A Comprehensive Monograph on Zidovudine (DB00495): From Historical Landmark to Modern Clinical Practice

Executive Summary

Zidovudine, chemically known as 3'-azido-3'-deoxythymidine and widely recognized by the abbreviation AZT, represents a landmark molecule in the history of medicine and the fight against the Human Immunodeficiency Virus (HIV). As a small molecule drug classified as a nucleoside reverse transcriptase inhibitor (NRTI), its mechanism of action involves intracellular phosphorylation to an active triphosphate metabolite, which then inhibits the HIV-1 reverse transcriptase enzyme and terminates viral DNA chain synthesis. This report provides a comprehensive, expert-level monograph on Zidovudine, synthesizing data on its historical significance, physicochemical properties, complex pharmacology, clinical applications, and detailed safety profile.

First synthesized in 1964 as a potential anticancer agent and later abandoned, Zidovudine was rediscovered in the mid-1980s as a potent inhibitor of HIV replication. Its subsequent development and approval by the U.S. Food and Drug Administration (FDA) on March 19, 1987, under the brand name Retrovir, was unprecedented in its speed. This was driven by the urgent public health crisis of the AIDS epidemic and dramatic, albeit preliminary, clinical trial results showing a significant survival benefit. Zidovudine was the first approved therapy for HIV/AIDS, fundamentally transforming the disease from a universally fatal diagnosis into a treatable condition.

The initial use of Zidovudine as a high-dose monotherapy was fraught with challenges, most notably severe dose-limiting toxicities—primarily bone marrow suppression (anemia and neutropenia) and mitochondrial toxicity (myopathy, lactic acidosis)—and the rapid emergence of viral resistance. The failure of monotherapy was a seminal lesson in virology, empirically demonstrating the necessity of combination antiretroviral therapy (cART). Consequently, Zidovudine evolved to become a key component of the first multi-drug regimens, a paradigm that remains the standard of care for HIV treatment today.

Clinically, Zidovudine is indicated for the treatment of HIV-1 infection in adults and children (in combination with other agents) and, most notably, for the prevention of perinatal (mother-to-child) transmission of HIV. While its significant toxicity profile has led to its replacement by safer and better-tolerated agents in most first-line treatment guidelines, its role in preventing vertical transmission remains a historic public health achievement. Its pharmacokinetic profile is characterized by good oral absorption, broad tissue distribution, including into sanctuary sites like the central nervous system and semen, and primary clearance through hepatic glucuronidation and renal excretion. Dosing requires careful adjustment in special populations, including neonates and patients with renal or hepatic impairment, to mitigate the risk of toxicity.

This report concludes that while Zidovudine's role in the modern HIV treatment arsenal is now limited, its legacy is profound and multifaceted. It served as the first weapon against a global pandemic, taught the medical community invaluable lessons about viral resistance and the importance of combination therapy, catalyzed a new era of patient activism that reshaped the drug development landscape, and remains a textbook example of mechanism-based drug toxicity and the shifting calculus of risk versus benefit in medicine.

Historical Context and Developmental Significance: The Dawn of Antiretroviral Therapy

The story of Zidovudine is inextricably linked with the fear, urgency, and scientific mobilization that defined the early years of the HIV/AIDS epidemic. Its journey from a forgotten laboratory compound to the first beacon of hope for millions is a defining chapter in modern medicine, marked by scientific ingenuity, regulatory flexibility, intense controversy, and the powerful influence of patient advocacy.

From Oncology Failure to Antiviral Hope

Zidovudine's origins lie not in virology, but in cancer research. The compound, 3'-azido-3'-deoxythymidine, was first synthesized in 1964 by Dr. Jerome Horowitz at the Detroit Institute of Cancer Research.[1] The scientific rationale was to create an antimetabolite, a "fraudulent" building block of DNA, that would be incorporated into the genetic material of rapidly dividing cancer cells and halt their replication.[1] However, when tested in mouse models, the compound proved ineffective against cancer and was subsequently shelved, its formula residing in the public domain for two decades.[1]

In the early 1980s, as the world grappled with the emergence of a mysterious and devastating new illness—Acquired Immunodeficiency Syndrome (AIDS)—the scientific community raced to identify its cause. Once the Human Immunodeficiency Virus (HIV) was identified as the causative retrovirus in 1983-1984, the search for a treatment began with desperate urgency. At the pharmaceutical company Burroughs Wellcome (now part of GlaxoSmithKline) and the U.S. National Cancer Institute (NCI), researchers led by Dr. Samuel Broder initiated a massive screening program, testing thousands of existing compounds for any activity against HIV.[2]

In 1984, drawing on its expertise in antiviral drug development, Burroughs Wellcome resynthesized Horowitz's shelved compound, then known internally as Compound S.[5] In laboratory assays, it demonstrated remarkably potent activity, inhibiting the replication of HIV in vitro.[2] The azido group at the 3' position of the sugar ring, which made it a poor anticancer agent, was perfectly suited to disrupt the action of reverse transcriptase, the unique enzyme HIV uses to convert its RNA genome into DNA within human cells. This discovery transformed an abandoned molecule into the world's most promising candidate for the first-ever AIDS treatment.

The Controversial and Accelerated Path to Approval

The social and political climate of the mid-1980s cannot be overstated. With no available treatments, an AIDS diagnosis was a death sentence. This created immense public pressure on regulatory bodies, particularly the U.S. Food and Drug Administration (FDA), to abandon traditional, lengthy review processes and deliver a therapeutic solution.[1]

Human clinical trials for Zidovudine began in mid-1985.[6] A pivotal, multicenter, double-blind, placebo-controlled trial was launched to test the drug's efficacy in nearly 300 patients with advanced AIDS or AIDS-Related Complex (ARC).[1] The results were dramatic and swift. After only 16 to 19 weeks, an independent data and safety monitoring board recommended that the trial be stopped prematurely.[1] The reason was a stark difference in mortality: in that short period, 19 patients in the placebo group had died, compared to only one patient in the Zidovudine group.[1]

This profound survival benefit, coupled with intense pressure from patient activists and public health officials, led the FDA to approve Zidovudine in record time. On March 19, 1987, just 20 months after the start of major trials, Zidovudine was approved under the brand name Retrovir.[1] This was a fraction of the typical 8-to-10-year drug development timeline.[1] The initial approval was for a narrow indication: the management of adult patients with symptomatic HIV infection who had either a history of

Pneumocystis carinii pneumonia (PCP) or a CD4+ T-cell count below 200 cells/mm³.[8] Prior to this, on July 17, 1985, Zidovudine had been granted an Orphan Drug designation for the treatment of AIDS, a status intended to encourage the development of drugs for rare diseases.[8]

