Drug Interactions between mitotane and sofosbuvir / velpatasvir / voxilaprevir

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.

MONITOR: Coadministration with mitotane, a potent CYP450 3A4 inducer, may decrease the plasma concentrations and therapeutic efficacy of drugs that are substrates of the CYP450 3A4 isoenzyme. In one pilot study of 5 adult patients with adrenocortical carcinoma, etoposide clearance was 2-fold higher with concomitant mitotane (doses determined by patient-specific trough plasma levels) than after mitotane discontinuation, and 2.5-fold higher than the reference population of patients who received etoposide alone.

MANAGEMENT: Caution is advised when mitotane is used concomitantly with drugs that are substrates of CYP450 3A4, particularly sensitive substrates or those with a narrow therapeutic range. Monitoring for potential loss of therapeutic efficacy is recommended. According to product labeling, enzyme induction is likely to persist after the discontinuation of mitotane treatment. The prescribing information for concomitant medications may be consulted to assess the benefits versus risks of coadministration, as well as any dosage adjustments that may be required during coadministration and/or following the discontinuation of a potent CYP450 3A4 inducer.

MONITOR: Coadministration with inhibitors of organic anion transporting polypeptides (OATP) 1B1 and/or 1B3 may increase the plasma concentrations of voxilaprevir, which is a substrate of the hepatic uptake transporters. When a single 100 mg dose of voxilaprevir was administered with a single 600 mg dose of the potent OATP 1B1/1B3 inhibitor cyclosporine (n=24), mean voxilaprevir peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 19.0- and 9.4-fold, respectively. Inhibition of P-glycoprotein (P-gp)- and breast cancer resistance protein (BCRP)-mediated intestinal transport and CYP450 3A4-mediated metabolism of voxilaprevir may also contribute to the overall interaction with cyclosporine. The safety of such high levels of voxilaprevir has not been established.

MANAGEMENT: Caution and monitoring are advised when voxilaprevir is used with OATP 1B1 or 1B3 inhibitors.