Zidovudine

Zidovudine is an antiviral drug of direct effect. It is included in the group of nucleotide, as well as nucleoside inhibitors of revertase.

Indications of the zidovudine

It is shown in combination therapy with other antiretroviral drugs used in HIV therapy for adults and children.

It is also used in the HIV-positive pregnancy test (with a period of 14+ weeks) - in order to prevent the transmission of pathology to the fetus, and to provide primary prevention of the disease in the newborn.

[1]

Release form

Produced in the form of capsules with a volume of 100 or 250 mg. In the blister - 10 capsules. In the package - 10 plates (the volume of capsules 100 mg) or 4 plates (the volume of capsules 250 mg).

[2], [3], [4], [5]

Pharmacodynamics

Zidovudine is a selective inhibitor of the DNA replication of the virus.

After passing into the cell (infected or intact) with the participation of elements such as thymidylate kinase and thymidine kinase, as well as non-specific kinase, a process of phosphorylation takes place, as a result of which mono-, and also di-triphosphate compounds are formed.

The substance of zidovudine-triphosphate is a substrate of viral revertase. It indirectly affects the formation of DNA virus within the matrix of the zidovudine DNA carrier. The substance has similarities with thymidine triphosphate in the structure, it is its competitor for synthesis with the enzyme. The component is built into the viral DNA provirus chain, thereby blocking its further growth. It also increases the number of T4 cells and enhances the body's immune response to infectious processes.

The delayed properties of zidovudine relative to HIV revertase are approximately 100-300 times greater than its inhibitory properties with respect to human DNA polymerase.

In vitro testing demonstrated that the use of a 3-fold combination of nucleoside LS analogs or 2 nucleoside analogs, together with a protease inhibitor, more effectively inhibits HIV-induced cytopathic properties than monotherapy or a combination of 2 drugs.

[6], [7], [8],

Pharmacokinetics

The active ingredient is well absorbed from the digestive tract, the bioavailability indicator is 60-70%. The peak of plasma indices after the use of the capsule in the amount of 5 mg / kg every 4 hours is 1.9 μg / l. To achieve a peak serum concentration, the drug takes 0.5-1.5 hours.

The substance passes through the BBB, and its average values inside the CSF are approximately 24% of the plasma concentration. It also passes through the placenta and is observed inside the blood of the fetus and amniotic fluid. Synthesis with protein is 30-38%.

Inside the liver, the conjugation process is carried out with the participation of glucuronic acid. The main product of disintegration is 5-glucuronylidothymidine, which is excreted through the kidneys and has no antiviral properties. Excretion of zidovudine is performed by the kidneys - 30% of the substance is removed unchanged, and about 50-80% - in the form of glucuronides.

The half-life of the active ingredient from whey under condition of healthy renal function is about 1 hour (for adults), and in the condition of a disorder in the kidneys (with a QC value of less than 30 ml / minute) is 1.4-2.9 hours. In children of age 2 weeks / 13 years this period is about 1-1.8 hours, and in adolescents 13-14 years old it is about 3 hours. In newborns, whose mothers took drugs, this figure is approximately 13 hours.

The medicine does not cumulate inside the body. In persons suffering from insufficiency or cirrhosis of the liver, cumulation can be observed due to a decrease in the intensity of the synthesis process with glucuronic acid. In patients with kidney failure, decay products can accumulate (conjugates together with glucuronic acid), which increases the likelihood of developing a toxic effect.

[9], [10], [11], [12], [13], [14],

Dosing and administration

The therapeutic course should be supervised by a doctor with experience in the field of HIV treatment.

Children with a weight of 30+ kg, as well as adults, are required to take 500-600 mg per day (per 2 drinks) per day. The drug should be combined with other antiretroviral drugs.

To ensure the use of a single dosage of drugs, you need to swallow the capsule whole, not chewing and not opening it. If the patient is not able to swallow the whole capsule, it is allowed to open it, and then mix the contents with food or liquid (eat / drink this portion immediately after opening the capsule).

For children weighing 21-30 kg, the dosage is 200 mg twice daily (also in combination with other antiretroviral drugs).

For children weighing 14-21 kg, the dose is 100 mg in the morning, followed by 200 mg at bedtime.

For children weighing 8-14 kg, 100 mg of medication is prescribed twice a day.

Children weighing less than 8 kg, unable to swallow the whole capsule, are given a medication in the form of an oral solution.

