Lamivudine and Zidovudine

Indications

• HIV infection in combination with other antiretroviral drugs
• Chronic hepatitis B infection with evidence of viral replication and active liver inflammation or fibrosis

Dosage

Children: For children aged 3 months to

Adults: For HIV infection, the adult dose is 150 mg every 12 hours or alternatively 300 mg once daily. For chronic hepatitis B, the recommended dose is 300 mg once daily.

Mechanism of action

Lamivudine is phosphorylated intracellularly to its active form, lamivudine triphosphate (L-TP). This active metabolite is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination. Lamivudine competes with deoxycytidine triphosphate for binding to reverse transcriptase, and its incorporation into DNA results in the disruption of DNA synthesis due to the absence of a 3'-OH group necessary for chain elongation.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), lamivudine disrupts the viral DNA synthesis pathway, particularly for HIV-1 and HBV. The active metabolite formed competes with natural nucleotides and incorporates into the growing viral DNA chain, ultimately leading to chain termination. This action inhibits the replication of the virus, thereby reducing viral load in infected individuals.

Pharmacokinetics

Lamivudine is absorbed via passive diffusion and is rapidly phosphorylated to its active triphosphate form within cells. Its bioavailability is approximately 80-85% when taken orally. The drug has a half-life of about 5-7 hours in plasma and is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. Renal impairment necessitates dose adjustments, particularly in patients with creatinine clearance below 50 mL/min.

Contra-indications

• Severe hypersensitivity to lamivudine or any of its excipients
• Patients with decompensated liver disease when used for chronic hepatitis B

Adverse effects

• Peripheral neuropathy
• Headache
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Malaise
• Cough
• Pharyngitis
• Respiratory tract infections
• Alopecia
• Arthralgia

Interactions

• Trimethoprim may increase exposure to lamivudine
• Concomitant use with other antiretroviral drugs should be evaluated for cross-resistance

Precautions

• Monitor liver function tests every 3 months in patients with chronic hepatitis B
• Recurrent hepatitis may occur upon discontinuation in chronic hepatitis B patients
• Use with caution in renal impairment; dose adjustments may be necessary if creatinine clearance is less than 50 mL/min

Pregnancy

Lamivudine is classified as category B, indicating that there are no known risks in humans, but caution should be exercised. It may be used during pregnancy if deemed necessary by the healthcare provider.

Breast-feeding

Lamivudine can be used with caution while breastfeeding, provided adequate measures are taken to prevent hepatitis B infection in infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Lamivudine 150 mg tablets
• Lamivudine 300 mg tablets
• Epivir 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

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination. Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

Pharmacodynamics

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.

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.