Panovir

Mechanism of action

Sofosbuvir blocks the HCV NS5B RNA-dependent RNA polymerase, an enzyme the virus needs to replicate. It is a nucleotide prodrug, so it is first broken down inside the cell into the active uridine analog triphosphate (GS-461203). The NS5B polymerase can build GS-461203 into HCV RNA, and once it is in, it acts as a chain terminator. In a biochemical assay, GS-461203 inhibited the polymerase activity of recombinant NS5B from HCV genotype 1b, 2a, 3a and 4a, with IC50 values from 0.36 to 3.3 micromolar. It does not inhibit human DNA polymerases or human RNA polymerases, and it does not inhibit mitochondrial RNA polymerase.

Velpatasvir blocks the HCV NS5A protein, which the virus also needs to replicate. Resistance selection in cell culture and cross-resistance studies point to NS5A as the target of velpatasvir.

Pharmacodynamics

Cardiac electrophysiology

A thorough QT trial with an active control (Moxifloxacin 400 mg) looked at the effect of Sofosbuvir on the QTc interval, at 400 mg (the recommended dosage) and at 1200 mg (three times the recommended dosage). At three times the recommended dose, Sofosbuvir does not prolong QTc to any clinically relevant extent. A second thorough QT trial, also with Moxifloxacin 400 mg as the active control, tested Velpatasvir 500 mg, which is five times the recommended dosage. At that dose, Velpatasvir does not prolong the QTc interval to any clinically relevant extent either.

Pregnancy: If Sofosbuvir + Velpatasvir is given with Ribavirin, the combination must not be used in pregnant women or in men whose female partners are pregnant. For the risks Ribavirin carries in pregnancy, please read the Ribavirin prescribing information.

Lactation: No one knows yet whether the components of Velpatasvir and Sofosbuvir, or their metabolites, pass into human breast milk. It is also not known whether they affect milk production or have any effect on a breastfed infant.

Females and males of reproductive potential: If Sofosbuvir and Velpatasvir is given with Ribavirin, what the Ribavirin information says about pregnancy testing, contraception and infertility applies to the combination as well. The Ribavirin prescribing information has more detail.

Geriatric Patients: A population pharmacokinetic analysis in people infected with HCV covered ages 18 to 82 years. Within that range, age had no clinically relevant effect on exposure to Sofosbuvir, GS-331007 or Velpatasvir.

Patients with Renal Impairment: Sofosbuvir was studied in HCV negative subjects after a single 400 mg dose. The groups were mild renal impairment (eGFR between 50 to less than 80 mL/min/1.73 m2), moderate (eGFR between 30 to less than 50 mL/min/1.73 m2) and severe (eGFR less than 30 mL/min/1.73 m2), plus subjects with ESRD who needed hemodialysis. Compared with subjects who had normal renal function (eGFR greater than 80 mL/min/1.73 m2), the Sofosbuvir AUC0-inf was 61%, 107% and 171% higher in mild, moderate and severe impairment. The GS-331007 AUC0-inf was 55%, 88% and 451% higher, respectively. In subjects with ESRD, the Sofosbuvir and GS-331007 AUC0-inf was 28% and 1280% higher when Sofosbuvir was given 1 hour before hemodialysis, and 60% and 2070% higher when it was given 1 hour after hemodialysis, respectively, again compared with normal renal function. A 4 hour hemodialysis session removed approximately 18% of the administered dose. Velpatasvir was studied as a single 100 mg dose in HCV negative subjects with severe renal impairment (eGFR less than 30 mL/min by Cockcroft-Gault). Its pharmacokinetics showed no clinically relevant differences between these subjects and healthy subjects.

Patients with Hepatic Impairment: Sofosbuvir was studied with 7-day dosing of 400 mg in HCV-infected subjects who had moderate and severe hepatic impairment (Child-Pugh Class B and C, respectively). Compared with subjects with normal hepatic function, the Sofosbuvir AUC0-24 was 126% and 143% higher in moderate and severe impairment, while the GS-331007 AUC0-24 was 18% and 9% higher, respectively. A population pharmacokinetics analysis in HCV-infected subjects found that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on exposure to Sofosbuvir and GS-331007. Velpatasvir was studied as a single 100 mg dose in HCV negative subjects with moderate and severe hepatic impairment (Child-Pugh Class B and C). Its plasma exposure (AUCinf) was similar in subjects with moderate impairment, subjects with severe impairment and control subjects with normal hepatic function. The population pharmacokinetics analysis in HCV-infected subjects also showed that cirrhosis (including decompensated cirrhosis) had no clinically relevant effect on exposure to Velpatasvir.

There is no specific antidote for an overdose of Sofosbuvir & Velpatasvir. If an overdose happens, the patient must be monitored for any sign of toxicity. Treatment is general supportive care, which means checking vital signs and watching the patient's clinical status.

Hemodialysis can remove the main circulating metabolite of Sofosbuvir, GS-331007, quite efficiently, with an extraction ratio of 53%. It is unlikely to remove much Velpatasvir, because Velpatasvir is highly bound to plasma protein.

Keep Sofosbuvir + Velpatasvir in a cool, dry place, preferably below 30°C. Keep it out of reach of children.