The approval, while celebrated as a breakthrough, remains one of the most controversial in FDA history. Critics argued that the trial was stopped too early, preventing the collection of long-term efficacy and safety data. Questions were raised about the trial's blinding, with some suggesting that the drug's distinct side effects may have allowed patients and doctors to guess their treatment assignment. The episode highlighted the profound ethical dilemmas of conducting placebo-controlled trials for a fatal disease when a promising, albeit unproven, therapy emerges.[1]

The developmental trajectory of Zidovudine cannot be fully understood without considering the powerful influence of patient advocacy groups. The AIDS crisis spurred the rise of sophisticated and vocal patient activism, most notably through organizations like the AIDS Coalition to Unleash Power (ACT UP). The initial pricing of Zidovudine at approximately $8,000 per year (over $17,000 in today's currency) made it the most expensive drug in history at the time and inaccessible to many.[1] This, combined with the controversies surrounding its trial and its severe side effects, galvanized activists. They staged massive protests, demanding lower prices and greater access. This activism fundamentally reshaped the relationship between patients, pharmaceutical companies, and regulatory agencies. It forced the FDA to create new pathways for accelerated approval and to incorporate patient perspectives into the drug development process, a legacy that endures across all fields of medicine.

Evolution in Clinical Practice and Legacy

Initially, Zidovudine was administered as a high-dose monotherapy, with daily doses often reaching 1200 mg or 1500 mg.[9] While it provided a clear, short-term clinical benefit by reducing opportunistic infections and prolonging survival, this approach was associated with severe toxicity and, critically, was ultimately unsustainable.[7]

Within a few years of its introduction, clinicians observed that many patients who initially responded well to Zidovudine would eventually relapse, their viral loads rebounding and their clinical condition deteriorating.[1] This clinical observation led to a seminal discovery in virology: the rapid emergence of drug-resistant HIV. Research revealed that under the selective pressure of the drug, the HIV reverse transcriptase enzyme was accumulating a series of specific genetic mutations, now known as Thymidine Analogue Mutations (TAMs), at codons 41, 67, 70, 210, 215, and 219.[9] These mutations altered the enzyme's structure, reducing its affinity for Zidovudine and rendering the drug ineffective.[2]

The failure of Zidovudine monotherapy provided an invaluable, albeit harsh, lesson. It empirically proved that targeting a highly mutable retrovirus like HIV at a single point in its lifecycle was a flawed strategy. This understanding of viral genetics and resistance became the foundational principle for a new treatment paradigm: combination antiretroviral therapy (cART), or what was then called Highly Active Antiretroviral Therapy (HAART). By combining Zidovudine with other NRTIs (such as didanosine, zalcitabine, and lamivudine) and, later, drugs from different classes like protease inhibitors, clinicians could attack the virus at multiple steps simultaneously.[2] This multi-pronged attack made it statistically improbable for the virus to develop all the necessary resistance mutations at once, leading to durable viral suppression.

While the development of safer, more potent, and more convenient antiretroviral agents has largely relegated Zidovudine from first-line therapy in most parts of the world, its historical importance is undiminished. It was the drug that first turned the tide against AIDS. Furthermore, its demonstrated ability to dramatically reduce mother-to-child transmission of HIV in the landmark ACTG 076 trial was a monumental public health victory, saving countless lives and establishing a new standard of care for pregnant women living with HIV.[11] Zidovudine was not just a drug; it was a scientific, social, and political catalyst that changed the course of a global pandemic.

Physicochemical Profile and Pharmaceutical Formulations

A thorough understanding of Zidovudine's physicochemical characteristics is fundamental to appreciating its formulation, pharmacokinetics, and biological activity. This section provides a detailed technical characterization of the Zidovudine drug substance and its marketed pharmaceutical products.

Chemical Identity and Structure

Zidovudine is a synthetic small molecule belonging to the class of pyrimidine 2',3'-dideoxyribonucleosides.[13] Its identity is precisely defined by a set of internationally recognized identifiers.

• DrugBank ID: DB00495 [User Query]
• CAS Number: 30516-87-1 [13]
• Chemical Name: The most common chemical name is 3'-azido-3'-deoxythymidine.[13]
• IUPAC Name: According to the rules of the International Union of Pure and Applied Chemistry, its systematic name is 1--5-methylpyrimidine-2,4-dione.[13]
• Synonyms and Abbreviations: In clinical and research literature, it is widely known by several names, including the abbreviations ZDV and AZT (for azidothymidine). Other identifiers include the code names BW-A509U and NSC 602670.[9]
• Molecular Formula: The empirical formula for Zidovudine is C10​H13​N5​O4​.[13]
• Structural Description: Zidovudine is a structural analogue of the endogenous nucleoside thymidine. Its defining chemical feature, which is responsible for its mechanism of action, is the substitution of the hydroxyl (−OH) group at the 3' position of the deoxyribose sugar moiety with an azido (−N3​) group. This modification prevents the formation of phosphodiester linkages necessary for DNA chain elongation.[13] The molecule consists of a pyrimidine base (thymine) linked to this modified sugar.

Physicochemical Properties

The physical and chemical properties of Zidovudine dictate its behavior in biological systems and its suitability for pharmaceutical formulation.

• Molecular Weight: The average molecular mass is approximately 267.24 g/mol.[5]
• Appearance: In its pure form, Zidovudine is a white to off-white crystalline powder or presents as needles.[3]
• Melting Point: The reported melting point range is between 106 °C and 122 °C, depending on the crystallization solvent.[3]
• Solubility: Zidovudine exhibits good solubility in water, reported as 25 mg/mL at 25 °C, and is also soluble in ethanol.[3] Its Biopharmaceutics Classification System (BCS) class is reported as 1 or 3, indicating high solubility.[16]
• Acidity (pKa): The dissociation constant (pKa​) is reported in the range of 9.53 to 9.96, reflecting the weakly acidic nature of the imide proton on the thymine ring.[3]
• Lipophilicity (LogP): The partition coefficient (LogP) values are consistently negative, around -0.1, indicating that the molecule is hydrophilic (more soluble in water than in lipids).[14] This property, along with others, contributes to its favorable "drug-like" profile, meeting the criteria of Lipinski's Rule of Five with zero violations.[18]
• Stability: The compound is sensitive to light and is hygroscopic (tends to absorb moisture from the air). When stored properly, the supplied drug substance is stable for at least two years.[16]

The favorable physicochemical properties of Zidovudine were a crucial, albeit fortuitous, factor in its rapid clinical development. A successful drug for a chronic condition like HIV ideally requires oral administration for outpatient management. Zidovudine's good water solubility and hydrophilic nature allow for reliable absorption from the gastrointestinal tract and high oral bioavailability. This enabled the straightforward development of multiple dosage forms, including oral capsules for adults and a liquid solution for pediatric patients, which was essential for its widespread adoption as the first-line treatment in the late 1980s and early 1990s. Its inherent "drug-like" characteristics were a key practical advantage for a repurposed compound.