When preventing the movement of the virus from mother to fetus - for pregnant women (with a period of more than 14 weeks), the daily dosage is 500 mg (100 mg 5 times per day) of the drug orally (treatment in this mode lasts until delivery). At birth Zidovudine in the form of an infusion solution is administered in the amount of 2 mg / kg for 1 hour, and then at a rate of 1 mg / kg / hour all the time until the moment of cutting the umbilical cord.

For newborns, the drug is given as an oral solution in the amount of 2 mg / kg every 6 hours (starting 12 hours after birth and continuing until the child reaches 6 weeks of age). If oral drug use is not possible, the infant is injected with an infusion solution in / in the way for 1.5 hours / every 6 hours after the half hour.

If a cesarean section is planned, the infusion should begin 4 hours before the operation. If false birth has begun, you need to cancel the medication infusion.

[23], [24], [25], [26]

Use of the zidovudine during pregnancy

It is established that the drug is able to penetrate the human placenta. Since there is only limited information on the use of zidovudine in pregnant women, it is possible to take it for up to 14 weeks only in cases where the possible benefits for women exceed the likelihood of negative signs in the fetus.

There is evidence of a moderate transient increase in lactate levels within the serum. The cause of this may be mitochondrial dysfunction that occurs in infants and newborns exposed to nucleoside reverse transcriptase inhibitors during intrauterine development or during childbirth. But there is no data on the clinical significance of this fact.

There are also single data on the delay in development and various neurological pathologies. But the relationship between these disorders and the effect of nucleoside reverse transcriptase inhibitors during intrauterine development or during labor was not established. This information does not influence the current recommendations on the use of antiretroviral drugs in pregnant women (to prevent the vertical transmission of HIV infection).

Contraindications

Among the contraindications of drugs:

• the presence of hypersensitivity to zidovudine or other elements of the drug;
• too low a number of neutrophils (less than 0.75 × 10 9 / L) or abnormally low hemoglobin in the blood (less than 7.5 g / dl or 4.65 mmol / l);
• the presence in the newborn of hyperbilirubinemia, requiring additional treatment methods, other than the method of phototherapy, or with an increase in the transaminase index is 5+ times higher than normal.

[15], [16], [17], [18], [19]

Side effects of the zidovudine

Due to the use of drugs it is possible to develop such adverse reactions:

• organs of the cardiovascular system: pain in the sternum, a strong heartbeat and the development of cardiomyopathy;
• organs of the lymphatic and hematopoietic systems: development of thrombocyto-, leuko-, neutropa- or pancytopenia (with bone marrow hypoplasia);
• organs of the National Assembly: dizziness with headaches, a feeling of drowsiness or vice versa insomnia, impairment of mental activity, development of seizures, paresthesia or tremor. In addition, the appearance of hallucinations, confusion, psychomotor agitation and problems with diction, the development of encephalopathy or ataxia, as well as coma;
• mental disorders: development of depression or anxiety;
• organs of the sternum with mediastinum and respiratory system: the appearance of a cough or dyspnea;
• Gastrointestinal organs: abdominal pain, nausea, diarrhea, vomiting and bloating. In addition, dyspepsia, pigmentation of the oral mucosa, problems with swallowing, a disorder of taste buds and the development of gastritis or pancreatitis;
• organs of the digestive system: a transient increase in the activity of liver enzymes, the development of jaundice, hyperbilirubinemia, hepatitis, and in addition, a disorder of the hepatic function (for example, severe form of hepatomegaly along with steatosis);
• organs of the urination system: an increase in the blood concentration of creatinine, as well as urea, and in addition, frequent urination;
• organs of ODA and connective tissue: development of myopathy or myalgia;
• metabolic processes: the development of anorexia, lactic acidosis or hyperlactatemia, and besides accumulation / redistribution on the body of fat stores;
• mammary glands and organs of the reproductive system: development of gynecomastia;
• organs of the immune system, subcutaneous tissue, as well as the skin: manifestations of intolerance - itching, rashes, angioedema, alopecia, hyperemia and photosensitivity, and besides urticaria, severe sweating, as well as pigmentation of nails and skin;
• Other: increased fatigue, a feeling of malaise, the development of fever, chills, asthenia, and in addition flu-like syndrome, and the emergence of common pain.

[20], [21], [22]

Overdose

There are no specific manifestations of drug overdose - it usually manifests as symptoms of an adverse reaction (headaches, severe fatigue, vomiting, and sometimes hematological changes occur). There is information about the use of drugs in an unknown quantity, in which the active substance in the blood exceeded the required therapeutic concentrations by 16+ times, but this did not cause any biochemical, medicinal or hematological complications.

