Xtandi Drug Interactions

Potential for other medicinal products to affect enzalutamide exposures: CYP2C8 inhibitors: In a drug-drug interaction study in healthy volunteers, a single 160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of gemfibrozil (strong CYP2C8 inhibitor). Gemfibrozil increased the AUC_0-inf of enzalutamide plus N-desmethyl enzalutamide by 2.2-fold with minimal effect on C_max. Co-administration of enzalutamide with strong CYP2C8 inhibitors (e.g. gemfibrozil) should be avoided if possible.
CYP3A4 inhibitors: In a drug-drug interaction study in healthy volunteers, a single 160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of itraconazole (strong CYP3A4 inhibitor).
Itraconazole increased the AUC_0-inf of enzalutamide plus N-desmethyl enzalutamide by 1.3-fold with no effect on C_max. No dose adjustment is necessary when enzalutamide is co-administered with inhibitors of CYP3A4.
CYP2C8 and CYP3A4 inducers: In a drug-drug interaction study in healthy volunteers, a single 160 mg oral dose of enzalutamide was administered alone or after multiple oral doses of rifampin (moderate CYP2C8 and strong CYP3A4 inducer). Rifampin decreased the AUC_0-inf of enzalutamide plus N-desmethyl enzalutamide by 37% with no effect on C_max. No dose adjustment is necessary when enzalutamide is co-administered with inducers of CYP2C8 or CYP3A4.
Potential for enzalutamide to affect exposures to other medicinal products: Enzyme induction: Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. The reduction in plasma concentrations can be substantial, and lead to lost or reduced clinical effect. There is also a risk of increased formation of active metabolites. Enzymes that may be induced include CYP3A in the liver and gut, CYP2B6, CYP2C9, CYP2C19, and uridine 5'-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). Some transporters may also be induced, e.g. multidrug resistance-associated protein 2 (MRP2) and the organic anion transporting polypeptide 1B1 (OATP1B1).
In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Co-administration of enzalutamide (160 mg once daily) with single oral doses of sensitive CYP substrates in prostate cancer patients resulted in an 86% decrease in the AUC of midazolam (CYP3A4 substrate), a 56% decrease in the AUC of S-warfarin (CYP2C9 substrate), and a 70% decrease in the AUC of omeprazole (CYP2C19 substrate). UGT1A1 may have been induced as well. In a clinical study in patients with metastatic CRPC, Xtandi (160 mg once daily) had no clinically relevant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m² by infusion every 3 weeks). The AUC of docetaxel decreased by 12% [geometric mean ratio (GMR)=0.882 (90% CI: 0.767, 1.02)] while C_max decreased by 4% [GMR=0.963 (90% CI: 0.834, 1.11)].
Interactions with certain medicinal products that are eliminated through metabolism or active transport are expected. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers.
Groups of medicinal products that can be affected include, but are not limited to: Analgesics (e.g. fentanyl, tramadol); Antibiotics (e.g. clarithromycin, doxycycline); Anticancer agents (e.g. cabazitaxel); Antiepileptics (e.g. carbamazepine, clonazepam, phenytoin, primidone, valproic acid); Antipsychotics (e.g. haloperidol); Antithrombotics (e.g. acenocoumarol, warfarin, clopidogrel); Betablockers (e.g. bisoprolol, propranolol); Calcium channel blockers (e.g. diltiazem, felodipine, nicardipine, nifedipine, verapamil); Cardiac glycosides (e.g. digoxin); Corticosteroids (e.g. dexamethasone, prednisolone); HIV antivirals (e.g. indinavir, ritonavir); Hypnotics (e.g. diazepam, midazolam, zolpidem); Immunosuppressives (e.g. tacrolimus); Proton pump inhibitors (e.g. omeprazole); Statins metabolized by CYP3A4 (e.g. atorvastatin, simvastatin); Thyroid agents (e.g. levothyroxine).
The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment, and dose adjustment should be considered as appropriate. In consideration of the long half-life of enzalutamide (5.8 days, see Pharmacology: Pharmacokinetics under Actions), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment.
CYP1A2, CYP2C8 substrates: Enzalutamide (160 mg once daily) did not cause a clinically relevant change in the AUC or C_max of caffeine (CYP1A2 substrate) or pioglitazone (CYP2C8 substrate). The AUC of pioglitazone increased by 20% while C_max decreased by 18%. The AUC and C_max of caffeine decreased by 11% and 4%, respectively. No dose adjustment is indicated when a CYP1A2 or CYP2C8 substrate is co-administered with enzalutamide.
P-gp substrates: In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. A mild inhibitory effect of enzalutamide, at steady-state, on P-gp was observed in a study in patients with prostate cancer that received a single oral dose of the probe P-gp substrate digoxin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC and C_max of digoxin increased by 33% and 17%, respectively. Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with enzalutamide and may require dose adjustment to maintain optimal plasma concentrations.
BCRP substrates: Based on in vitro data, inhibition of breast cancer resistance protein (BCRP) cannot be excluded. However, at steady-state, enzalutamide did not cause a clinically meaningful change in exposure to the probe BCRP substrate rosuvastatin in patients with prostate cancer that received a single oral dose of rosuvastatin before and concomitantly with enzalutamide (concomitant administration followed at least 55 days of once daily dosing of 160 mg enzalutamide). The AUC of rosuvastatin decreased by 14% while C_max increased by 6%. No dose adjustment is necessary when a BCRP substrate is co-administered with Xtandi.
MRP2, OAT3 and OCT1 substrates: Based on in vitro data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemically) cannot be excluded. Theoretically, induction of these transporters is also possible, and the net effect is presently unknown.
Effect of food on enzalutamide exposures: Food has no clinically significant effect on the extent of exposure to enzalutamide. In clinical trials, Xtandi was administered without regard to food.