Table 1: Physicochemical and Structural Identifiers of Zidovudine

Property	Value	Source(s)
DrugBank ID	DB00495	[User Query]
CAS Number	30516-87-1	15
IUPAC Name	1--5-methylpyrimidine-2,4-dione	13
Common Synonyms	AZT, ZDV, 3'-azido-3'-deoxythymidine, Retrovir	9
Molecular Formula	C10​H13​N5​O4​	15
Molecular Weight	267.24 g/mol	13
Appearance	White to off-white crystalline powder	3
Melting Point	106-122 °C	3
Water Solubility	25 mg/mL (at 25 °C)	3
pKa	9.68	3
LogP	~ -0.1	14
Canonical SMILES	CC1=CN(C(=O)NC1=O)C2CC(C(O2)CO)N=[N+]=[N-]	18
InChIKey	HBOMLICNUCNMMY-XLPZGREQSA-N	18

Pharmaceutical Formulations and Manufacturers

Zidovudine has been marketed globally in various formulations to meet the needs of different patient populations.

• Brand Names: The original and most recognized brand name is Retrovir, marketed by ViiV Healthcare.[8] A foreign brand name is Aztec.[17]
• Available Forms: Zidovudine is available by prescription in several dosage forms:
• Oral Capsules: Typically containing 100 mg of Zidovudine.[9]
• Oral Solution/Syrup: A liquid formulation, usually at a concentration of 10 mg/mL (50 mg per 5 mL), which is critical for pediatric dosing.[3]
• Intravenous (IV) Injection: A solution for infusion, typically 10 mg/mL, used for patients who cannot take oral medication and for intrapartum administration during labor to prevent mother-to-child transmission.[3]
• Oral Tablets: A 300 mg tablet formulation was previously available but has since been discontinued in many markets due to shifts in treatment practices.[9]
• Fixed-Dose Combination Tablets: To simplify treatment regimens, Zidovudine is a component of co-formulated tablets, most notably Combivir (Zidovudine/lamivudine) and Trizivir (Zidovudine/lamivudine/abacavir).[11]
• Major Manufacturers:
• Brand (Retrovir): The innovator product is manufactured and marketed by ViiV Healthcare, a specialist HIV company established through a partnership between GlaxoSmithKline (GSK), Pfizer, and Shionogi.[6]
• Generic: Following patent expiry, several companies began producing generic versions of Zidovudine, making the treatment more affordable and accessible globally. Major generic manufacturers include Indian pharmaceutical companies such as Aurobindo Pharma and Cipla.[25]
• Active Pharmaceutical Ingredient (API) Suppliers: The global supply chain for the Zidovudine API is robust, with key producers located in India (e.g., Hetero Labs, Mylan) and China (e.g., Sinoway Industrial, Shanghai Acebright, Shanghai Desano Chem).[30]

Comprehensive Pharmacological Profile

The therapeutic and toxic effects of Zidovudine are dictated by its complex interactions with both viral and host cellular machinery. A detailed understanding of its pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drug) is essential for its safe and effective clinical use.

Mechanism of Action (Pharmacodynamics)

Zidovudine functions as a highly specific inhibitor of the HIV life cycle through a multi-step intracellular process.

Prodrug Activation

Zidovudine itself is an inactive prodrug. To exert its antiviral effect, it must first be converted into its pharmacologically active form, zidovudine-5'-triphosphate (ZDV-TP), through anabolic phosphorylation by host cell enzymes within lymphocytes.[15] This is a sequential, three-step enzymatic cascade:

1. Zidovudine is first converted to zidovudine-5'-monophosphate (ZDV-MP). This initial step is catalyzed primarily by the cellular enzyme thymidine kinase 1 (TK1).[21]
2. ZDV-MP is then phosphorylated to zidovudine-5'-diphosphate (ZDV-DP) by thymidylate kinase. This conversion is the slowest and therefore the rate-limiting step in the activation pathway, controlling the overall production of the active metabolite.[21]
3. Finally, ZDV-DP is converted to the active ZDV-TP by nucleoside diphosphate kinase.[15]

Inhibition of HIV-1 Reverse Transcriptase (RT)

The active ZDV-TP metabolite disrupts HIV replication via a dual mechanism targeting the viral reverse transcriptase (RT) enzyme, which is essential for creating a DNA copy of the viral RNA genome.[21]

1. Competitive Inhibition: ZDV-TP structurally mimics the natural nucleoside, deoxythymidine triphosphate (dTTP). It therefore acts as a competitive inhibitor, binding to the active site of HIV-1 RT and preventing the natural substrate from being incorporated into the newly synthesized viral DNA.[21] The basis for Zidovudine's therapeutic window lies in its selectivity; ZDV-TP has an approximately 100-fold greater affinity for HIV RT than for the primary human DNA polymerase (polymerase alpha), meaning it preferentially targets the virus.[5]
2. DNA Chain Termination: More critically, when HIV RT incorporates ZDV-TP into the growing proviral DNA strand, replication is permanently halted. The 3'-azido group on Zidovudine lacks the 3'-hydroxyl group necessary to form the next 3'-5' phosphodiester bond. This inability to extend the DNA strand results in obligatory chain termination, effectively aborting the reverse transcription process and preventing the virus from successfully integrating its genetic material into the host cell's genome.[14]

Off-Target Effects and Toxicity Mechanism

While relatively selective, ZDV-TP is not entirely specific to the viral enzyme. It also acts as a weak inhibitor of human cellular DNA polymerases, most significantly DNA polymerase gamma. This enzyme is located exclusively within the mitochondria and is solely responsible for the replication of mitochondrial DNA (mtDNA).[21] The inhibition of polymerase gamma by ZDV-TP interferes with the maintenance and replication of mtDNA. Over time, this leads to a depletion of mtDNA, which impairs the function of the mitochondrial respiratory chain and disrupts cellular energy production. This mitochondrial dysfunction is the unifying molecular mechanism underlying several of Zidovudine's most severe and characteristic toxicities, including skeletal myopathy, lactic acidosis, and hepatic steatosis (fatty liver).[21]

Pharmacokinetics (ADME)

The disposition of Zidovudine in the body involves a series of processes including absorption, distribution, metabolism, and excretion (ADME).

