. In mice and rats, zidovudine was observed to be mutagenic to chromosomes in multiple micronucleus tests given zidovudine orally. Many chromosomal fragments can be seen in peripheral blood lymphocytes after AIDS patients have been treated with zidovudine. The clinical significance of these findings is unknown. In in vivo and in vitro tests, even high concentrations of abacavir have a low tendency to cause chromosome disruption. Therefore, any possible risks in the clinic must be weighed against the expected therapeutic benefits.
No trials have been conducted on the carcinogenicity of lamivudine, abacavir, and zidovudine. Lamivudine has not been found to be carcinogenic in long-term oral carcinogenesis studies in rats and mice. There is no data on the carcinogenic risk of abacavir in animal trials. In a carcinogenicity study of rats and mice taking zidovudine orally, vaginal epithelial tumors were found to develop at an advanced stage of treatment. A subsequent intravaginal carcinogenicity study confirmed the hypothesis that caused the vaginal tumor, that rodent's vaginal epithelium was locally exposed to high levels of unmetabolized zidovudine in urine. No other tumors related to zidovudine were found in rats and mice in the above studies, regardless of gender.
In addition, two transplacental carcinogenicity studies were performed in mice. In one of the studies conducted by the National Cancer Institute, pregnant mice were given the maximum tolerated dose of zidovudine from days 12-18 of pregnancy. One year after birth, the incidence of reproductive tract tumors in the lungs, livers, and females of daughters exposed to the highest dose (420 mg / kg, according to body weight) increased.
In the second study, mice were given zidovudine up to 40 mg / kg for 24 months, and exposure to the drug began on the 10th day of pregnancy. Treatment-related conditions are limited to advanced vaginal epithelial tumors, and their incidence and time to onset are similar to those of standard-dose oral carcinogenicity studies. Therefore, the second study failed to show that zidovudine is a placental carcinogen.
Based on the increased tumor incidence in the first transplacental carcinogenesis study, it was concluded that the hypothetical risk should be weighed against its proven efficacy.
Reproductive toxicity: Lamivudine has not been found to have teratogenic effects in animal tests, but with relatively low systemic drug exposure, lamivudine can increase early embryo death in rabbits, which is consistent with human conditions. Similar effects were not found in rat experiments, even under high systemic drug exposure.
Zidovudine works similarly in both animals but must be exposed to high systemic drug exposure. Obstetric toxic doses given to rats during organogenesis will increase the incidence of malformations, but no evidence of fetal malformations was seen at low doses.
Abacavir is toxic to developing rat embryos and fetuses, but not to rabbits. These effects include weight loss in the fetus, fetal edema, and fetal skeletal abnormalities / deformations, early intrauterine death and stillbirth. Due to this embryo-fetal toxicity, the teratogenic effects of abacavir are inconclusive.
Studies of fertility in rats have shown that abacavir has no effect on male or female fertility. Neither lamivudine nor zidovudine had any effect on fertility. For male patients, zidovudine does not affect sperm count, shape, and motility. ^[3]

Abacavir pharmacokinetics:

