Drug–drug interaction potential in men treated with enzalutamide: Mind the gap

Abstract

AIMSMetastatic castration-resistant prostate cancer (mCRPC) patients are generally older patients with several co-morbidities and are therefore at increased risk of complications due to drug-drug interactions (DDIs). We assessed the prevalence of potential DDIs in a cohort of mCRPC patients treated with enzalutamide. METHODSWe conducted a retrospective review of pharmacy records to retrieve individual drug histories of mCRPC patients who started enzalutamide therapy in a tertiary care setting. Potential DDIs were analysed using two international drug interaction compendia: Lexicomp ® and Micromedex ® , and the Dutch drug database. Two potential pharmacodynamic DDIs were analysed. RESULTSA total of 105 records were evaluated for potential DDIs with enzalutamide. Of 205 different co-medications, 56 were flagged by at least one of the three compendia: Lexicomp, Micromedex and the Dutch drug database flagged for potential DDIs in 85%, 54% and 32%, respectively. Eighty-five per cent of DDIs were classified as major. The median number of co-medications per patient was 11 (range 1-26). The median (range) number of interactions per patient was 4 (0-10), 1 (0-5) and 0 (0-2) for Lexicomp, Micromedex and the Dutch drug database, respectively. In 23% and 45% of all patients, a potential DDI was found with PPIs and CNS depressants, respectively. CONCLUSIONSA high prevalence of potential DDIs was found. The inclusion and grading of potential DDIs was highly variable between the three drug interaction compendia. Physicians, nurses and pharmacists should be aware of this potential problem, which might require intensive monitoring or alternative treatment strategies to prevent suboptimal treatment of the co-morbidities in patients treated with enzalutamide. British Journal of Clinical Pharmacology WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Enzalutamide is an inducer of several CYP450 enzymes; a strong inducer of CYP3A4 and a moderate inducer of CYP2C19 and CYP2C9.• mCRPC patients are generally older patients potentially with several co-morbidities and therefore at increased risk of complications due to drug-drug interactions. WHAT THIS STUDY ADDS• There is limited awareness of the drug interaction potential of enzalutamide. This is the first study that describes the high prevalence (85%) of potential major DDIs for patients treated with enzalutamide in a real live cohort.• The high prevalence (45%) of CNS interactions in this cohort requires attention, especially as the use of CNS depressants in combination with enzalutamide further increases the risk for cognitive side effects.• Future drug interaction studies with potential victims of enzalutamide are needed to assess the clinical relevance of these potential interactions.

Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial

“…The present analyses of the phase III ARAMIS trial demonstrated that almost all patients with nmCRPC receiving androgen-deprivation therapy with androgen receptor inhibitor therapy have comorbid conditions that require the use of concomitant medications. Individual patient data in ARAMIS indicated that many patients were receiving multiple comedications, as others have also reported [10]. As expected in this population (median age 74 years), the most common comorbidities included hypertension and other cardiovascular disorders, obesity, hyperlipidemia, osteoarthritis, and diabetes.…”

“…The potential for DDIs is an important consideration when selecting an androgen receptor-targeting therapy for patients with nmCRPC. Loss of efficacy with treatments for patients’ comorbidities or sustaining an increased risk of AEs are potential outcomes of DDIs [10, 24]. Extensive investigation in preclinical/phase I studies indicated that darolutamide has a favorable DDI profile.…”

A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration‐resistant metastatic prostate cancer

“…Furthermore, this case represents a further example of the lack of information on an important drug-drug interaction. Consistent with our recently published article in the journal, no uniform recommendation on the management was found for three widely used drug interaction databases (Micromedex®, Lexicomp®, and the drug Dutch database) [17].…”

Prevalence of potential drug–drug interactions in outpatients of a general hospital in China: a retrospective investigation

“…We did not obtain totality data such as herbal medicines, OTC drugs and vitamins taken by outpatients, which might contribute to the underestimation of pDDIs. Third, there are several available DDI databases with the disparities in the inclusion of pDDIs and the severity grading [28]. However, only one screening database was employed to estimate the prevalence of pDDIs.…”