Zidovudin

Zidovudine is a direct-acting antiviral drug. It belongs to the group of nucleotide and nucleoside reverse transcriptase inhibitors.

Indications Zidovudina

Indicated for combination therapy with other antiretroviral drugs used in HIV therapy for adults and children.

It is also used in case of an HIV-positive test in a pregnant woman (at 14+ weeks) – in order to prevent the transmission of the pathology to the fetus, and to ensure primary prevention of the disease in the newborn.

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Release form

Available in capsules of 100 or 250 mg. Blister pack contains 10 capsules. Package contains 10 strips (capsule volume 100 mg) or 4 strips (capsule volume 250 mg).

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Pharmacodynamics

Zidovudine is a selective inhibitor of viral DNA replication processes.

After entering the cell (infected or undamaged), with the participation of such elements as thymidylate kinase and thymidine kinase, as well as non-specific kinase, the process of phosphorylation occurs, as a result of which mono-, as well as di- and triphosphate compounds are formed.

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

The inhibitory properties of zidovudine against HIV reverse transcriptase are approximately 100-300 times greater than its inhibitory properties against human DNA polymerase.

In vitro testing has demonstrated that the use of a 3-drug combination of nucleoside analogues or 2 nucleoside analogues together with a protease inhibitor is more effective in suppressing HIV-induced cytopathic properties than monotherapy or a combination of 2 drugs.

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Pharmacokinetics

The active ingredient is well absorbed from the gastrointestinal tract, with a bioavailability rate of 60-70%. The peak plasma levels after taking a capsule of 5 mg/kg every 4 hours are 1.9 μg/l. The drug requires 0.5-1.5 hours to reach peak serum concentration.

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

The process of conjugation with glucuronic acid occurs inside the liver. The main breakdown product is 5-glucuronyl azidothymidine, which is excreted through the kidneys and has no antiviral properties. Zidovudine is excreted by the kidneys - 30% of the substance is excreted unchanged, and another 50-80% is excreted in the form of glucuronides.

The half-life of the active ingredient from serum, provided healthy renal function, is about 1 hour (for adults), and in case of renal dysfunction (with a CC value of less than 30 ml/minute), it is 1.4-2.9 hours. In children aged 2 weeks/13 years, this period is about 1-1.8 hours, and in adolescents aged 13-14 years, it is about 3 hours. In newborns whose mothers took the drug, this figure is approximately 13 hours.

The drug does not accumulate inside the body. In people suffering from liver failure or cirrhosis, accumulation may be observed due to a decrease in the intensity of the synthesis process with glucuronic acid. In patients with renal failure, decay products (conjugates with glucuronic acid) may accumulate, which increases the likelihood of developing a toxic effect.

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Dosing and administration

The treatment course should be supervised by a physician with experience in HIV treatment.

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

To ensure the use of a whole dose of the drug, it is necessary to swallow the capsule whole, without chewing or opening it. If the patient is unable to swallow the whole capsule, it is allowed to open it and then mix the contents with food or liquid (this portion must be eaten/drinked immediately after opening the capsule).

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

For children weighing 14-21 kg, the dose is 100 mg in the morning, then 200 mg before bedtime.

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

For children weighing less than 8 kg who are unable to swallow a whole capsule, the medicine is prescribed in the form of an oral solution.

To prevent the transfer of the virus from mother to fetus - for pregnant women (over 14 weeks), the daily dosage is 500 mg (100 mg 5 times a day) of the drug orally (treatment in this mode lasts until delivery). During delivery, Zidovudine in the form of an infusion solution is administered at a rate 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 prescribed as an oral solution in the amount of 2 mg/kg every 6 hours (start 12 hours after birth and continue until the child reaches 6 weeks of age). If oral administration of the drug is impossible, the child is given an infusion solution intravenously within half an hour - 1.5 mg/kg every 6 hours.

If a cesarean section is planned, the infusion should be started 4 hours before the operation. If false labor begins, the infusion of the drug should be stopped.

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Use Zidovudina during pregnancy

The drug has been shown to be able to penetrate the human placenta. Since there is limited information on the use of zidovudine in pregnant women, it is only permitted to be taken during pregnancy up to 14 weeks if the potential benefit to the woman outweighs the likelihood of adverse effects on the fetus.

There are reports of a moderate transient increase in serum lactate levels. This may be due to mitochondrial dysfunction that occurs in infants and neonates exposed to nucleoside reverse transcriptase inhibitors in utero or at birth. However, there are no data on the clinical significance of this finding.

There are also isolated data on developmental delays and various neurological pathologies. However, the relationship between these disorders and the action of nucleoside reverse transcriptase inhibitors during intrauterine development or at birth has not been established. This information does not affect the current recommendations for the use of antiretroviral drugs in pregnant women (to prevent vertical transmission of HIV infection).

Contraindications

Among the contraindications of the drug:

• the presence of hypersensitivity to zidovudine or other components of the drug;
• an excessively low neutrophil count (less than 0.75 x 10 9/L) or abnormally low hemoglobin levels in the blood (less than 7.5 g/dL or 4.65 mmol/L);
• the presence of hyperbilirubinemia in a newborn, requiring additional treatment methods other than phototherapy, or when the transaminase level increases by 5+ times above the norm.