Absorption: Oral abacavir, lamivudine and zidovudine are quickly and well absorbed in the gastrointestinal tract. Under normal circumstances, the absolute bioavailability of oral abacavir, lamivudine, and zidovudine in adults is 83%, 80-85%, and 60-70%, respectively.
Pharmacokinetic studies on HIV-1 infected patients found that when used alone or in combination with lamivudine / zidovudine and abacavir, abacavir, lamivudine and Zidovudine has similar steady-state pharmacokinetic parameters. Steady-state parameter values obtained from bioequivalence studies of this product in healthy volunteers were similar.
A bioequivalence study of the lamivudine / zidovudine combination with 150 mg of lamivudine and 300 mg of zidovudine was also conducted, and the absorption rate and amount of drugs for food were also studied. Impact. The results show that when taken on an empty stomach, the lamivudine / zidovudine compound preparation is bioequivalent to the simultaneous use of 150 mg lamivudine and 300 mg zidovudine.
A bioequivalence study was performed with this product and 300 mg abacavir, 150 mg lamivudine, and 300 mg zidovudine at the same time, and the effect of food on the rate and amount of drug absorption was also studied. . The results show that when taken on an empty stomach, this product is bioequivalent to AUC and Cmax with a single formulation of 300 mg abacavir, 150 mg lamivudine, and 300 mg zidovudine. Food reduces the absorption of this product [slightly reduced Cmax (average 18-32%), increased Tmax (about 1 hour)], but does not change the degree of absorption (AUC). These changes are not clinically relevant, so it is recommended to take this product without food restrictions.
When taking zidovudine and lamivudine at the same time, a moderate increase in Cmax (28%) of zidovudine was observed, but the overall exposure level (AUC) did not change significantly. Zidovudine has no effect on the pharmacokinetics of lamivudine. The effects of abacavir zidovudine (20% reduction in Cmax) and lamivudine (35% reduction in Cmax) were observed.
Distribution: Intravenous studies have shown that the average distribution volumes of abacavir, lamivudine, and zidovudine are 0.8, 1.3, and 1.6 L / kg, respectively. Above the therapeutic dose range, the pharmacokinetics of lamivudine are linear and its plasma protein binding rate is limited (in vitro tests, the binding rate of lamivudine to serum proteins is <36%). The binding rate of zidovudine to plasma proteins is 34-38%. In vitro studies of the combination of abacavir with plasma proteins showed that at therapeutic doses, abacavir showed low and moderate binding to human plasma proteins (about 49%). This shows that the possibility of these drugs interacting with other drugs through plasma protein conversion is very low.
This product is unlikely to cause drug-drug interactions due to conversion of binding sites.
Data show that abacavir, lamivudine and zidovudine can enter the cerebrospinal fluid through the central nervous system. After 2-4 hours of oral administration, the average concentrations of lamivudine and zidovudine in cerebrospinal fluid and serum were 0.12 and 0.50, respectively. The actual amount of lamivudine passed and its relationship with clinical efficacy are unknown.
Studies have confirmed that the abcavivir cerebrospinal fluid / plasma AUC ratio is 30-44%. Abacavir 600 mg twice a day, the observed peak concentration value is 9 times the IC50 value of 0.08 ug / mL or 0.26 uM.
Metabolism: Metabolism of lamivudine is a secondary route of its clearance, and its primary drug is mainly eliminated through renal clearance. Lamivudine has less hepatic metabolism (5-10%) and low binding to plasma proteins, so fewer drug interactions occur.
Zidovudine's main metabolite in plasma and urine is 5'-glucuronic acid, and about 50-80% of the dose used is excreted by the kidneys. One metabolite of zidovudine after intravenous injection has been confirmed to be 3'-amino-3'-deoxypyrimidine (AMT).
Abacavir is mainly metabolized by the liver, and less than 2% of the dose is cleared by the kidney through the prototype. The main metabolic pathway in men is to excrete about 66% of the drug to 5'carboxylic acid-5'-glucuronide through alcohol dehydrogenase and glucuronidation.
Clearance: The elimination half-life of lamivudine is 5-7 hours, and the average systemic clearance is 0.32 L / h / kg. It is mainly cleared by the kidney through the organic cation transport system (> 70%). Patients with renal impairment have reduced lamivudine clearance due to renal insufficiency. Patients with creatinine clearance (smaller than or equal to) 50 mL / min need to reduce the dose.
According to the study of intravenous zidovudine, the average terminal plasma half-life is 1.1 hours, the average systemic clearance is 1.6 L / h / kg, and the renal clearance is about 0.34 L / h / kg. It is filtered through the glomerulus And renal tubular secretion and excretion. Zidovudine plasma levels are elevated in patients with advanced renal failure.
The average half-life of abacavir is about 1.5 hours. After multiple oral doses of 300 mg twice daily, there was no significant accumulation of abacavir. Abacavir's elimination is firstly metabolized by the liver, and then metabolites are mainly excreted by the urine. Metabolites and prototypes in the urine account for about 83% of the abacavir dose, and the rest are cleared through feces.
Special Populations: Patients with liver injury: Patients with no liver injury taking this product. Limited data from patients with cirrhosis suggest that reduced glucuronidation may lead to accumulation of zidovudine in patients with liver damage. Data from patients with moderate to severe liver injury indicate that liver dysfunction does not significantly affect the pharmacokinetics of lamivudine. Abacavir is mainly metabolized by the liver. Safety analysis data support patients with mild liver injury taking abacavir 300 mg twice daily. There are no data on the pharmacokinetics of abacavir in patients with moderate to severe liver injury, so this product is contraindicated in patients with moderate to severe liver injury.
Renal Impairment Patients: Lamivudine's clearance half-life has been measured at 5-7 hours. Its average systemic clearance is about 0.32 L / h / kg, which is mainly cleared by the kidney through the organic cation transport system (> 70%). Studies in patients with renal impairment have shown that renal dysfunction can affect clearance of lamivudine.
From the intravenous injection of zidovudine, it is known that the average terminal plasma half-life is 1.1 hours, the average systemic clearance is 1.6 L / h / kg, and the renal clearance is about 0.34 L / h / kg. Renal tubules are secreted and excreted. Zidovudine plasma levels are elevated in patients with advanced renal failure.
Abacavir is mainly metabolized by the liver, and about 2% of abacavir is excreted by the kidney in its original form. Pharmacokinetics are the same in patients with advanced kidney disease and those with normal kidney function, so there is no need to adjust the dose in case of renal damage.
Since the doses of lamivudine and zidovudine may need to be adjusted, it is recommended to use abacavir, lamivudine for patients with reduced renal function (smaller than or equal to 50 mL / min) And Zidovudine. This product is contraindicated in patients with advanced kidney disease.
Elderly patients: No pharmacokinetic data are available for patients over 65 years of age. ^[3]

Abakawe expert review

This product is well tolerated, does not produce drug resistance, and has a synergistic effect with most anti-AIDS drugs. Its efficacy is equivalent to that of protease inhibitors, and has a higher efficacy / price ratio. For patients who have developed resistance with other drugs, they can be added or replaced with this drug, which can effectively inhibit the HIV virus. In a clinical study in combination with Combivir, after 24 weeks of treatment, 65% of patients in the abacavir / Combivir group (n = 282) and indinavir / Combivir group (n = 280) had plasma. HIV-IRNA was below 400 / ml, and CD4 cell counts increased by 103 / mm3 and 105 / mm3, respectively; in another comparison, abacavir / epivir / zidovudine (n = 87) and lamivudine ( (n = 86) In the study of efficacy and safety, at 48 weeks of treatment, the proportion of patients with HIV-IRNA levels below 400 / ml was 64% and 60%, respectively. ^[4]