Pharmacology of Sofosbuvir
Sofosbuvir, a prodrug of 2'-deoxy-2'-fluoro-2'-C-methyluridine monophosphate, is a specific nucleotide analogue inhibitor of the HCV NS5B polymerase that acts as a false substrate for the RdRp, leading to chain termination after incorporation into the newly synthesised RNA chain. The drug needs two additional phosphorylations to be activated. Sofosbuvir has a potent antiviral activity covering all HCV genotypes. Dose findings studies showed optimal inhibition of HCV replication by a once daily dose of 400 mg.
Sofosbuvir is a once-daily drug which can be taken with or without food. The drug traverses the GI tract and remains intact during absorption, resulting in high exposure in the liver. It is absorbed rapidly with a median tmax of 1 h (range 0.5–3.0 h). The elimination is rapid with median t½ in the range of 0.48–0.75 h. The active metabolite of sofosbuvir, GS-331007, exhibits a longer median tmax of 4 h (range 1.5–8) and a half life ranging from 7.27 to 11.80 h.
Sofosbuvir is mainly eliminated by the kidneys at a rate of 76%. Clearance of the drug is rapid, with median half life in the range of 0.48–0.75 h. No dose adjustment seems necessary in patients with renal clearance >30 mL/min, whereas modification of doses or dosing intervals may be required in patients with moderate to severe renal impairment or haemodialysis.
One of the additional advantages of sofosbuvir and other drugs of the same family is their low potential for DDI, because their metabolism is not linked to the CYP3A4 pathway. A recent study conducted in healthy volunteers assessed the potential for pharmacokinetic interactions between sofosbuvir and the immunosuppressants cyclosporine and tacrolimus and revealed that sofosbuvir did not affect the exposure to calcineurin inhibitors and only a slight increase in the concentration of sofosbuvir was observed in individuals who received cyclosporine. In addition, no clinically significant interactions have been observed with methadone or with antiretroviral therapies in HCV/HIV co-infected patients such as the nucleosidic reverse transcriptase inhibitors tenofovir and emtricitabine, the non-nucleosidic reverse transcriptase inhibitors efavirenz and rilpivirine or the protease inhibitors darunavir or ritonavir.