Patient GD is a 78 yo male coming into the pharmacy with a question about a prescription from his oncologist. He was recently prescribed apalutamide 240 mg PO daily for treatment of his prostate cancer. He is wondering if his new prescription would affect any of his existing medications. GD has a past medical history of prostate cancer, atrial fibrillation, hypertension, and an ischemic stroke that happened 6 months ago. His current medication list includes degarelix 80 mg injected SC every 28 days, diltiazem XR 240 mg PO daily, warfarin 5 mg PO daily, lisinopril 10 mg PO daily, and aspirin 81 mg PO daily. Which of the following medications does apalutamide have potential drug-drug interactions? (Select all that apply) 

A. Degarelix 

B. Diltiazem 

C. Warfarin 

D. Lisinopril

E. Aspirin  

Correct answers with rationale: B and C

Apalutamide is an androgen receptor inhibitor used in the treatment of advanced prostate cancer. The drug is a substrate of CYP3A4(minor) while also being a strong inducer of CYP3A4 and CYP2C19.  Apalutamide is a major substrate of CYP2C8 and a minor substrate of 3A4. There is the possibility of apalutamide inducing its own metabolism (autoinduction) and requiring a dose increase, however this effect is not as dramatic as it is with a drug like carbamazepine.

Answer choice A is incorrect as degarelix is a gonadotropin releasing hormone antagonist primarily metabolized by the hepatobiliary route via peptide hydrolysis, not by CYP enzymes. A similar drug, relugolix, is affected by strong CYP3A inducers such as apalutamide. 

Answer choice B is correct as diltiazem is a moderate CYP3A4 inhibitor and coadministration with apalutamide could lead to increased levels of apalutamide, leading to potentially increased apalutamide toxicity such as increased blood pressure, fatigue, and seizures. In addition, diltiazem is a major substrate of CYP3A4 as well. Apalutamide, through induction of CYP3A4, will potentially decrease the concentrations of diltiazem, leading to decreased efficacy of the patient’s rate control and potential worsening of his atrial fibrillation. 

Answer choice C is correct as warfarin consists of a pair of two enantiomers, R-warfarin and S-warfarin. S-warfarin is the active form of warfarin in the use for anticoagulation. R-Warfarin is metabolized by CYP3A4 while S-warfarin is metabolized by CYP2C9. Apalutamide does possess weak CYP 2C9 induction which could potentially decrease warfarin concentrations, decrease INR, and potentially increase the patient’s risk of thrombotic event. One study referenced in the package insert demonstrated that AUC of S-warfarin decreased by 46% when co-administered with apalutamide.  

Answer choice D is incorrect as lisinopril is primarily excreted unchanged without appreciable CYP metabolism. Even though there is not a direct drug-drug interaction, apalutamide has a side effect of increased blood pressure, thus lisinopril may need to be titrated up in response to increased blood pressure. 

Answer choice E is incorrect as aspirin is metabolized primarily through hepatic conjugation, not through CYP enzymes. Aspirin also does not have an effect on CYP enzymes. 

See everyone next week!

References: 

Package insert apalutamide: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210951s001lbl.pdf 

NAPLEX Exam Competencies Covered: Area 3 – Develop or Manage Treatment Plans, Section 3.8 – Drug interactions