Sofosbuvir - How It Works
Clinical pharmacology details from the US FDA-approved label: how Sofosbuvir works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C virus [see Microbiology ].
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VOSEVI is a fixed-dose combination of sofosbuvir, velpatasvir, and voxilaprevir which are DAA agents against the hepatitis C virus [see Microbiology ].
12.2 Pharmacodynamics Cardiac Electrophysiology The effect of sofosbuvir 400 mg (recommended dosage) and 1200 mg (3 times the recommended dosage) on QTc interval was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial.
At a dose 3 times the recommended dose, sofosbuvir does not prolong QTc to any clinically relevant extent.
The effect of velpatasvir 500 mg (5 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial.
At a dose 5 times the recommended dose, velpatasvir does not prolong QTc interval to any clinically relevant extent.
The effect of voxilaprevir 900 mg (9 times the recommended dosage) was evaluated in an active-controlled (moxifloxacin 400 mg) thorough QT trial.
At a dose 9 times the recommended dose, voxilaprevir does not prolong QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics The pharmacokinetic properties of the components of VOSEVI are provided in Table 4.
The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite GS-331007, velpatasvir, and voxilaprevir are provided in Table 5.
Table 4 Pharmacokinetic Properties of the Components of VOSEVI Sofosbuvir Velpatasvir Voxilaprevir CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1.
Absorption T max (h) 2 4 4 Effect of food (relative to fasting) Values refer to geometric mean systemic exposure.
VOSEVI should be taken with food. ↑ 64% to 144% ↑ 40% to 166% ↑ 112% to 435% Distribution % Bound to human plasma proteins 61–65 >99 >99 Blood-to-plasma ratio 0.7 0.5–0.7 0.5–0.8 Metabolism Metabolism Cathepsin A CES1 HINT1 CYP2B6 CYP2C8 CYP3A4 CYP3A4 Elimination Major route of elimination SOF: metabolism GS-331007 GS-331007 is the primary circulating nucleotide metabolite of SOF. : glomerular filtration and active tubular secretion Biliary excretion Biliary excretion t 1/2 (h) t 1/2 values refer to median terminal plasma half-life.
SOF: 0.5 GS-331007 : 29 17 33 % Of dose excreted in urine Single dose administration of [ 14 C] SOF, [ 14 C] VEL, [ 14 C] VOX in mass balance studies.
80 Predominantly as GS-331007.
0.4 0 % Of dose excreted in feces 14 94 (77% Percent of dose. as parent) 94 (40% as parent) Table 5 Multiple Dose Pharmacokinetic Parameters of Sofosbuvir and its Metabolite, GS-331007, Velpatasvir, and Voxilaprevir Following Oral Administration in HCV-Infected Adults Parameter Mean (%CV) Sofosbuvir From Population PK analysis, N = 1038 GS-331007 From Population PK analysis, N = 1593 Velpatasvir From Population PK analysis, N = 1595 Voxilaprevir From Population PK analysis, N = 1591 CV = coefficient of variation; NA = not applicable.
C max (nanogram per mL) 678 744 311 192 AUC tau (nanogram∙hr per mL) 1665 12834 4041 2577 C trough (nanogram per mL) NA NA 51 47 Sofosbuvir and GS-331007 AUC 0–24 and C max were similar in healthy adult subjects and subjects with HCV infection.
Relative to healthy subjects (N=137), velpatasvir AUC 0–24 and C max were 41% lower and 39% lower, respectively, in HCV-infected subjects.
Relative to healthy subjects (N=63), voxilaprevir AUC 0–24 and C max were both 260% higher in HCV-infected subjects.
Sofosbuvir and GS-331007 AUCs are near dose-proportional over the dose range of 200 mg to 1200 mg.
Velpatasvir AUC increases in a greater than proportional manner from 5 to 50 mg and in a less than proportional manner from 50 to 450 mg in healthy volunteers.
Pharmacokinetics
12.3 Pharmacokinetics The pharmacokinetic properties of the components of VOSEVI are provided in Table 4. The multiple dose pharmacokinetic parameters of sofosbuvir and its metabolite GS-331007, velpatasvir, and voxilaprevir are provided in Table 5. Table 4 Pharmacokinetic Properties of the Components of VOSEVI Sofosbuvir Velpatasvir Voxilaprevir CES1 = carboxylesterase 1; HINT1 = histidine triad nucleotide-binding protein 1. Absorption T max (h) 2 4 4 Effect of food (relative to fasting) Values refer to geometric mean systemic exposure. VOSEVI should be taken with food. ↑ 64% to 144% ↑ 40% to 166% ↑ 112% to 435% Distribution % Bound to human plasma proteins 61–65 >99 >99 Blood-to-plasma ratio 0.7 0.5–0.7 0.5–0.8 Metabolism Metabolism Cathepsin A CES1 HINT1 CYP2B6 CYP2C8 CYP3A4 CYP3A4 Elimination Major route of elimination SOF: metabolism GS-331007 GS-331007 is the primary circulating nucleotide metabolite of SOF. : glomerular filtration and active tubular secretion Biliary excretion Biliary excretion t 1/2 (h) t 1/2 values refer to median terminal plasma half-life. SOF: 0.5 GS-331007 : 29 17 33 % Of dose excreted in urine Single dose administration of [ 14 C] SOF, [ 14 C] VEL, [ 14 C] VOX in mass balance studies. 80 Predominantly as GS-331007. 0.4 0 % Of dose excreted in feces 14 94 (77% Percent of dose. as parent) 94 (40% as parent) Table 5 Multiple Dose Pharmacokinetic Parameters of Sofosbuvir and its Metabolite, GS-331007, Velpatasvir, and Voxilaprevir Following Oral Admi