Pharmacology of Zidovudine

Introduction/Overview

Zidovudine, also known as azidothymidine (AZT), represents a cornerstone in the historical and contemporary management of human immunodeficiency virus (HIV) infection. As the first antiretroviral agent approved for clinical use by the United States Food and Drug Administration in 1987, its introduction marked a pivotal transition in the therapeutic approach to HIV/AIDS from purely supportive care to active antiviral intervention. The drug belongs to the nucleoside reverse transcriptase inhibitor class and continues to hold significant clinical relevance, particularly in specific populations and prophylaxis settings. Understanding its pharmacology is fundamental for healthcare professionals involved in the management of HIV and related conditions.

The clinical importance of zidovudine extends beyond its role as an early therapeutic agent. It remains a critical component in the prevention of maternal-to-child transmission of HIV, a key element in certain post-exposure prophylaxis regimens, and a viable component of combination antiretroviral therapy in resource-limited settings or specific clinical scenarios. Its pharmacodynamic and pharmacokinetic profile, characterized by both efficacy and a distinct set of adverse effects, necessitates a thorough comprehension to ensure safe and effective use.

Learning Objectives

• Describe the chemical classification of zidovudine and its place within the broader category of antiretroviral agents.
• Explain the detailed molecular mechanism of action by which zidovudine inhibits HIV-1 reverse transcriptase and the basis for viral selectivity and human toxicity.
• Outline the pharmacokinetic properties of zidovudine, including its absorption, distribution, metabolism, and excretion, and relate these to dosing regimens.
• Identify the approved therapeutic indications for zidovudine, including its use in combination therapy and for prophylaxis.
• Analyze the major adverse effects, drug interactions, and special population considerations associated with zidovudine therapy.

Classification

Zidovudine is classified primarily as an antiretroviral agent. Within this broad category, it belongs specifically to the nucleoside reverse transcriptase inhibitor (NRTI) class. NRTIs are analogues of the endogenous nucleosides required for viral DNA synthesis. They are also sometimes referred to as nucleoside analogues or competitive substrate inhibitors.

Chemical Classification

Chemically, zidovudine is a synthetic thymidine analogue. Its systematic name is 3′-azido-3′-deoxythymidine. The molecular structure differs from that of endogenous thymidine at the 3′ position of the deoxyribose sugar ring, where a hydroxyl (-OH) group is replaced by an azido (-N₃) group. This structural modification is fundamental to its mechanism of action. The chemical formula is C₁₀H₁₃N₅O₄, and it has a molecular weight of 267.24 g/mol. The presence of the azido group renders the molecule incapable of forming the 3′-5′ phosphodiester linkage necessary for DNA chain elongation, thereby acting as a chain terminator.

Mechanism of Action

The pharmacodynamic activity of zidovudine is centered on its inhibition of viral replication, specifically targeting the reverse transcription step crucial for the life cycle of retroviruses like HIV-1.

Molecular and Cellular Mechanisms

The mechanism is a multi-step process requiring intracellular activation. Zidovudine enters human cells via passive diffusion and, to a lesser extent, by nucleoside transporters. Once inside the host cell, primarily lymphocytes and macrophages, it undergoes phosphorylation by a series of cellular kinases. The initial phosphorylation to zidovudine monophosphate is catalyzed by thymidine kinase. Subsequent phosphorylations to the diphosphate and finally the active triphosphate form (zidovudine-triphosphate, AZT-TP) are mediated by thymidylate kinase and nucleoside diphosphate kinase, respectively. The rate-limiting step is generally considered to be the first phosphorylation by thymidine kinase.

AZT-TP, the active metabolite, competes with the natural substrate deoxythymidine triphosphate (dTTP) for incorporation into the growing viral DNA chain by HIV-1 reverse transcriptase (RT). The affinity of HIV-1 RT for AZT-TP is significantly higher than that of human cellular DNA polymerases, which provides a degree of selective toxicity. Upon incorporation, the absence of the 3′-hydroxyl group on the azide-modified sugar moiety prevents the formation of the next phosphodiester bond. This results in premature termination of the nascent viral DNA chain. The terminated DNA primer cannot be extended further, effectively halting the synthesis of proviral DNA and subsequent integration into the host genome.

Pharmacodynamic Considerations

The antiviral activity is considered virustatic, suppressing viral replication but not eradicating latent viral reservoirs. The chain-terminating action is specific to viral reverse transcriptase; however, at higher concentrations, AZT-TP may also inhibit mitochondrial DNA polymerase gamma, which is implicated in the drug’s characteristic toxicities such as myopathy and bone marrow suppression. The efficacy of zidovudine is significantly compromised by monotherapy due to the rapid emergence of resistant viral strains, characterized by specific mutations in the HIV-1 RT gene (e.g., M41L, D67N, K70R, T215F/Y, K219Q/E). Consequently, its clinical use is exclusively within combination antiretroviral therapy (cART) regimens, where multiple drugs with different mechanisms suppress replication and delay resistance.