Absorption

Following oral administration, Zidovudine is rapidly and almost completely absorbed from the gastrointestinal tract. However, it undergoes extensive first-pass metabolism in the liver, which reduces its systemic bioavailability to approximately 60-70% in adults.[20] The administration of Zidovudine with food, particularly a high-fat meal, can decrease the rate of absorption (lower peak concentration) but does not significantly alter the overall extent of absorption (the total area under the curve, or AUC).[20]

Distribution

Zidovudine is widely distributed throughout the body tissues and fluids, with an apparent volume of distribution (Vd​) of approximately 1.6 L/kg.[12] Its binding to plasma proteins is relatively low, in the range of 34-38%, allowing a large fraction of the drug to remain free and active.[16] A critically important feature of its distribution is its ability to penetrate key physiological and viral sanctuary sites. It effectively crosses the blood-brain barrier, achieving concentrations in the cerebrospinal fluid (CSF) that are approximately 50% of those in plasma (CSF:Plasma ratio ~0.5).[24] This penetration is crucial for its activity against HIV-associated neurological conditions. Furthermore, it penetrates the placental barrier to protect the fetus and concentrates in seminal fluid, reaching levels nearly six times higher than in plasma, which is relevant for reducing the risk of sexual transmission.[24]

Metabolism

Zidovudine is extensively metabolized, primarily in the liver. Its metabolism does not involve the cytochrome P450 (CYP450) enzyme system, which minimizes the potential for many common drug-drug interactions.[24] The metabolic pathways are:

1. Glucuronidation (Major Pathway): The predominant metabolic fate of Zidovudine is conjugation with glucuronic acid to form an inactive metabolite, 3'-azido-3'-deoxy-5'-O-β-D-glucuronylthymidine (GZDV). This reaction is catalyzed by the UDP-glucuronosyltransferase enzyme isoform UGT2B7 and accounts for over 70% of the drug's clearance.[21]
2. Reduction (Minor Pathway): A small fraction of the dose (<1%) undergoes reduction of the azido moiety to form 3'-amino-3'-deoxythymidine (AMT). Although this is a minor clearance pathway, the AMT metabolite is 5- to 7-fold more toxic to human hematopoietic progenitor cells than the parent drug. This pathway is therefore thought to make a significant contribution to Zidovudine's characteristic bone marrow suppressive effects.[21]

Excretion

Elimination of Zidovudine and its metabolites occurs primarily through the kidneys. Approximately 14-29% of an administered dose is excreted unchanged in the urine, while the majority (around 45-74%) is excreted as the inactive GZDV metabolite.[20] Renal clearance of the parent drug greatly exceeds the glomerular filtration rate, indicating that it is actively secreted into the renal tubules in addition to being filtered.[24] The disposition and clearance of Zidovudine are also influenced by various drug transporters from the Solute Carrier (SLC) family (for uptake) and the ATP-binding cassette (ABC) family, including ABCB1 (MDR1), ABCC4 (MRP4), ABCC5 (MRP5), and ABCG2 (BCRP), which mediate its efflux from cells.[20]

Pharmacokinetic Variability in Special Populations

The pharmacokinetic profile of Zidovudine is not uniform across all patients and is significantly altered in certain populations, necessitating careful dose adjustments.

• Neonates: The pharmacokinetics in newborns are highly dynamic and dependent on postnatal age, reflecting the immaturity of their drug elimination pathways.
• Premature Neonates: Exhibit markedly reduced Zidovudine clearance (CL) and a dramatically prolonged elimination half-life (t1/2​). Studies report an average clearance of 2.53 mL/min/kg and a half-life of 7.2 hours, compared to ~21.7 mL/min/kg and ~1.1 hours in adults, respectively.[12]
• Full-Term Neonates: Elimination is also reduced, though less severely than in premature infants. In the first two weeks of life, clearance averages 10.9 mL/min/kg and the half-life is 3.12 hours. These pathways mature rapidly, and clearance increases with advancing postnatal age.[12] Bioavailability is also higher in neonates (up to 89%) compared to older children and adults.[20]
• Renal Impairment: Since renal excretion is a major elimination route, patients with severe renal impairment (creatinine clearance <15 mL/min) or those requiring dialysis experience a roughly 50% reduction in Zidovudine clearance. This leads to drug accumulation and an increased risk of toxicity, mandating a dose reduction.[24]
• Hepatic Impairment: As the liver is the primary site of metabolism via glucuronidation, patients with significant hepatic disease, such as cirrhosis, have impaired formation of the GZDV metabolite. This results in decreased clearance and potential accumulation of the active parent drug, which may necessitate a dosage reduction and requires close monitoring.[24]

The pharmacological profile of Zidovudine creates a delicate therapeutic balance. Its efficacy is entirely dependent on intracellular conversion to ZDV-TP, yet this same active metabolite is directly responsible for the off-target mitochondrial toxicity. Its clearance is highly dependent on the function of two major organ systems, the liver and the kidneys. Consequently, any immaturity (as in neonates) or impairment (as in patients with organ disease) in these systems can lead to the accumulation of Zidovudine. This accumulation drives higher intracellular concentrations of the active ZDV-TP, which simultaneously enhances the antiviral effect and magnifies the risk of severe, mechanism-based toxicities like anemia, myopathy, and lactic acidosis. This direct causal chain explains why vigilant monitoring of organ function and precise dose adjustments in special populations are not merely recommendations but critical safety imperatives for this drug.

Table 2: Summary of Key Pharmacokinetic Parameters Across Patient Populations

Parameter	Adults	Full-Term Neonates (<14 days)	Premature Neonates	Patients with Severe Renal Impairment	Patients with Hepatic Impairment
Bioavailability (%)	60-70	~89	Not well defined, likely high	Unchanged	Potentially increased
Elimination T½ (hours)	~1.1	~3.1	~7.2	Increased	Increased
Clearance	~21.7 ml/min/kg	~10.9 ml/min/kg	~2.5 ml/min/kg	Reduced by ~50%	Reduced
Volume of Distribution (L/kg)	~1.6	~1.6	~1.6	Unchanged	Unchanged
Protein Binding (%)	34-38	Not well defined	Not well defined	Unchanged	Unchanged
Primary Elimination Route	Hepatic glucuronidation, Renal excretion	Reduced hepatic & renal clearance	Markedly reduced hepatic & renal clearance	Impaired renal excretion	Impaired hepatic metabolism
Sources:		12

Clinical Efficacy and Therapeutic Applications

The clinical utility of Zidovudine has been defined by decades of clinical trials, evolving from a standalone miracle drug to a component of complex combination regimens. Its efficacy has been established in several key areas, though its role has been redefined by the advent of newer agents.

