Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide

Abstract

Two novel oral drugs that target androgen signaling have recently become available for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone acetate inhibits the synthesis of the natural ligands of the androgen receptor, whereas enzalutamide directly inhibits the androgen receptor by several mechanisms. Abiraterone acetate and enzalutamide appear to be equally effective for patients with mCRPC pre- and postchemotherapy. Rational decision making for either one of these drugs is therefore potentially driven by individual patient characteristics. In this review, an overview of the pharmacokinetic characteristics is given for both drugs and potential and proven drug–drug interactions are presented. Additionally, the effect of patient-related factors on drug disposition are summarized and the limited data on the exposure–response relationships are described. The most important pharmacological feature of enzalutamide that needs to be recognized is its capacity to induce several key enzymes in drug metabolism. The potency to cause drug–drug interactions needs to be addressed in patients who are treated with multiple drugs simultaneously. Abiraterone has a much smaller drug–drug interaction potential; however, it is poorly absorbed, which is affected by food intake, and a large interpatient variability in drug exposure is observed. Dose reductions of abiraterone or, alternatively, the selection of enzalutamide, should be considered in patients with hepatic dysfunction. Understanding the pharmacological characteristics and challenges of both drugs could facilitate decision making for either one of the drugs.

Lactate dehydrogenase predicts combined progression‐free survival after sequential therapy with abiraterone and enzalutamide for patients with castration‐resistant prostate cancer

“…A number of hypotheses have been proposed to explain the difference in cross‐resistance between these two agents. First, enzalutamide induces CYP3A4, an enzyme responsible for abiraterone metabolism; thus, abiraterone used after enzalutamide might be metabolized earlier. Indeed, a recent prospective study indicated a correlation between plasma trough levels of abiraterone and both PSA response and PFS .…”

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

“…The DDI profiles of abiraterone and enzalutamide have recently been described by Del Re et al . and are shown to be very different . Potential DDIs with abiraterone are likely to cause increased plasma levels of co‐administered drugs metabolized through CYP2D6 (risk of toxicity) which are ~20% of all drugs, while enzalutamide causes decreased plasma levels of co‐administered drugs (risk of subtherapy) metabolized through CYP3A4, CYP2C19 and CYP2C9, which are involved in the biotransformation of ~50% of all drugs .…”

Considerations for interactions of drugs used for the treatment of COVID-19 with anti-cancer treatments

“…Idelalisib (Ballantyne and Garnock-Jones, 2013), Crizotinib (Forde and Rudin, 2012), Fedratinib (Xu et al, 2014), Dasatinib (Haouala et al, 2011), Abiraterone (Benoist et al, 2016), Bicalutamide (Meulenbeld et al, 2013), Aprepitant (Majumdar et al, 2003), Imatinib (Majumdar et al, 2003) Increase the level of CQ CYP2D6 inducers --CYP2D6 inhibitors…”