Erleada Drug Interactions

Medications that Inhibit CYP2C8: In a drug-drug interaction study, the C_max of apalutamide decreased by 21% while AUC increased by 68% following co-administration of Apalutamide (Erleada) as a 240 mg single dose with gemfibrozil (strong CYP2C8 inhibitor). Simulations suggest that gemfibrozil may increase the steady-state C_max and AUC of apalutamide by 32% and 44%, respectively. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound active metabolite), the steady-state C_max and AUC may increase by 19% and 23%, respectively (see Figure 11). No initial dose adjustment is necessary however, consider reducing the Apalutamide (Erleada) dose based on tolerability (see Dose modification under Dosage & Administration). Mild or moderate inhibitors of CYP2C8 are not expected to affect the exposure of apalutamide.
Medications that Inhibit CYP3A4: In a drug-drug interaction study, the C_max of apalutamide decreased by 22% while AUC was similar following co-administration of Apalutamide (Erleada) as a 240 mg single dose with itraconazole (strong CYP3A4 inhibitor). Simulations suggest that ketoconazole (strong CYP3A4 inhibitor) may increase the steady-state C_max and AUC of apalutamide by 38% and 51%, respectively. For the active moieties, the steady-state C_max and AUC may increase by 23% and 28%, respectively (see Figure 11). No initial dose adjustment is necessary however, consider reducing the Apalutamide (Erleada) dose based on tolerability (see Dose modification under Dosage & Administration). Mild or moderate inhibitors of CYP3A4 are not expected to affect the exposure of apalutamide.
Medications that Induce CYP3A4 or CYP2C8: The effects of CYP3A4 or CYP2C8 inducers on the pharmacokinetics of apalutamide have not been evaluated in vivo. Simulations suggest that rifampin (strong CYP3A4 and moderate CYP2C8 inducer) may decrease the steady-state C_max and AUC of apalutamide by 25% and 34%, respectively. For the active moieties, the steady-state C_max and AUC may decrease by 15% and 19%, respectively (see Figure 11).
Acid lowering agents: Apalutamide is not ionizable under relevant physiological pH condition, therefore acid lowering agents (e.g. proton pump inhibitor, H₂-receptor antagonist, antacid) are not expected to affect the solubility and bioavailability of apalutamide.
Medications that affect transporters: In vitro, apalutamide and its N-desmethyl metabolite are substrates for P-gp but not BCRP, OATP1B1, and OATP1B3. Because apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide and therefore, inhibition or induction of P-gp is not expected to affect the bioavailability of apalutamide.
Effect of Apalutamide (Erleada) on drug metabolizing enzymes: In vitro studies showed that apalutamide and N-desmethyl apalutamide are moderate to strong CYP3A4 and CYP2B6 inducers, are moderate inhibitors of CYP2B6 and CYP2C8, and weak inhibitors of CYP2C9, CYP2C19, and CYP3A4. Apalutamide and N-desmethyl apalutamide do not affect CYP1A2 and CYP2D6 at therapeutically relevant concentrations.
In humans, Apalutamide (Erleada) is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9. In a drug-drug interaction study using a cocktail approach, co-administration of Apalutamide (Erleada) with single oral doses of sensitive CYP substrates resulted in a 92% decrease in the AUC of midazolam (CYP3A4 substrate), 85% decrease in the AUC of omeprazole (CYP2C19 substrate), and 46% decrease in the AUC of S-warfarin (CYP2C9 substrate). Apalutamide (Erleada) did not cause clinically meaningful changes in exposure to the CYP2C8 substrate (see Figure 4). Concomitant use of Apalutamide (Erleada) with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of efficacy if medication is continued. If given with warfarin, monitor International Normalized Ratio (INR) during Apalutamide (Erleada) treatment.
Induction of CYP3A4 by apalutamide suggests that UDP-glucuronosyl transferase (UGT) may also be induced via activation of the nuclear pregnane X receptor (PXR). Concomitant administration of Apalutamide (Erleada) with medications that are substrates of UGT can result in lower exposure to these medications. Use caution if substrates of UGT must be co-administered with Apalutamide (Erleada) and evaluate for loss of efficacy.
Effect of apalutamide on drug transporters: Apalutamide was shown to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. A drug-drug interaction study using a cocktail approach showed that co-administration of Apalutamide (Erleada) with single oral doses of sensitive transporter substrates resulted in a 30% decrease in the AUC of fexofenadine (P-gp substrate) and 41% decrease in the AUC of rosuvastatin (BCRP/OATP1B1 substrate) but had no impact on C_max (see Figure 11). Concomitant use of Apalutamide (Erleada) with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP or OATP1B1 must be co-administered with Apalutamide (Erleada) and evaluate for loss of efficacy if medication is continued.
Based on in vitro data, inhibition of organic cation transporter 2 (OCT2), organic anion transporter 3 (OAT3) and multidrug and toxin extrusions (MATEs) by apalutamide and its N-desmethyl metabolite cannot be excluded. No in vitro inhibition of organic anion transporter 1 (OAT1) was observed. Simulations suggest that apalutamide does not cause clinically meaningful changes in exposure to metformin (OCT2/MATEs substrate) and benzylpenicillin (OAT3 substrate) (see Figure 11).

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