Treatment of HIV-1 Infection

Zidovudine is indicated for the treatment of HIV-1 infection in adults and children.[27] A foundational principle of its modern use is that it must

always be administered in combination with other antiretroviral agents. The use of Zidovudine as monotherapy is clinically inappropriate and no longer practiced due to the certain and rapid development of viral resistance.[32]

The first major clinical trials, such as ACTG 019, provided the initial evidence for its efficacy. These studies demonstrated that, compared to placebo, Zidovudine could significantly delay the clinical progression to AIDS in individuals who were either asymptomatic or had early symptoms of HIV infection.[9] It was shown to prolong survival and reduce the incidence of opportunistic infections in patients with advanced disease.[7]

Throughout the 1990s and early 2000s, Zidovudine served as a cornerstone of antiretroviral therapy. Numerous clinical trials evaluated its efficacy as part of a "backbone" in combination with a wide array of other drugs. These included other NRTIs like lamivudine and abacavir, non-nucleoside reverse transcriptase inhibitors (NNRTIs) like nevirapine and delavirdine, and protease inhibitors (PIs) like indinavir and ritonavir.[37] These combination regimens were vastly superior to monotherapy, leading to durable suppression of viral load and robust immune system recovery. However, due to its significant long-term toxicity profile, particularly hematologic and mitochondrial toxicities, and the development of safer, more potent, and more conveniently dosed alternatives, Zidovudine is no longer recommended as a first-line agent in most major international HIV treatment guidelines.[29]

Prevention of Perinatal (Mother-to-Child) Transmission (PMTCT)

Perhaps Zidovudine's most enduring and impactful clinical application is in the prevention of mother-to-child transmission of HIV. This indication is supported by landmark clinical trial evidence that established a new standard of care and dramatically reduced the incidence of pediatric HIV worldwide. The pivotal study demonstrated that a three-part Zidovudine regimen could reduce the rate of vertical HIV transmission by approximately two-thirds.[11]

The approved regimen for PMTCT involves:

1. Antepartum: Oral Zidovudine administered to the pregnant woman, typically starting after the 14th week of gestation and continuing until the onset of labor.[27]
2. Intrapartum: Intravenous (IV) Zidovudine administered to the mother during labor and delivery.[36]
3. Postpartum: Oral Zidovudine administered to the newborn infant for the first several weeks of life.[27]

In this specific clinical context, the immense benefit of preventing a lifelong, incurable infection in a child is considered to far outweigh the potential short-term risks of the medication to the mother and infant.[11]

Other Clinical Uses and Investigations

Beyond its primary indications, Zidovudine has been used or investigated for other related conditions.

• Post-Exposure Prophylaxis (PEP): In the past, Zidovudine was a key component of regimens for non-occupational post-exposure prophylaxis (nPEP) following potential sexual or other exposures to HIV.[32] Early studies estimated its efficacy in this setting to be high, though it has largely been replaced by better-tolerated agents in current PEP guidelines.[32]
• Investigational Uses: Clinical trials have explored the use of Zidovudine for various HIV-associated comorbidities, including hematologic disorders like cytopenias [38], HIV-associated dementia [37], and psoriasis in HIV-positive patients.[37] It has also been studied for its activity against another human retrovirus, HTLV-1, which causes Adult T-cell Leukemia/Lymphoma (ATL).[32] Furthermore, studies have evaluated its use in specific patient populations, such as those with chronic renal failure.[35]

Viral Resistance

The development of viral resistance is the primary factor limiting the long-term efficacy of Zidovudine monotherapy. Resistance arises from the accumulation of specific point mutations in the gene encoding the HIV reverse transcriptase enzyme. These are collectively known as Thymidine Analogue Mutations (TAMs) because they are selected for by thymidine analogues like Zidovudine and stavudine.[9]

The key TAMs occur at specific amino acid positions (codons) within the reverse transcriptase enzyme, most notably at codons 41, 67, 70, 210, 215, and 219.[9] The mutation at position 215 (e.g., T215Y/F) is considered particularly significant for conferring high-level resistance to Zidovudine.[9] The accumulation of multiple TAMs not only reduces susceptibility to Zidovudine but can also confer broad cross-resistance to other drugs in the NRTI class, thereby complicating future treatment options and limiting the effectiveness of subsequent regimens.[9] It is also clinically crucial to recognize the antagonistic relationship between Zidovudine and stavudine; these two drugs compete for the same intracellular activation pathway and should never be used together.[3]

The clinical profile of Zidovudine provides a perfect illustration of the shifting nature of the risk-benefit calculus in medicine. The adverse effects that make it a suboptimal choice for first-line therapy today were considered entirely acceptable in 1987, when the only alternative was the near-certainty of death from AIDS. In that context, the drug's ability to offer even a temporary survival benefit, despite its toxicity, was a monumental breakthrough. As the therapeutic landscape evolved with the introduction of dozens of safer and more effective drugs, the threshold for acceptable risk in chronic, first-line therapy was lowered dramatically, leading to Zidovudine's displacement. However, for the specific, time-limited indication of PMTCT, the calculus remains firmly in its favor. The profound, lifelong benefit of preventing a pediatric HIV infection far outweighs the minimal risk associated with a few months of drug exposure to the mother and infant, a period too short to induce the most severe long-term toxicities like lipoatrophy or cumulative myelosuppression. This demonstrates that a drug's clinical value is not an absolute constant but is highly dependent on the specific clinical context, the available alternatives, and the nature of the disease being treated.

Dosing, Administration, and Therapeutic Monitoring

The clinical application of Zidovudine requires precise dosing tailored to the specific indication, patient population, and organ function. Careful administration and vigilant therapeutic monitoring are essential to maximize efficacy while minimizing the risk of its significant toxicities.

Dosing Regimens

Dosing for Zidovudine varies substantially based on the patient's age, weight, and the clinical goal (treatment vs. prevention).

• Adult HIV-1 Treatment: The standard recommended oral dose for adults is 300 mg twice daily, administered as part of a combination antiretroviral regimen.[27]
• Pediatric HIV-1 Treatment (6 weeks to <18 years): Dosing in children is more complex and can be calculated based on either body weight or body surface area (BSA) to ensure appropriate exposure.
• Weight-Based Dosing:
• 4 kg to <9 kg: 12 mg/kg twice daily.[27]
• 9 kg to <30 kg: 9 mg/kg twice daily.[27]
• ≥30 kg: 300 mg twice daily (adult dose).[9]
• BSA-Based Dosing: An alternative method is 240 mg/m² twice daily.[33] Clinicians may need to compare both calculations to determine the most appropriate dose.
• Prevention of Mother-to-Child Transmission (PMTCT): This involves a three-part regimen with distinct dosing for the mother and newborn.
• Maternal (Antepartum): For pregnant women after 14 weeks of gestation, the dose is 100 mg orally five times per day until the start of labor.[27]
• Maternal (Intrapartum): During labor and delivery, an intravenous (IV) loading dose of 2 mg/kg is administered over one hour, followed by a continuous IV infusion of 1 mg/kg/hour until the umbilical cord is clamped.[36]
• Neonatal: Dosing for the newborn begins within 12 hours of birth and continues for six weeks. It is stratified by gestational age to account for immature drug metabolism in premature infants:
• ≥35 weeks gestation: 4 mg/kg orally every 12 hours.[33]
• 30 to <35 weeks gestation: 2 mg/kg orally every 12 hours for the first 14 days, then increased to 3 mg/kg every 12 hours thereafter.[33]
• <30 weeks gestation: 2 mg/kg orally every 12 hours for the first 4 weeks, then increased to 3 mg/kg every 12 hours thereafter.[33]
• An older neonatal dosing regimen is 2 mg/kg orally every 6 hours.[27]

Dose Adjustments in Special Populations

Failure to adjust the Zidovudine dose in patients with impaired drug clearance or those experiencing toxicity can lead to severe adverse events.