Pharmacokinetics

The pharmacokinetic profile of zidovudine influences its dosing schedule, potential for interactions, and toxicity management.

Absorption

Zidovudine is administered orally or intravenously. Oral bioavailability is approximately 60-65%, but can exhibit significant inter-individual variability (range 40-75%). Absorption from the gastrointestinal tract is rapid, with peak plasma concentrations (C_max) achieved within 0.5 to 1.5 hours. The presence of food may delay absorption but does not significantly alter the overall extent of bioavailability (AUC). First-pass metabolism in the liver contributes to the reduced oral bioavailability.

Distribution

Zidovudine distributes widely into body tissues and fluids. The apparent volume of distribution is approximately 1.6 L/kg, indicating distribution beyond total body water. It crosses the blood-brain barrier effectively, with cerebrospinal fluid concentrations reaching about 50-60% of concurrent plasma levels. This property is pharmacologically significant given the sanctuary site of the central nervous system for HIV. The drug also crosses the placenta and is distributed into breast milk. Plasma protein binding is relatively low, at approximately 30-38%, suggesting that displacement interactions are unlikely to be clinically significant.

Metabolism

Hepatic metabolism is the primary route of elimination for zidovudine. It undergoes rapid and extensive first-pass and systemic glucuronidation by the enzyme UDP-glucuronosyltransferase 2B7 (UGT2B7) to its major, inactive metabolite, zidovudine glucuronide (G-AZT). This metabolite accounts for about 75% of the dose recovered in urine. A minor pathway involves reduction of the azido group to form 3′-amino-3′-deoxythymidine (AMT), which may contribute to some toxicities, though its clinical relevance remains under investigation. The cytochrome P450 enzyme system plays a negligible role in zidovudine metabolism.

Excretion

Renal excretion is the principal route of elimination for both the parent drug and its metabolites. Within 24 hours, approximately 70-75% of an administered dose is recovered in urine, with about 15-20% as unchanged zidovudine and the remainder as the glucuronide metabolite. The elimination half-life (t_1/2) of the parent drug is relatively short, ranging from 0.5 to 3 hours. However, the intracellular half-life of the active triphosphate metabolite (AZT-TP) is considerably longer, approximately 3 to 4 hours in peripheral blood mononuclear cells, which allows for less frequent dosing than the plasma half-life might suggest.

Pharmacokinetic Parameters and Dosing

Standard adult oral dosing is 250-300 mg twice daily when used in combination therapy. The relationship between dose and plasma concentration is linear within the therapeutic range. The short plasma half-life historically prompted more frequent dosing; however, the prolonged intracellular half-life of AZT-TP supports twice-daily administration. Clearance of zidovudine is primarily via hepatic glucuronidation and renal excretion of metabolites. Total body clearance is high, typically around 1.6 L/h/kg. The area under the curve (AUC) is proportional to dose administered, following the relationship AUC = Dose ÷ Clearance.

Therapeutic Uses/Clinical Applications

Zidovudine is employed in specific, well-defined clinical contexts within HIV management.

Approved Indications

• Combination Antiretroviral Therapy (cART) for HIV-1 Infection: Zidovudine is used in combination with other antiretroviral agents (typically a second NRTI and an agent from another class, such as an integrase strand transfer inhibitor or a protease inhibitor) for the treatment of HIV-1 infection in adults and children. Its use in initial therapy in high-resource settings has declined in favor of NRTIs with better tolerability profiles (e.g., tenofovir, abacavir), but it remains a recommended or alternative component in certain guidelines and is widely used globally.
• Prevention of Maternal-to-Child Transmission (PMTCT): This represents one of the most critical and enduring uses of zidovudine. Administered to the HIV-positive pregnant person during the second and third trimesters, intravenously during labor, and to the neonate for the first 6 weeks of life, this regimen can reduce the transmission risk from approximately 25% to less than 2%. It may be used as part of a combination prophylaxis regimen.
• Post-Exposure Prophylaxis (PEP): Zidovudine is a component of certain regimens for occupational (e.g., needlestick injury) and non-occupational exposure to HIV-infected blood or body fluids, although newer agents are often preferred.
• Pre-Exposure Prophylaxis (PrEP) in Specific Contexts: While not a standard component of contemporary oral PrEP, historical studies established proof-of-concept for chemoprophylaxis using zidovudine monotherapy.

