Pharmacokinetic Drug Interaction Studies with Enzalutamide

Abstract

Background and ObjectivesTwo phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC).MethodsA parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg).ResultsCoadministration of gemfibrozil increased the composite area under the plasma concentration–time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4.ConclusionsIf a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0283-1) contains supplementary material, which is available to authorized users.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…Gemfibrozil has raised the AUC of the androgen receptor antagonist enzalutamide by 4.3-fold, and itraconazole raised it by 1.4-fold compared with control (Gibbons et al, 2015). These results agree well with the in vitro findings that CYP2C8 is the predominant enzyme in the elimination of enzalutamide.…”

“…Then, M6 is further metabolized by CYP2C8 to the active metabolite N-demethyl enzalutamide (M2), which accounts for approximately 50% of the total drug exposure in plasma. CYP2C8 seems to be the predominant enzyme involved in enzalutamide pharmacokinetics also in vivo (section VI.C.5; Gibbons et al, 2015). Eagling et al, 1994 5-HT, 5-hydroxytryptamine (serotonin); 5-MeO-DIPT, 5-methoxy-N,N-diisopropyltryptamine; 9cUAB30, (2E,4E,6Z,8E)-8-(39,4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid; ARB, angiotensin II receptor blocker; ATP, adenosine triphosphate; BYZX, [(E)-2-(4-((diethylamino)methyl)benzylidene)-5,6-dimethoxy-2,3-dihydroinden-one]; CCB, calcium channel blocker; Compound A, [(+)-(5S,6R,7R)-2-isopropylamino-7-[4-methoxy-2-((2R)-3-methoxy-2-methylpropyl)-5- (3,4-methylenedioxyphenyl) cyclopenteno[1,2-b] pyridine 6-carboxylic acid]; DPP, dipeptidyl peptidase; DRI, dopamine reuptake inhibitor; chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxy-1-(4-imidazolylmethyl)-1H-indazole dihydrochloride 3.5 hydrate; ERA, endothelin receptor antagonist; FTI, farnesyl transferase inhibitor; GABA, g-aminobutyric acid; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A;IN-1130, 3-((5-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-imidazol-2-yl)methyl)benzamide; K11777, N-methyl-piperazine-Phe-homoPhevinylsulfone-phenyl; L-775,606, (1-(3-(5-(1,2, 4-triazol-4-yl)-1H-indol-3-yl)propyl)-4-(2-(3-fluorophenyl)ethyl)piperazine); LABA, long-acting b-adrenoceptor agonist; LTRA, leukotriene receptor antagonist; MAO, monoamine oxidase; mGLUR, metabotropic glutamate receptor; c-mpl, myeloproliferative leukemia; NaSSA, noradrenergic and specific serotonergic antidepressant; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside analog reverse transcriptase inhibitor; NS, nonstructural protein; NSAID, nonsteroidal anti-inflammatory drug; PDE, phosphodiesterase; PGD2, prostaglandin D2; PKI, protein kinase inhibitor; PPAR, peroxisome proliferatoractivated receptor; PPI, proton pump inhibitor; sGC, soluble guanylate cyclase; SERM, selective estrogen receptor modulator; SMS, serotonin modulator and stimulator; SSRI, selective serotonin reuptake inhibitor; STS, steroid sulfatase; T-5, methyl 2-(4-aminophenyl)-1-oxo-7-(pyridin-2-ylmethoxy)-4-(3,4,5-trimethoxyphenyl)-1,2-dihydroisoquinoline-3-carboxylate; TCA, tricyclic antidepressant; TXRA, thromboxane A2 receptor antagonist; VKA, vitamin K antagonist; XO, xanthine oxidase.…”

In Vitro and In Vivo Drug-Drug Interaction Studies to Assess the Effect of Abiraterone Acetate, Abiraterone, and Metabolites of Abiraterone on CYP2C8 Activity

“…CYP450 2C8 (CYP2C8), in particular, has emerged relatively recently as an important enzyme that is responsible for the metabolism of a diverse group of drugs in humans, including repaglinide, pioglitazone, rosiglitazone, paclitaxel, dasabuvir, and the androgen-signaling inhibitor enzalutamide (Daily and Aquilante, 2009;Gibbons et al, 2015). Available data suggest that genetic variation in CYP2C8 can alter drug disposition in vivo (Niemi et al, 2003(Niemi et al, , 2005Kirchheiner et al, 2006).…”

The Role of Drug Exposure in Clinical Development: To What Extent Is Pharmacokinetic Assessment Needed in a Drug Development Programme?

“…Gibbons et al present summary data from multiple studies in this issue, providing a snapshot of exposure to enzalutamide and its key metabolites in healthy volunteers and patients requiring treatment for castration-resistant prostate cancer [2,3]. Exposure data from these key studies aid understanding of how different pieces come together and contribute towards drug approval and, importantly, any dose-related labelling recommendations.…”

“…The major active metabolite, N-desmethyl-enzalutamide, with activity comparable to that of the parent compound and found at systemic levels similar to those of enzalutamide, was also measured. This study provides a good example of utilization of modelbased population analyses, the absence of which could lead to underestimation of the impact of DDIs [3]. The analyses recommended halving the 160 mg dose of enzalutamide to 80 mg when co-administering it with a CYP2C8 inhibitor to avoid the adverse events observed at exposures achieved with doses [240 mg in the FTIH study.…”