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Side effects Zidovudina

As a result of using the drug, the following side effects may develop:

• cardiovascular system: chest pain, strong heartbeat and development of cardiomyopathy;
• organs of the lymphatic and hematopoietic systems: development of thrombocytopenia, leukopenia, neutro- or pancytopenia (with bone marrow hypoplasia);
• organs of the nervous system: dizziness with headaches, a feeling of drowsiness or, on the contrary, insomnia, deterioration of mental activity, development of seizures, paresthesia or tremor. In addition, the appearance of hallucinations, confusion, psychomotor agitation and problems with diction, development of encephalopathy or ataxia, as well as a comatose state;
• mental disorders: development of depression or anxiety;
• organs of the sternum with mediastinum and respiratory system: the appearance of cough or dyspnea;
• Gastrointestinal organs: abdominal pain, nausea, diarrhea, vomiting and bloating. In addition, dyspeptic symptoms, pigmentation of the oral mucosa, problems with swallowing, taste bud disorders and the development of gastritis or pancreatitis;
• digestive system organs: transient increase in the activity of liver enzymes, development of jaundice, hyperbilirubinemia, hepatitis, and also liver dysfunction (for example, severe hepatomegaly with steatosis);
• urinary system organs: increased concentration of creatinine and urea in the blood, and in addition, increased urination;
• musculoskeletal system and connective tissues: development of myopathy or myalgia;
• metabolic processes: development of anorexia, lactic acidosis or hyperlactatemia, and in addition, accumulation/redistribution of fat reserves in the body;
• mammary glands and reproductive system organs: development of gynecomastia;
• organs of the immune system, subcutaneous tissue, and skin: manifestations of intolerance - itching, rashes, angioedema, baldness, hyperemia and photosensitivity, as well as urticaria, severe sweating, as well as pigmentation of the nails and skin;
• others: increased fatigue, feeling of malaise, development of fever, chills, asthenia, and in addition, a flu-like syndrome, as well as the appearance of general pain.

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Overdose

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

In case of drug overdose, a thorough examination of the patient is required to identify possible symptoms of poisoning, and then prescribe the necessary supportive treatment.

Peritoneal dialysis and hemodialysis procedures have little effect on the excretion of zidovudine, but they increase the excretion of its glucuronide breakdown product.

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Interactions with other drugs

Zidovudine excretion occurs primarily through the conjugation process within the liver, converting it into an inactive glucuronide degradation product. Active components eliminated through hepatic metabolism are capable of inhibiting the metabolism of zidovudine.

There are no data on the effect of zidovudine on the pharmacokinetic properties of atovaquone, but it should be taken into account that the latter is able to reduce the metabolism rate of zidovudine relative to its glucuronide breakdown product (the AUC of the component increases by 33%, but the maximum plasma concentration of glucuronide decreases by 19%). With a daily dosage of atovaquone of 500 or 600 mg taken over a period of 3 weeks, in the treatment of acute pneumonia caused by Pneumocystis carinii, the frequency of adverse reactions increases individually. This is due to the increased zidovudine level in the blood plasma. With a long-term treatment course using atovaquone, it is necessary to carefully monitor the patient's condition.

Clarithromycin can reduce the absorption of zidovudine, which is why a 2-hour interval is required between taking these medications.

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

There is information about decreased blood levels of phenytoin in individual patients (when used in combination with zidovudine), although there is also information that one patient had, on the contrary, increased values. As a result, in case of simultaneous administration of these drugs, it is necessary to closely monitor phenytoin values.

When combined with methadone, valproic acid or fluconazole, the AUC of zidovudine increases with a corresponding decrease in its clearance coefficient. Since information is limited, the clinical significance of this fact is unknown. The patient should be closely monitored to promptly detect the presence of symptoms of zidovudine toxicity.

When zidovudine is used as part of combination therapy for HIV, an exacerbation of anemia symptoms has been observed, which is associated with the use of ribavirin (although the exact mechanism of this fact is still unclear). As a result, it is not recommended to combine these drugs. The doctor will need to prescribe an alternative analogue for combination antiretroviral treatment (if such has already been started) instead of zidovudine. This measure is especially important for people with a history of anemia caused by taking zidovudine.

Limited data indicate that probenecid may prolong the half-life and AUC of zidovudine and may also reduce glucuronidation. Renal excretion of glucuronide (and possibly zidovudine) is reduced by probenecid.

According to limited data, combination with rifampicin reduces the AUC of zidovudine by approximately 48%±34%, but the clinical significance of this fact could not be established.

When used in combination with stavudine, inhibition of the phosphorylation processes of this substance inside cells is possible. For this reason, 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, as well as lorazepam, dapsone, oxazepam, clofibrate, and cimetidine with isoprinosine (and other drugs)) can affect the metabolism of zidovudine by competitively inhibiting glucuronidation or directly inhibiting microsomal metabolism in the liver. Therefore, the possible effect of the combined use of these drugs should be taken into account, especially during chronic treatment.

Concomitant use (mainly in acute cases) with myelosuppressive or nephrotoxic drugs (for example, dapsone, biseptol and systemic pentamidine, as well as flucytosine, interferon and amphotericin with vincristine, as well as ganciclovir and doxorubicin with vinblastine) may cause an increase in the negative properties of zidovudine. If these drugs must be used simultaneously, careful monitoring of renal function and hematological parameters is required. If necessary, the dosage of both drugs or one of them should be reduced.

Because patients taking zidovudine may develop opportunistic infections, antimicrobial drugs are sometimes prescribed for prophylaxis. These include pyrimethamine, co-trimoxazole, and acyclovir with pentamidine (in aerosol form). Limited data from clinical trials indicate that the combination of these drugs does not increase the incidence of adverse reactions to zidovudine.

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Storage conditions

The medicine must be stored in conditions suitable for medicines, inaccessible to children. The temperature cannot exceed 25 ^o C.

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Shelf life

Zidovudine is permitted to be used for 2 years from the date of release of the drug.

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