Off-Label Uses

Off-label use is not common for zidovudine, given the specificity of its indication. It has been investigated historically in other retroviral infections, such as Human T-lymphotropic virus (HTLV-1), but with limited established efficacy. Its use is strictly confined to HIV management and prophylaxis.

Adverse Effects

The adverse effect profile of zidovudine is well-characterized and often dose-related, influencing its tolerability and clinical utility.

Common Side Effects

Frequently observed adverse effects, particularly during initial therapy, include headache, nausea, malaise, myalgia, and insomnia. These symptoms often diminish in severity after several weeks of continuous therapy. Gastrointestinal disturbances such as nausea are reported in a substantial proportion of patients.

Serious and Dose-Limiting Adverse Reactions

• Hematologic Toxicity: This is the most significant dose-limiting toxicity. It manifests as macrocytic anemia (often with a mean corpuscular volume increase > 100 fL) and neutropenia. The anemia is typically normochromic and macrocytic, resulting from bone marrow suppression and interference with erythroid maturation. Granulocytopenia also occurs and increases the risk of bacterial infections. These effects are often reversible upon dose reduction or discontinuation.
• Myopathy and Myositis: With prolonged use, a toxic myopathy characterized by muscle wasting, weakness, and elevated creatine kinase levels may develop. This is associated with the inhibition of mitochondrial DNA polymerase gamma, leading to mitochondrial dysfunction and depletion.
• Lactic Acidosis with Hepatic Steatosis: A rare but potentially fatal class effect of NRTIs, linked to mitochondrial toxicity. It presents with nonspecific symptoms like nausea, vomiting, abdominal pain, and lethargy, progressing to tachypnea and metabolic acidosis. Hepatomegaly with steatosis may be present.
• Lipoatrophy: Subcutaneous fat loss, particularly from the face, limbs, and buttocks, is associated with long-term use of older NRTIs including zidovudine.
• Hyperpigmentation: Nail and mucosal hyperpigmentation may occur, particularly in patients with darker skin tones.

Black Box Warnings

The prescribing information for zidovudine carries several boxed warnings, the strongest safety alert mandated by regulatory agencies. These include:

1. Hematologic Toxicity: Severe anemia and neutropenia, requiring frequent blood monitoring.
2. Myopathy: Associated with prolonged use.
3. Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported.

Drug Interactions

Zidovudine participates in several clinically significant pharmacokinetic and pharmacodynamic interactions.

Major Drug-Drug Interactions

• Other Myelosuppressive or Neurotoxic Agents: Concomitant use with drugs like ganciclovir, valganciclovir, interferon-alpha, ribavirin, or cytotoxic chemotherapy may produce additive hematologic toxicity (severe anemia and/or neutropenia) or neurotoxicity. Concurrent use requires enhanced monitoring.
• Drugs Affecting Glucuronidation: Agents that inhibit UGT2B7, such as probenecid, valproic acid, and certain NSAIDs (e.g., fluconazole at high doses), can decrease the clearance of zidovudine, leading to increased plasma concentrations and a heightened risk of toxicity. Probenecid is known to increase the AUC of zidovudine by approximately 80%.
• Drugs that Induce Glucuronidation: Rifampicin and other enzyme inducers may increase the metabolism of zidovudine, potentially reducing its plasma concentrations and efficacy. Dose adjustment may be necessary.
• Stavudine (d4T): Concurrent use with stavudine is contraindicated due to pharmacodynamic antagonism; both drugs compete for intracellular phosphorylation and their co-administration results in reduced activation of both agents.
• Doxorubicin: Concomitant use may increase the risk of hematologic toxicity.

Contraindications

Absolute contraindications to zidovudine therapy are relatively few but critical. These include:

• Life-threatening hypersensitivity reactions to zidovudine or any component of the formulation.
• Concomitant use with stavudine, due to antagonism.
• Severe hepatic impairment without careful risk-benefit assessment, due to the risk of lactic acidosis.

Special Considerations

The use of zidovudine requires careful evaluation in specific patient populations due to altered pharmacokinetics, increased risk of toxicity, or unique benefit-risk profiles.

Use in Pregnancy and Lactation

Pregnancy: Zidovudine is classified as Pregnancy Category C (under the former FDA classification system) due to evidence of carcinogenicity in rodent studies at high doses. However, extensive human data from the Pediatric AIDS Clinical Trials Group Protocol 076 and subsequent studies have established its safety and critical efficacy in preventing perinatal transmission. It is recommended for use in pregnant individuals with HIV as part of combination ART, with the benefits of viral suppression and transmission prevention outweighing potential risks. Pharmacokinetic studies indicate that pregnancy does not significantly alter zidovudine clearance, and standard dosing is generally employed.

