Sofosbuvir
Sofosbuvir
Generic Name
Sofosbuvir
Mechanism
* Sofosbuvir is a phosphoramidate prodrug that is intracellularly metabolized to the active triphosphate GS‑461203.
* The active metabolite is a nucleotide analog of uridine‑5‑triphosphate.
* It is selectively incorporated into the viral RNA by the hepatitis C virus (HCV) NS5B RNA‑dependent RNA polymerase.
* Once incorporated, it causes chain termination by preventing addition of the next nucleotide.
* This action exclusively targets the HCV replication cycle, allowing high‐potency viral suppression with minimal impact on host cellular polymerases.
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral tablet; ~50 % bioavailability. Peak plasma concentration (Cmax) ~2.5 h after dosing. |
| Distribution | Protein binding ~87 % (mainly to alpha‑1‑acid glycoprotein). Widely distributed, crosses the blood‑brain barrier minimally. |
| Metabolism | Primarily hepatic via CYP3A4, CYP3A5 for the conversion of the prodrug and subsequent glucuronidation. Limited by 3'‑phosphodiesterase. |
| Excretion | Renally excreted (≈70 %) as the active metabolite (GS‑461203) via active tubular secretion (OAT1/OAT3).
The inactive metabolite (GS‑331007) is excreted unchanged. |
| Half‑life | Active metabolite ~30 h; parent drug 5–7 h.
Clearance ~27 mL/min/kg (renal). |
| Drug interactions | Strong CYP3A inducers (rifampin, carbamazepine) reduce exposure; potent CYP3A inhibitors (ketoconazole, itraconazole) increase exposure.
Avoid with glyburide, sulfonylureas, or statins that are CYP3A‑substrates.
Indications
* Chronic HCV infection (any genotype) – as part of direct‑acting antiviral (DAA) combinations:
* Sofosbuvir/ledipasvir (Harvoni®) – for genotype 1, 4, and 5.
* Sofosbuvir/velpatasvir (Epclusa®) – pan‑genotypic.
* Sofosbuvir + elbasvir/grazoprevir – for genotype 3.
* Treatment‑emergent or acquired resistance to other NS5B inhibitors (rare).
Contraindications
| Category | Details |
| Contraindicated | Hypersensitivity to sofosbuvir or any excipients. |
| Warnings | Renal impairment – eGFR < 30 mL/min/1.73 m²: dose adjustment or avoidance.
| Pregnancy Category | B – Animal studies show no teratogenicity, but human data limited; use only if benefits outweigh risks. |
| Drug interactions | Avoid concomitant use with strong CYP3A inducers; monitor for toxicity when combined with statins or other CYP3A drugs. |
Dosing
* Adult dose – 400 mg orally once daily (single tablet).
* Special populations:
* Severe renal impairment (eGFR 15–30 mL/min): 300 mg once daily if combined with other DAAs; consider dose reduction for monotherapy.
* Mild to moderate hepatic impairment (Child‑Pugh A & B): No adjustment.
* Concurrent statin therapy – use the lowest effective dose of statin.
* Administration – with or without food; take same time daily.
* Duration – typically 12 weeks; 24 weeks for treatment‑naïve patients with cirrhosis or prior DAA failure.
Adverse Effects
| Adverse Effect | Frequency | Remarks |
| Fatigue | Common | May be dose‑related; manage with rest. |
| Headache | Common | Usually mild; takes over‑the‑counter analgesics. |
| Myalgia | Common | Monitor creatine kinase if severe. |
| Insomnia | Common | Evaluate sleep hygiene. |
| Nausea | Rare | Antiemetic may be needed. |
| Anemia | Rare | CBC monitoring in high‑risk patients. |
| Liver enzyme elevation | Rare | Monitor AST/ALT at baseline and 4 weeks; hold therapy if >4× ULN. |
| Hypersensitivity/Allergic reactions | Very rare | Avoid re‑exposure. |
| Kidney function changes | Very rare | Increase serum creatinine >0.3 mg/dL; hold dose. |
Monitoring
* Baseline – CBC, LFTs, renal panel, HCV RNA genotype, viral load, pregnancy test if applicable.
* During therapy – LFTs at weeks 4 and 8; renal function at week 4 and end of therapy.
* Post‑therapy – HCV RNA at 12 weeks (SVR12) to confirm sustained virologic response.
* Drug‑interaction monitoring – Check serum statin levels if on high‑dose statin; adjust as necessary.
Clinical Pearls
1. Pan‑genotypic advantage – Sofosbuvir/Velpatasvir clears all HCV genotypes, making it ideal for travelers or patients with unknown genotype.
2. No dose adjustment for mild to moderate hepatic impairment – simplifies prescribing in cirrhotic patients; only severe hepatic disease may require monitoring.
3. Kidney‑safe profile in most patients – The drug is not significantly nephrotoxic; however, the active metabolite does accumulate in severe CKD, necessitating dose adjustments or discontinuation.
4. Avoid Strong CYP3A Inducers – Patients on rifampin or carbamazepine often fail therapy due to rapid drug clearance; consider alternative treatment.
5. Simultaneous use of gemfibrozil – Can increase serum bilirubin; monitor liver enzymes closely if co‑administered.
6. Co‑administration with a statin – Atorvastatin >20 mg or rosuvastatin >10 mg may increase statin levels; use lowest effective dose.
7. Rapid action – Viral decline within 48–72 h; early virologic response predicts sustained response, useful for assessing treatment efficacy in real time.
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• Key terms for quick reference: Sofosbuvir, HCV, NS5B polymerase inhibitor, DAAs, pharmacokinetics, renal impairment, CYP3A, SVR12.