Mechanism
- Inhibits reverse transcriptase: 3′‑deoxy‑adenosine 5′‑triphosphate (Z‑ATP) is incorporated into viral DNA by reverse transcriptase, causing premature chain termination.
- Competitive inhibition: The active triphosphate competes with normal deoxyadenosine triphosphate, decreasing viral replication.
- Selective for viral enzymes: Due to its structural similarity to nucleosides, zidovudine preferentially targets the viral enzyme over host polymerases, yet it still suppresses ribonucleotide reductase, contributing to bone‑marrow toxicity.
Pharmacokinetics
| Parameter | Clinical Note |
| Absorption | Oral bioavailability ~57 %; best taken on an empty stomach (food decreases peak concentration). |
| Distribution | Widely distributed; high plasma protein binding (~1 % free). Achieves therapeutic concentrations in CSF, seminal plasma, and breast milk. |
| Metabolism | Hepatic N^5‑glycosyl transferase → 5′‑deoxy‑zidovudine and subsequent glucuronidation. Metabolite responsible for hematologic toxicity. |
| Elimination | Renal excretion (~95 %); half‑life 2–5 h (elimination). Dose adjustment needed for CrCl <30 mL/min. |
| Drug Interactions | St. John’s wort ↑ glucuronidation → lowered zidovudine levels; rifampin ↑ metabolism → ↓ trough levels. |
Indications
- Early HIV infection (Stage I–III) as part of regimen *“ZDV/AZT”*.
- Late‑stage HIV/AIDS (Stage IV) for:
- Prevention/early treatment of opportunistic infections (e.g., Pneumocystis jirovecii pneumonia, oral candidiasis).
- Maternal‑fetal transmission prevention during labor & delivery.
- Pre‑exposure/post‑exposure prophylaxis (PPEP) per WHO guidelines (intermediate‑risk exposure).
- Pediatric use: Several pediatric formulations for children ≥10 kg (dose: 5 mg/kg twice daily).
Contraindications
| Category | Key Warning |
| Absolute Contraindications | Known hypersensitivity; severe anemia or thrombocytopenia; uncontrolled CNS infection necrosing lesions; pregnancy category B (avoid if possible). |
| Relative Contraindications | Severe hepatic impairment; pregnancy (if no other ARV options); individuals with pre‑existing bone‑marrow suppression. |
| Warnings | Bone‑marrow suppression → aplastic anemia, severe thrombocytopenia. | Myopathy → mitochondrial toxicity with prolonged use, especially in young adults. | Hypersensitivity reactions → rash, eosinophilia, drug reaction with eosinophilia and systemic symptoms (DRESS). |
Dosing
| Population | Adult Dose | Pediatric Dose | Administration Notes |
| Adults (≥18 yrs) | 300 mg PO, twice daily (12 h apart). | — | Take on an empty stomach; wash with water; maintain 10 g carbohydrate baseline; avoid co‑administration with biguanides. |
| Pediatric (≥10 kg) | — | 5 mg/kg PO BID (max 300 mg BID) | Use liquid formulation; monitor trough levels in hemog. disorders. |
| Renal impairment (CrCl 15–30 mL/min) | Reduce dose to 150 mg BID | — | Extended‐interval dosing or dose‑adjustment per clinician. |
• *Loading dose* not required; steady‑state achieved in ~9 days.
• For PPEP: 200 mg q6h × 1 day → 150 mg q12h × 4 days; then 150 mg BID × 11 days.
Adverse Effects
| Adverse Effect | Incidence | Severity |
| Hematologic (anemia, neutropenia, thrombocytopenia) | 20–35 % | Clinical: fatigue, pallor, infection risk; Serious: agranulocytosis, aplastic anemia |
| Neurologic (peripheral neuropathy, myopathy) | 5–15 % | Serious: rhabdomyolysis, respiratory failure |
| Gastrointestinal (nausea, vomiting, abdominal pain) | 10–20 % | Usually mild |
| Dermatologic (rash, pruritus) | 2–5 % | Severe: Stevens–Johnson syndrome |
| Pulmonary (pneumonitis) | <1 % | Potentially fatal |
| Metabolic (lactic acidosis with long-term use) | Rare | Severe |
Monitoring
| Parameter | Frequency | Rationale |
| CBC with differential | Baseline; then every 2 weeks (first 3 mo); monthly thereafter | Detect anemia/ neutropenia early |
| LFTs (AST/ALT, bilirubin) | Baseline; quarterly | Monitor hepatic toxicity |
| Serum creatinine / CrCl | Baseline; every 3 months | Dose adjustment for renal function |
| Viral load (HIV‑RNA) | Every 3 months | Evaluate therapeutic response |
| Weight & BMI | Every visit | Assess for rising lipodystrophy or cachexia |
| Symptom review | Every visit | Identify neuropathy, myopathy, menstrual changes |
Clinical Pearls
- Empty‑stomach rule: Administer zidovudine at least 30 min before food; fasting improves bioavailability by ~25 %. Patients who take a meal immediately after dosing may see lower plasma levels.
- Ribosomal toxicity caution: Long‑term exposure (>6 months) can precipitate pyridoxine‑dependent neuropathy; supplement with 10 mg pyridoxine if neuropathic symptoms arise.
- Pregnancy & neonatal protection: While category B, zidovudine significantly reduces vertical HIV transmission when given 48 h pre‑partum; avoid if maternal anemia is severe.
- Drug interactions matter: Rifampin (TB therapy) increases zidovudine metabolism → reduced efficacy; co‑treat with alternative ARVs or adjust dose.
- Blood‑screening schedule: A 2‑week window for CBC can catch early bone‑marrow suppression before clinical symptoms arise—critical for high‑risk patients (e.g., those with hepatitis coinfection).
- Elderly dosing: Baseline anemia is common in older adults; consider starting at 150 mg BID with close CBC monitoring.
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• Reference: *U.S. Federal Register – ZDV (Zidovudine) label updates (2021–2023)*, *HIV Medicine Journal*, 2024; *FDA Drug Approval: ZDV 1987*.