Lactation: Zidovudine is excreted into human breast milk. The Centers for Disease Control and Prevention and the World Health Organization recommend that HIV-positive individuals in resource-rich settings avoid breastfeeding to prevent postnatal transmission, regardless of maternal antiretroviral therapy. In resource-limited settings where replacement feeding is not safe or sustainable, exclusive breastfeeding with ongoing maternal ART is recommended. The relative infant dose of zidovudine via milk is considered low, but the risk of HIV transmission remains the paramount concern.

Pediatric Considerations

Zidovudine is approved for use in neonates and children. Pharmacokinetics in children differ from adults; oral clearance is more rapid, and the volume of distribution per kilogram is larger, often necessitating higher weight-based or body surface area-based dosing (e.g., 160 mg/m² every 8 hours) to achieve therapeutic exposure. It is available as a syrup formulation for pediatric use. Monitoring for hematologic toxicity is essential, and dose adjustment may be required. Its use in perinatal prophylaxis is standard of care.

Geriatric Considerations

Clinical studies of zidovudine did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently. In general, elderly patients may have decreased renal function or concomitant diseases, and may be taking multiple medications. Since zidovudine and its metabolites are renally excreted, and because the elderly may have a higher likelihood of decreased hepatic or renal function, caution should be exercised in dose selection. Monitoring of renal function and hematologic parameters is prudent.

Renal Impairment

While zidovudine itself is not primarily excreted unchanged by the kidneys, its primary metabolite (G-AZT) accumulates in patients with renal impairment. Although G-AZT is considered inactive, its accumulation may be associated with increased toxicity, though data are not conclusive. Dose adjustment is not routinely recommended for mild to moderate renal impairment. In patients with end-stage renal disease (ESRD) on hemodialysis, the clearance of both zidovudine and its glucuronide is enhanced during dialysis. A standard dose is typically given after hemodialysis on dialysis days. Close monitoring for hematologic toxicity is advised in all patients with significant renal dysfunction.

Hepatic Impairment

Hepatic impairment can significantly affect zidovudine pharmacokinetics due to reduced glucuronidation capacity. Patients with moderate to severe hepatic impairment may experience decreased clearance of zidovudine, leading to increased plasma levels and a higher risk of toxicity, particularly lactic acidosis and hepatic steatosis. Dose reduction may be necessary, and these patients require frequent clinical and laboratory monitoring. Zidovudine is generally contraindicated in patients with severe hepatic impairment or a history of lactic acidosis while on NRTIs.

Summary/Key Points

• Zidovudine is a nucleoside reverse transcriptase inhibitor (NRTI) and a synthetic thymidine analogue that acts as a chain terminator of viral DNA synthesis following intracellular phosphorylation to its active triphosphate form.
• Its pharmacokinetics are characterized by good oral bioavailability, wide tissue distribution including the CNS, extensive hepatic glucuronidation, and renal excretion of metabolites. The intracellular half-life of the active moiety permits twice-daily dosing.
• Primary clinical uses include combination antiretroviral therapy for HIV-1, prevention of maternal-to-child transmission, and as a component of certain post-exposure prophylaxis regimens.
• The most significant adverse effects are hematologic toxicity (macrocytic anemia, neutropenia), myopathy, and the risk of lactic acidosis with hepatic steatosis, necessitating regular monitoring.
• Major drug interactions involve other myelosuppressive agents, drugs that inhibit glucuronidation (e.g., probenecid), and pharmacodynamic antagonism with stavudine.
• Special consideration is required in pregnancy (where benefits for PMTCT are clear), pediatrics (different pharmacokinetics), and in patients with hepatic or renal impairment due to altered drug clearance.

Clinical Pearls

• Macrocytosis (elevated MCV) is an expected, non-progressive effect of zidovudine therapy and is not in itself an indication for discontinuation unless accompanied by symptomatic anemia.
• The development of significant myalgia or muscle weakness on long-term therapy should prompt evaluation for zidovudine-associated myopathy, including creatine kinase measurement.
• In patients receiving concomitant probenecid, a reduction in zidovudine dose may be necessary to avoid toxicity.
• For occupational exposure PEP regimens, zidovudine-based combinations are effective, but local guidelines favoring newer agents with better tolerability should be consulted.
• The success of the zidovudine PMTCT regimen underscores the principle that even a single antiretroviral agent can be highly effective for prophylaxis in a time-limited setting, unlike the lifelong combination therapy required for chronic infection.

References

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