When an overdose of the drug requires a thorough examination of the patient to identify possible symptoms of poisoning, and then assign the necessary supportive treatment.

Procedures for peritoneal dialysis, as well as hemodialysis, have little effect on the excretion of zidovudine, but at the same time enhance the excretion of its glucuronide degradation product.

[27], [28], [29],

Interactions with other drugs

Excretion of zidovudine mainly occurs through the process of conjugation inside the liver, turning it into an inactive glucuronide degradation product. The active components, eliminated with the help of metabolic processes in the liver, can inhibit the metabolism of zidovudine.

There is no data on the effect of zidovudine on the pharmacokinetic properties of atovaquone, but it should be borne in mind that the latter is able to reduce the zidovidin metabolism relative to its glucuronide degradation product (AUC component is increased by 33%, but the maximum level of plasma glucuronide concentration is reduced by 19%). Under the condition of a daily dosage of 500 or 600 mg of atovaquone taken in the period of 3 weeks, the frequency of adverse reactions increases with the treatment of the acute form of pneumonia provoked by Pneumocystis carinii. This is due to the elevated zidovudine in the blood plasma. With a prolonged medical course using atovaquone, it is necessary to carefully monitor the patient's condition with special care.

Clarithromycin is able to reduce absorption of zidovudine, which requires a 2-hour interval between taking these medications.

When combined with lamivudine, there is a moderate increase in the peak level of zidovudine (by 28%), but no noticeable changes in the AUC are observed. Zidovudine does not affect the pharmacokinetic properties of lamivudine.

There is evidence of a reduced level in the blood of individual phenytoin patients (when combined with zidovudine), although there is also information that one patient was on the contrary up-regulated. Therefore, in the case of simultaneous administration of these drugs, it is necessary to closely monitor the indices of phenytoin.

When combined with methadone, valproic acid or fluconazole, the AUC of zidovudine increases with a corresponding decrease in the rate of its clearance rate. Since the information is limited, the clinical significance of this fact is not known. The patient must be carefully monitored to promptly detect the presence of symptoms of the toxic effects of zidovudine.

When zidovudine was used as part of combined HIV treatment, there was an exacerbation of the symptoms of anemia, which is associated with the use of ribavirin (but the exact mechanism of this fact is still unclear). Therefore, it is not recommended to combine these medications. The doctor will need to prescribe a different analogue for combined antiretroviral treatment instead of zidovudine (if this has already begun). In particular, this measure is important for people who have a history of anemia, provoked by zidovudine.

Limited evidence shows that probenecid is able to prolong the half-life, as well as the zidovudine AUC index, and in addition to weaken glucuronization. The excretion of glucuronide through the kidneys (also possibly zidovudine) is reduced by probenecid.

According to limited information, the combination with rifampicin reduces the AUC of zidovudine by about 48% ± 34%, but the clinical significance of this fact has not been established.

When combined with stavudine, oppression of phosphorylation of this substance inside cells is possible. Because of this, it is not recommended to use these drugs in combination.

Other interactions: Many active ingredients (including morphine with codeine and methadone, ketoprofen, aspirin and naproxen with indomethacin, and in addition lorazepam, dapsone, oxazepam, clofibrate and cimetidine with isoprinosine (as well as other drugs)) can affect the process metabolism of zidovudine by means of competitive inhibition of the glucuronization process or direct inhibition of microsomal metabolism in the liver. Because of this, it is necessary to take into account the possible effect of the combined use of these drugs, especially with constant treatment.

Combined use (mainly in acute cases) with myelosuppressive or nephrotoxic drugs (for example, dapsone, biseptol and systemic pentamidine, and besides flucytosine, interferon and amphotericin with vincristine, and ganciclovir and doxorubicin with vinblastine) may cause increased negative properties zidovudine. If you need to use these drugs at the same time, careful monitoring of renal function and hematological parameters will be required. If necessary, reduce the dosage of both drugs or one of them.

Since patients taking zidovudine may develop opportunistic infections, they are sometimes prescribed antimicrobial drugs for the purpose of prophylaxis. This list includes pyrimethamine, co-trimoxazole, and acyclovir with pentamidine (in the form of an aerosol). The limited information obtained in the course of clinical trials shows that when these drugs are combined, there is no increase in the incidence of adverse reactions to zidovudine.

[30], [31], [32]

Storage conditions

The medicine should be stored in suitable conditions for medicines, inaccessible to children. Temperature can not exceed 25 ^on S.

[33], [34], [35], [36], [37]

Shelf life

Zidovudine is allowed to be used within 2 years from the date of release of the drug.

[38]