• Renal Impairment: In patients with severe renal impairment (Glomerular Filtration Rate <10-15 mL/min) or those with end-stage renal disease on hemodialysis or peritoneal dialysis, the dose should be reduced. The recommended dosage is 100 mg every 6 to 8 hours.[25]
• Hepatic Impairment: While no specific dosage guidelines are established, a dose reduction may be necessary for patients with significant hepatic impairment (e.g., cirrhosis) due to decreased glucuronidation. These patients require close clinical and laboratory monitoring.[24]
• Management of Toxicity: If a patient develops significant anemia (hemoglobin <7.5 g/dL) or neutropenia (neutrophil count <0.75 x 10⁹/L), treatment with Zidovudine should be interrupted until there is evidence of bone marrow recovery. Dose reduction upon resumption of therapy may be considered.[25]

Administration and Monitoring

• Administration: Zidovudine can be taken with or without food. While taking it on an empty stomach may lead to higher peak plasma levels, administration with food can improve tolerability (e.g., reduce nausea) without significantly compromising overall drug exposure.[9] The oral solution formulation must be shaken well before use, and an accurate measuring device, not a household teaspoon, should be used to ensure correct dosing.[27]
• Therapeutic Monitoring: Due to its narrow therapeutic index and significant toxicity profile, regular monitoring is a critical component of care.
• Hematologic Monitoring: A complete blood count (CBC) with differential should be performed at baseline and monitored frequently thereafter, especially during the first 4 to 6 weeks of therapy when myelosuppression is most likely to occur. In patients with advanced HIV disease, monitoring every two weeks may be appropriate initially.[25]
• Hepatic and Metabolic Monitoring: Liver function tests (LFTs) should be monitored periodically. Patients should be closely observed for clinical signs and symptoms of lactic acidosis (e.g., unexplained tachypnea, nausea, vomiting, weakness) and hepatotoxicity.[25]
• Muscular Monitoring: Patients should be monitored for signs of myopathy, such as muscle pain or weakness, particularly with long-term use.[11]

Table 3: Recommended Dosing Regimens for Zidovudine by Indication and Population

Indication	Population	Route	Dose	Frequency	Key Considerations
HIV-1 Treatment	Adults & Adolescents (≥30 kg)	Oral	300 mg	Twice Daily	Must be used in combination with other antiretrovirals.
HIV-1 Treatment	Pediatrics (9 to <30 kg)	Oral	9 mg/kg	Twice Daily	Alternative BSA dosing: 240 mg/m² twice daily.
HIV-1 Treatment	Pediatrics (4 to <9 kg)	Oral	12 mg/kg	Twice Daily	Use oral solution and measure dose accurately.
PMTCT (Maternal)	Antepartum (>14 weeks)	Oral	100 mg	5 Times Daily	Continue until labor begins.
PMTCT (Maternal)	Intrapartum	IV	2 mg/kg load, then 1 mg/kg/hr	Continuous	Infuse load over 1 hour; continue infusion until cord clamp.
PMTCT (Neonate)	≥35 weeks gestation	Oral	4 mg/kg	Every 12 hours	Administer for the first 6 weeks of life.
PMTCT (Neonate)	30 to <35 weeks gestation	Oral	2 mg/kg -> 3 mg/kg	Every 12 hours	Dose increase occurs after 14 days of life.
Dose Adjustment	Severe Renal Impairment (GFR <15)	Oral	100 mg	Every 6-8 hours	Necessary due to decreased clearance.
Dose Adjustment	Severe Anemia/Neutropenia	Oral/IV	Interrupt Therapy	N/A	Withhold dose until bone marrow recovery is evident.
Sources:		9

Safety Profile, Toxicology, and Risk Management

The clinical use of Zidovudine is limited by a significant and well-characterized toxicity profile. Many of its adverse effects are severe and potentially life-threatening, necessitating black box warnings in its official labeling. A comprehensive understanding of these risks, along with contraindications and drug interactions, is paramount for safe prescribing.

Major Toxicities and Black Box Warnings

The U.S. FDA label for Zidovudine includes warnings for several major toxicities.

• Hematologic Toxicity: Dose-dependent bone marrow suppression is the principal and most common dose-limiting toxicity of Zidovudine.[20] This typically manifests as:
• Macrocytic Anemia: A decrease in red blood cells, often characterized by an increased mean corpuscular volume (MCV). It usually becomes apparent within 4 to 6 weeks of starting therapy.[25]
• Neutropenia: A reduction in neutrophils (a type of white blood cell), which increases the risk of bacterial infections. This also typically occurs within the first month of treatment.[25]

These effects are more common and more severe in patients with advanced HIV disease, pre-existing low bone marrow reserve, or low vitamin B12 or folate levels.9 Severe cases may require dose interruption, dose reduction, or supportive care with blood transfusions or colony-stimulating factors.27

• Mitochondrial Toxicity: This class effect of NRTIs is caused by the inhibition of mitochondrial DNA polymerase gamma and can manifest in several ways:

1. Lactic Acidosis and Severe Hepatomegaly with Steatosis: This is a rare but potentially fatal metabolic complication. The buildup of lactic acid results from impaired aerobic respiration. Clinical features may be nonspecific and include deep, rapid breathing (dyspnea, tachypnea), nausea, vomiting, abdominal pain, generalized weakness, and unexplained weight loss. If lactic acidosis or significant hepatotoxicity is suspected, Zidovudine treatment must be suspended immediately.[21]
2. Myopathy and Myositis: Symptomatic muscle disease, particularly with prolonged use, is another consequence of mitochondrial damage. It presents as muscle pain (myalgia), tenderness, weakness, and elevated levels of creatine kinase (CK) in the blood. In some cases, it can be debilitating.[11]

The safety profile of Zidovudine is a direct and predictable extension of its pharmacology. Its major adverse effects are not idiosyncratic but are rather mechanism-based toxicities. The drug's structure as a thymidine analogue allows it to be processed by the same cellular machinery that handles endogenous nucleosides. Its active metabolite, ZDV-TP, inhibits DNA synthesis, a process vital for all dividing cells. This non-specific effect on cellular replication directly explains its impact on the rapidly dividing hematopoietic progenitor cells in the bone marrow, leading to the predictable outcomes of anemia and neutropenia. Concurrently, the off-target inhibition of mitochondrial DNA polymerase gamma by ZDV-TP disrupts mitochondrial function, which provides a unified molecular explanation for a distinct cluster of toxicities: myopathy in muscle tissue, lactic acidosis reflecting a systemic energy crisis, and hepatic steatosis in the liver. Thus, the drug's most feared toxicities are inextricably linked to the very mechanisms that confer its antiviral efficacy. This explains why these adverse effects are often dose-limiting and underscores why the development of subsequent antiretroviral drugs focused so heavily on improving selectivity and minimizing off-target effects on host polymerases.

