Drug Interactions between lorlatinib and sofosbuvir / velpatasvir

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may significantly decrease the plasma concentrations of sofosbuvir and other direct-acting antiviral agents that may be given with sofosbuvir in fixed-dose combination products such as ledipasvir and velpatasvir. Induction of P-gp-mediated efflux in the intestine decreases the oral bioavailability of these antiviral agents, which are substrates of the transporter. The interaction has been studied with rifampin, a potent inducer of P-gp and CYP450 isoenzymes. In 17 healthy volunteers, administration of a single 400 mg dose of sofosbuvir during multiple dosing of rifampin 600 mg once daily reduced mean sofosbuvir peak plasma concentration (Cmax) and systemic exposure (AUC) by 77% and 72%, respectively. Likewise, administration of a single 90 mg dose of ledipasvir to 31 healthy volunteers during multiple dosing of rifampin 600 mg once daily decreased mean ledipasvir Cmax and AUC by 35% and 59%, respectively. When a single 100 mg dose of velpatasvir was given with rifampin 600 mg once daily to 12 healthy volunteers, velpatasvir Cmax decreased by 71% and AUC decreased by 82%.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of P-gp inducers should generally be avoided during treatment with sofosbuvir, given either as a single-ingredient product or as a fixed-dose combination product with ledipasvir or velpatasvir.

GENERALLY AVOID: Coadministration with potent or moderate inducers of CYP450 isoenzymes may decrease the plasma concentrations of velpatasvir, which has been shown in vitro to be metabolized by CYP450 2B6, 2C8, and 3A4. The interaction has been studied with efavirenz, a moderate CYP450 2B6 and 3A4 inducer. In 14 healthy volunteers, administration of sofosbuvir-velpatasvir 400 mg -100 mg once daily with efavirenz/emtricitabine/tenofovir disoproxil fumarate 600 mg/200 mg/300 mg once daily decreased mean velpatasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 47%, 53% and 57%, respectively, compared to administration of sofosbuvir-velpatasvir alone. No clinically relevant pharmacokinetic changes were observed for sofosbuvir or its predominant circulating metabolite, GS-331007.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of sofosbuvir-velpatasvir with potent or moderate CYP450 inducers is not recommended.