Drug Interactions between apalutamide and emtricitabine / nelfinavir / tenofovir disoproxil

MONITOR: Coadministration with drugs that are inducers of CYP450 3A4 may decrease the plasma concentrations of protease inhibitors (PIs), which are primarily metabolized by the isoenzyme.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, protease inhibitors should be used cautiously with agents that induce CYP450 3A4, particularly if only one PI is used in the antiretroviral regimen. Coadministration of atazanavir without ritonavir and carbamazepine, phenobarbital, or phenytoin is not recommended. Antiretroviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.

MONITOR: Coadministration with apalutamide may decrease the plasma concentrations of drugs that are substrates of the metabolic enzymes CYP450 3A4, CYP450 2C19, CYP450 2C9, and uridine diphosphate glucuronosyltransferase (UGT), as well as substrates of the membrane transporters organic anion transporting polypeptide (OATP) 1B1, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). According to the prescribing information, coadministration of apalutamide with single oral doses of sensitive CYP450 substrates resulted in a 92% decrease in the systemic exposure (AUC) of midazolam, a CYP450 3A4 substrate; 85% decrease in the AUC of omeprazole, a CYP450 2C19 substrate; and 46% decrease in the AUC of S(-) warfarin, a CYP450 2C9 substrate. These results indicate strong induction of CYP450 3A4 and 2C19 by apalutamide, and weak induction of CYP450 2C9. Coadministration of apalutamide with single oral doses of transporter substrates resulted in a 30% decrease in the AUC of fexofenadine, a P-gp substrate, and 41% decrease in the AUC of rosuvastatin, a BCRP/OATP1B1 substrate. These results suggest that apalutamide is a weak inducer of membrane transporters. Apalutamide may also induce UGT according to the prescribing information; however, no pharmacokinetic data from studies with UGT substrates are available.

MANAGEMENT: Caution is advised when apalutamide is used concomitantly with drugs that are substrates of CYP450 3A4, CYP450 2C19, CYP450 2C9, UGT, OATP1B1, P-gp and/or BCRP, particularly sensitive substrates or those with a narrow therapeutic range. Substitution for these medications is recommended when possible, or monitor for potential loss of therapeutic efficacy if coadministration is required. The prescribing information for concomitant medications should be consulted to assess the benefits versus risks of coadministration of a CYP450 inducer like apalutamide and for any dosage adjustments that may be required.