Zidovudine oral solution

Indications

• HIV infection
• Prevention of maternal-fetal HIV transmission

Dosage

Children: Refer to BNF for Children for appropriate dosing information.

Adults: 250–300 mg twice daily; for prevention of maternal-fetal transmission, seek specialist advice.

Mechanism of action

Zidovudine is a structural analog of thymidine. It is phosphorylated to its active triphosphate metabolite, zidovudine triphosphate (ZDV-TP), which inhibits HIV-1 reverse transcriptase by competing with the natural substrate dGTP and causing DNA chain termination upon incorporation into the viral DNA. While it has some inhibitory effects on mammalian DNA polymerases, its primary action is on the viral reverse transcriptase due to a higher affinity for the viral enzyme compared to cellular enzymes.

Pharmacodynamics

As an NRTI, zidovudine demonstrates antiviral activity against HIV-1 by competitively inhibiting the reverse transcriptase enzyme. The incorporation of zidovudine triphosphate into viral DNA prevents the formation of the essential phosphodiester bonds, terminating DNA synthesis. This mechanism leads to a decrease in viral load and assists in the management of HIV infection.

Pharmacokinetics

Zidovudine is rapidly absorbed following oral administration, with peak plasma concentrations occurring within 30 to 90 minutes. It is extensively metabolized in the liver, primarily via glucuronidation, and has a half-life of approximately 1 hour. The drug is excreted mainly in the urine as metabolites. Dosage adjustments may be necessary in patients with renal impairment due to increased risk of accumulation.

Contra-indications

• Severe hypersensitivity to zidovudine or any excipient
• Significant anemia or neutropenia
• Severe hepatic impairment

Adverse effects

• Common: Leucopenia, malaise, myalgia, neutropenia
• Uncommon: Bone marrow disorders, dyspnoea, fever, generalised pain, myopathy
• Rare: Alertness decreased, anxiety, appetite decreased, cardiomyopathy, chest pain, chills, cough, depression, drowsiness, dyspepsia, gynaecomastia
• Very rare: Lipoatrophy, metabolic effects including hyperlipidaemia and hyperglycaemia

Interactions

• Ribavirin: Severe interaction increasing risk of anaemia and/or leucopenia
• Leflunomide: Unknown interaction but may increase exposure
• Teriflunomide: Unknown interaction but may increase exposure

Precautions

• Use with caution in patients with pre-existing liver disease, including hepatomegaly and hepatitis
• Monitor for symptoms of hyperlactataemia, lactic acidosis, and progressive hepatomegaly
• Regular monitoring of blood counts recommended due to risk of myelosuppression

Pregnancy

Zidovudine is classified as a Category C drug. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Zidovudine is recommended for the prevention of maternal-fetal transmission of HIV.

Breast-feeding

Zidovudine is excreted in breast milk. The decision to breastfeed should take into account the mother's need for the drug and any potential adverse effects on the breastfed infant.

Storage

Store at room temperature between 15°C to 30°C. Protect from light and moisture. Keep out of reach of children.

Formulations

• Oral tablet: 100 mg, 300 mg
• Oral solution: 10 mg/mL
• Intravenous solution: 200 mg/20 mL

Mechanism of action

Zidovudine, a structural analog of thymidine, is a prodrug that must be phosphorylated to its active 5′-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). It inhibits the activity of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. It competes with the natural substrate dGTP and incorporates itself into viral DNA. It is also a weak inhibitor of cellular DNA polymerase α and γ. Zidovudine triphosphate can bind to and inhibit some mammalian cellular DNA polymerases, particularly beta- and gamma- polymerases, in vitro. However, zidovudine triphosphate appears to have a much greater affinity for viral RNA-directed DNA polymerase than for mammalian DNA polymerases. /Zidovudine triphosphate/ ... The antiretroviral activity of zidovudine appears to depend on intracellular conversion of the drug to a triphosphate metabolite; thus zidovudine triphosphate and not unchanged zidovudine appears to be the pharmacologically active form of the drug. Zidovudine is converted to zidovudine monophosphate by cellular thymidine kinase; the monophosphate is phosphorylated to zidovudine diphosphate via cellular thymidylate kinase and then to the triphosphate via other cellular enzymes. ... Conversion of the drug to the active triphosphate derivative occurs in both virus infected and uninfected cells. ... Zidovudine triphosphate appears to compete with thymidine triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA. Following incorporation of zidovudine triphosphate into the viral DNA chain instead of thymidine triphosphate, DNA synthesis is prematurely terminated because the 3'-azido group of zidovudine prevents further 5' to 3' phosphodiester linkages. In addition, zidovudine monophosphate competitively inhibits thymidylate kinase, resulting in decreased formation of thymidine triphosphate; thus, the drug can decrease concentrations of this natural substrate for RNA-directed DNA polyerase and facilitate binding of zidovudine triphosphate to the enzyme. The drug also appears to decrease 2'-deoxycytidine triphosphate concentrations, but the mechanism of this effect is not known. ... Antibacterial action of zidovudine appears to result from premature termination of bacterial DNA synthesis secondary to incorporation of phosphorylated zidovudine in the bacterial DNA chain. In vitro exposure of susceptible bacteria to the drug results in bacterial elongation and death secondary to cell lysis. ... The antibacterial action appears to depend on conversion of zidovudine to the active phosphorylated form via bacterial enzymes rather than via host enzymes. Zidovudine monophosphate, diphosphate, and triphosphate exhibit antibacterial activity in vitro with the triphosphate being most active and the monophosphate being least active. Susceptibility of bacteria to zidovudine appears to depend in large part on the presence of bacterial thymidine kinase. ... Organisms lacking thymidine kinase ... have been resistant to zidovudine, while those with relatively high concentrations of the enzyme ... have been highly susceptible to the drug; in addition, mutants resistant to the drug have had relatively low concentrations of the enzyme. The antibacterial activity of zidovudine also appears to depend in part on other factors such as permeability of the organism to the drug. Zidovudine appears to alter nucleoside metabolism within host cells, resulting in decreased levels of thymidine triphosphate, 2'-deoxycytidine triphosphate, and several other deoxynucleoside triphosphates.

Pharmacodynamics

Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Zidovudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.