Other Common and Significant Adverse Effects

Beyond the major warnings, Zidovudine is associated with a range of other adverse effects.

• Gastrointestinal Effects: Nausea, vomiting, anorexia (loss of appetite), and abdominal pain are very common, particularly when initiating therapy. These symptoms are often transient and may improve over time.[9]
• Constitutional and Neurological Symptoms: Headache, malaise (a general feeling of discomfort), insomnia, and dizziness are frequently reported side effects.[9]
• Lipoatrophy: Long-term treatment with Zidovudine (and its related analogue, stavudine) is strongly associated with the loss of subcutaneous fat. This is most noticeable in the face (facial wasting), limbs, and buttocks, and can be cosmetically disfiguring and stigmatizing for patients.[9]
• Hepatic Effects: Modest and transient elevations of liver enzymes (transaminases) can occur.[25] In patients co-infected with Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV), there is an increased risk for severe and potentially fatal hepatic decompensation when on combination antiretroviral therapy.[25]
• Immune Reconstitution Inflammatory Syndrome (IRIS): In patients with severe immune deficiency at the time of starting ART, the recovering immune system may mount an exaggerated inflammatory response to pre-existing, subclinical opportunistic infections (e.g., tuberculosis, cytomegalovirus). This can cause a paradoxical worsening of symptoms and requires specific management.[29]
• Skin and Nail Changes: Rash, itching, and discoloration of the skin and/or nails have been reported.[11]

Contraindications

The use of Zidovudine is strictly contraindicated in the following situations:

• Patients with a history of clinically significant hypersensitivity (allergic reaction) to Zidovudine or any of the excipients in the formulation.[25]
• Patients with pre-existing, severe hematologic abnormalities, specifically abnormally low neutrophil counts (<0.75 x 10⁹/L) or low hemoglobin levels (<7.5 g/dL).[25]

Drug-Drug Interactions

Clinically significant drug interactions can alter the efficacy or toxicity of Zidovudine.

Table 4: Clinically Significant Drug-Drug Interactions with Zidovudine

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation
Stavudine (d4T)	Pharmacodynamic (Antagonism)	Both drugs are thymidine analogues and compete for the same intracellular phosphorylation pathway (thymidine kinase). This can reduce the activation of both drugs.	Avoid concomitant use.
Ribavirin	Pharmacodynamic (Antagonism) & Additive Toxicity	Ribavirin can inhibit the phosphorylation of Zidovudine, reducing its antiviral activity. It also increases the risk of severe anemia when used with Zidovudine.	Coadministration is not advised.
Ganciclovir, Interferon-alfa, other Myelosuppressive Agents	Pharmacodynamic (Additive Toxicity)	These agents also suppress bone marrow function. Concomitant use results in an additive or synergistic increase in the risk of severe anemia and neutropenia.	Avoid coadministration if possible. If necessary, monitor hematologic parameters with extreme vigilance.
Probenecid	Pharmacokinetic (Inhibition of Metabolism/Excretion)	Probenecid inhibits the glucuronidation of Zidovudine in the liver and may also block its renal tubular secretion.	This leads to increased Zidovudine plasma levels and a significantly higher risk of toxicity.
Trimethoprim	Pharmacokinetic (Inhibition of Excretion)	Trimethoprim can inhibit the renal elimination of Zidovudine.	This can result in higher than expected concentrations of Zidovudine, increasing the risk of adverse effects. Monitor closely.
Phenytoin	Pharmacokinetic (Variable)	Reports suggest that Zidovudine can alter phenytoin plasma levels (reports of low levels).	Monitor phenytoin levels if coadministration is necessary.
Sources:		3

Conclusion: The Enduring Legacy of Zidovudine

Zidovudine occupies a unique and monumental place in the annals of pharmacology and public health. More than just a chemical compound, it stands as a historical artifact of a pivotal moment in the global response to a pandemic and as a critical teacher from which the medical and scientific communities have learned profound lessons. Its journey from a failed cancer drug to the first weapon against HIV/AIDS is a testament to scientific serendipity and the power of targeted research in a time of crisis.

The approval of Zidovudine in 1987 was a watershed event. It single-handedly transformed HIV/AIDS from an inexorably fatal illness into a treatable, albeit still serious, chronic condition.[2] For the first time, it offered tangible hope to millions facing certain death, slowing the progression of the disease and prolonging life. This breakthrough paved the way for the entire field of antiretroviral drug development, creating the scientific and regulatory framework upon which all subsequent therapies were built.

Equally important are the lessons learned from Zidovudine's limitations. The rapid emergence of viral resistance to monotherapy was a stark and definitive demonstration of HIV's high mutation rate and the biological necessity of combination therapy.[2] This failure was, in fact, a crucial scientific success, as it established the foundational principle of cART that remains the global standard of care today. Furthermore, its severe, mechanism-based toxicities provided a textbook case study in drug safety, highlighting the critical importance of understanding a drug's off-target effects. The direct link between its inhibition of mitochondrial DNA polymerase and its signature toxicities—myopathy, lactic acidosis, and hepatosteatosis—drove research toward developing agents with greater selectivity and improved safety profiles.[21]

The story of Zidovudine is also inseparable from the rise of patient activism. The controversies surrounding its accelerated approval, severe side effects, and prohibitively high initial cost galvanized a generation of activists who fundamentally altered the landscape of drug development.[1] Their demands for faster access, more humane clinical trials, and a voice in the regulatory process created a new paradigm of patient-centric medicine that has had far-reaching impacts beyond HIV.

In contemporary clinical practice, Zidovudine's role has been significantly curtailed. It has been superseded in most first-line regimens by drugs that are safer, more potent, and more convenient. Yet, its value persists in specific niches, most notably in the prevention of mother-to-child transmission, where its short-term use continues to be a life-saving intervention.[11]

In conclusion, while the clinical use of Zidovudine has waned, its impact is indelible. It was the drug that first gave humanity a foothold in the fight against AIDS. It taught the world about retroviral resistance, the imperative of combination therapy, the complexities of drug toxicity, and the power of an informed and activated patient community. Zidovudine's legacy is not merely that of an old drug, but that of a scientific and social catalyst whose influence remains deeply embedded in the practice of medicine today.

