Sovaldi
Sovaldi
Generic Name
Sovaldi
Mechanism
- Retro‑viral polymerase inhibitor
- 4, R‑(3′‑deoxy‑3′‑fluoro‑5′‑methyl‑1′,3′‑dioxolane‑2′‑yl‑1′‑propargyl‑2′‑β‑phosphoramidate)
- Cleaved intracellularly → sofosbuvir triphosphate
- Selectively inhibits HCV NS5B RNA‑dependent RNA polymerase by competing with natural nucleotides and causing chain termination.
- Exhibits a high genetic barrier to resistance.
Pharmacokinetics
| Parameter | Key Data |
| Absorption | ~35 % bioavailability; peak plasma concentration Tmax ≈ 3–5 h. |
| Distribution | ~79 % plasma protein binding; extensive tissue penetration (liver > plasma). |
| Metabolism | Prodrug conversion to sofosbuvir‑TP via hepatic esterases and phosphoramidases. No clinically relevant CYP450 interactions. |
| Elimination | Mainly renal (≈ 70 % excreted unchanged as GS‑9148); terminal half‑life ~5–6 h. |
| Dose adjustment | Not required for mild–moderate hepatic impairment; caution when GFR < 30 mL/min (dose 400 mg QD). |
Indications
- Curative therapy for chronic HCV in patients with any genotype (1–6) when combined with or as monotherapy (with or without ribavirin).
- Standard 12‑week regimen for naïve, genotype‑1, non‑cirrhotic adults.
- 8‑week regimen for HCV‑1a/1b non‑cirrhotic when combined with ledipasvir; extended up to 24 weeks for cirrhotics.
- Approved for HCV GT‑2/3/5/6 when used with ledipasvir/sofosbuvir or glecaprevir/pibrentasvir.
Contraindications
- Contraindicated in patients with known hypersensitivity to any component of the formulation.
- Severe renal impairment (CrCl < 30 mL/min) – use with caution; monitor renal function closely.
- Pregnancy: Category B—caution; teratogenic potential uncertain; use contraception.
- Drug interactions: Not an inhibitor/inducer of major CYP450 enzymes; however, co‑administration with strong inhibitors/inducers of P-gp may alter exposure.
- Liver disease: Not recommended in decompensated cirrhosis (Child‑Pugh B/C) when used alone.
Dosing
- Preferred: 400 mg oral tablet once daily (≥ 12 h interval).
- With ledipasvir: Take simultaneously at bedtime with a meal rich in fat to improve absorption.
- With ribavirin: Continue ribavirin dose (1000–1200 mg/m²) per standard regimens.
- Missed dose: Take within 3 h of scheduled time; next dose at normal time.
Adverse Effects
| Category | Typical Events |
| Common ( 10 %) | Hepatotoxicity (transient ALT/AST ↑), severe renal dysfunction (rare), hypersensitivity reactions, thrombocytopenia (esp. with ribavirin). |
Monitoring
- Baseline: CBC, CMP, HCV RNA level, viral genotype, renal function.
- During therapy:
- HCV RNA at week 4 (rapid virologic response), week 12 (end of therapy), 12 weeks post‑therapy (sustained virologic response).
- LFTs at weeks 4, 8, 12.
- CBC when ribavirin co‑administered.
- Renal function at baseline, week 4, and at last dose if CrCl < 70 mL/min.
Clinical Pearls
- High barrier to resistance: Sofosbuvir’s single‑nucleotide substitution requirement dramatically reduces the emergence of resistant variants, making it safe in patients with prior NS5A/L.
- Weight‐based dosing unnecessary: Fixed 400 mg daily dose is appropriate for all adults irrespective of body weight.
- Co‑administration with food: While food does not affect efficacy, a higher‑fat meal increases peak concentration by ~30 %, useful in patients with concurrent ledipasvir to improve overall regimen exposure.
- Special populations: For patients with mild hepatic impairment (Child‑Pugh A) or mild renal dysfunction (CrCl > 50 mL/min), no dose alteration is required.
- Monitoring tip: A transient rise in ALT/AST up to 3 × ULN early in therapy is common and typically self‑limited; treat only if > 5 × ULN or accompanied by bilirubin rise.
- Drug‑drug interactions: While sofosbuvir does not inhibit CYP3A4, caution with strong P‑gp inhibitors (e.g., ketoconazole) may necessitate dose adjustment for other concurrently started agents.
*References: FDA prescribing information, AASLD/IDSA guidelines, recent peer‑reviewed reviews (J. Hepatol. 2023; Clin. Gastroenterol. Hepatol. 2024).*