Works cited

1. AIDS Drug AZT: How It Got Approved 30 Years Ago | TIME, accessed July 15, 2025, https://time.com/4705809/first-aids-drug-azt/
2. The First AIDS Drugs | Center for Cancer Research, accessed July 15, 2025, https://ccr.cancer.gov/news/landmarks/article/first-aids-drugs
3. ZIDOVUDINE (AZT) 1. Exposure Data - IARC Publications, accessed July 15, 2025, https://publications.iarc.fr/_publications/media/download/2509/2a1f8a1329324f0797530cfb820e6d51abd36bf0.pdf
4. The History of HIV Treatment: Antiretroviral Therapy and More - WebMD, accessed July 15, 2025, https://www.webmd.com/hiv-aids/hiv-treatment-history
5. Zidovudine - Wikipedia, accessed July 15, 2025, https://en.wikipedia.org/wiki/Zidovudine
6. The 40 year fight against HIV | GSK, accessed July 15, 2025, https://www.gsk.com/en-gb/behind-the-science-magazine/the-40-year-fight-against-hiv/
7. A brief history of AZT | National Museum of American History, accessed July 15, 2025, https://americanhistory.si.edu/explore/stories/brief-history-azt
8. Search Orphan Drug Designations and Approvals - accessdata.fda ..., accessed July 15, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=8185
9. Zidovudine | aidsmap, accessed July 15, 2025, https://www.aidsmap.com/about-hiv/arv-background-information/zidovudine
10. Study Details | Safety and Efficacy of Zidovudine for Asymptomatic HIV-Infected Individuals, accessed July 15, 2025, https://clinicaltrials.gov/study/NCT00000736
11. AZT (zidovudine, Retrovir) | CATIE - Canada's source for HIV and hepatitis C information, accessed July 15, 2025, https://www.catie.ca/azt-zidovudine-retrovir
12. Zidovudine Pharmacokinetics in Premature Infants Exposed to Human Immunodeficiency Virus | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed July 15, 2025, https://journals.asm.org/doi/10.1128/aac.42.4.808
13. Zidovudine | C10H13N5O4 | CID 35370 - PubChem, accessed July 15, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Zidovudine
14. Zidovudine (T3D4720) - T3DB, accessed July 15, 2025, https://www.t3db.ca/toxins/T3D4720
15. Zidovudine (Azidothymidine, AZT, NSC 602670, ZDV, CAS Number: 30516-87-1), accessed July 15, 2025, https://www.caymanchem.com/product/15492/zidovudine
16. Zidovudine | 30516-87-1 - ChemicalBook, accessed July 15, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1354971.htm
17. Definition of zidovudine - NCI Drug Dictionary, accessed July 15, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/zidovudine
18. zidovudine | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed July 15, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4825
19. [Zidovudine (400 mg)] - CAS [30516-87-1] - USP Store, accessed July 15, 2025, https://store.usp.org/product/1724500
20. Zidovudine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00495
21. Zidovudine Pathway, Pharmacokinetics/Pharmacodynamics - PharmGKB, accessed July 15, 2025, https://www.pharmgkb.org/pathway/PA165859361
22. Zidovudine (intravenous route) - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/drugs-supplements/zidovudine-intravenous-route/description/drg-20072346
23. Zidovudine, ZDV tablets and capsules - Cleveland Clinic, accessed July 15, 2025, https://my.clevelandclinic.org/health/drugs/20848-zidovudine-zdv-tablets-and-capsules
24. Zidovudine PK Fact Sheet, accessed July 15, 2025, https://liverpool-hiv-hep.s3.amazonaws.com/fact_sheets/pdfs/000/000/100/original/HIV_FactSheet_ZDV_2016_Mar.pdf?1458130107
25. USFDA Approval March 27, 2006 Zidovudine Capsules 100 mg Aurobindo Pharma, Ltd. - Extranet Systems, accessed July 15, 2025, https://extranet.who.int/prequal/sites/default/files/whopar_files/PAR_Zidovudine100mg_Capsules.pdf
26. Generic Retrovir Availability - Drugs.com, accessed July 15, 2025, https://www.drugs.com/availability/generic-retrovir.html
27. Zidovudine (oral route) - Mayo Clinic, accessed July 15, 2025, https://www.mayoclinic.org/drugs-supplements/zidovudine-oral-route/description/drg-20066724
28. Safety of zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand - PMC, accessed July 15, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5350228/
29. Zidovudine Patient Drug Record | NIH - Clinical Info HIV.gov, accessed July 15, 2025, https://clinicalinfo.hiv.gov/en/drugs/zidovudine/patient
30. FDA-Approved Zidovudine API Manufacturers & Suppliers, accessed July 15, 2025, https://pharmaoffer.com/api-excipient-supplier/anti-hiv/zidovudine/fda
31. ZIDOVUDINE [AZT] API Manufacturers | Suppliers | Exporters - PharmaCompass.com, accessed July 15, 2025, https://www.pharmacompass.com/listed-active-pharmaceutical-ingredients/zidovudine-azt
32. Zidovudine - StatPearls - NCBI Bookshelf, accessed July 15, 2025, https://www.ncbi.nlm.nih.gov/books/NBK554419/
33. Azt - Mechanism, Indication, Contraindications, Dosing, Adverse ..., accessed July 15, 2025, https://www.pediatriconcall.com/drugs/azt/301
34. Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062) | Antimicrobial Agents and Chemotherapy - ASM Journals, accessed July 15, 2025, https://journals.asm.org/doi/10.1128/aac.39.12.2732
35. Renal Failure Chronic Completed Phase Trials for Zidovudine (DB00495) - DrugBank, accessed July 15, 2025, https://go.drugbank.com/indications/DBCOND0073727/clinical_trials/DB00495?status=completed
36. RETROVIR® (zidovudine) Tablets, Capsules, and Syrup Label - accessdata.fda.gov, accessed July 15, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019910s033lbl.pdf
37. Human Immunodeficiency Virus (HIV) Infections Completed Phase Trials for Zidovudine (DB00495) | DrugBank Online, accessed July 15, 2025, https://go.drugbank.com/indications/DBCOND0035016/clinical_trials/DB00495?status=completed
38. Zidovudine Completed Phase 1 Trials for Human Immunodeficiency Virus (HIV) Infections / Cytopenias Treatment - DrugBank, accessed July 15, 2025, https://go.drugbank.com/drugs/DB00495/clinical_trials?conditions=DBCOND0027986%2CDBCOND0035016&phase=1&purpose=treatment&status=completed
39. RETROVIR zidovudine (AZT) 100 mg capsules - NEW ZEALAND DATA SHEET, accessed July 15, 2025, https://www.medsafe.govt.nz/profs/datasheet/r/Retrovircapsoln.pdf
40. Zidovudine | PPTX - SlideShare, accessed July 15, 2025, https://www.slideshare.net/slideshow/zidovudine/37746772