Introduction

Abiraterone is an antiandrogen used in the treatment of metastatic castration-resistant prostate cancer and metastatic high-risk castration-sensitive prostate cancer.As abiraterone has poor oral bioavailability and is susceptible to hydrolysis by esterases, abiraterone acetate was developed as an orally bioavailable prodrug with enhanced stability and absorption. Here, the mechanism of action and pharmacological properties are summarized.

Mechanism of action of abiraterone acetate

CYP17 complex, an enzyme complex required for synthesis of androgen was first inhibited by ketoconazole. Ketoconazole shows weak and non-specific inhibitory effect on CYP17 via inhibiting 11β-hydroxylase, which cuts off the side chain of cholesterol ring of pregnenolone. This weak inhibition requires a large dose and for limited clinical effectiveness and increased drug-drug interaction due to nonspecific CYP inhibition. These limitations in the efficacy resulted in the need for a more selective and efficient inhibitory action on CYP17complex resulting in the development of abiraterone acetate with a better safety profile. A study showed the inhibitory concentrations of abiraterone acetate towards 17αhydroxylase and C17, 20-lyase are 4 and 2.9 nmol/l, respectively.In comparison, inhibitory concentrations of abiraterone acetate are 18 and 17nmol/l,while ketaconazole's being 65 and 26 nmol/l. CYP17 shows catalytic action and converts pregnenolone and progesterone to intermediate 17-hydroxy products which finally gets metabolized to androstenedione by C17, 20-lyase and DHEA. 17α-hydroxysteroid dehydrogenase present in testis converts DHEA and androstenedione to testosterone, and further gets converted to dihydrotestosterone (DHT) on 3β-hydroxysteroiddehydrogenase/isomerase action. Tissues at testicles, prostrate, and adrenal glands are the sites for expression of CYP17 which also has 17 times higher expression in mCRPC than primary prostrate tumors. Abiraterone is the active metabolite of abiraterone acetate which is formed upon hydrolysis and irreversibly inhibits CYP17. It is an agent with pregnenolone, as a parent structure and includes a 3-pyridyl and 16, 17double-bond substitution which are key functional groups essential for inhibiting CYP17. These substitutions increase the inhibitory action on CYP17 by 10–30 folds when compared to ketoconazole.Androgen production is also inhibited by interference with enzymeslike C17, 20-lyase and C17α-hydroxylase. CYP2D6 and CYP1A2 are also partially inhibited by abiraterone acetate and thus may hinder the metabolism of other drugs as observed in in-vitro studies. CYP17 enzyme complex plays a significant role in cortisol formation from cholesterol and androgens like testosterone biosynthesis. This results in testosterone blockage, from all tissues and simultaneously declining the synthesis of hormones like cortisol (Figure. 1). This mechanism of negative feedback by steroids results in increased production of ACTH in the pituitary, which results into hormonal upsurge. This leads to the mineralocorticoid excess syndrome, characterized by hypokalemia, peripheral edema, and hypertension. This effect may be overcome by low dose steroid like prednisone along with abiraterone acetate. However abiraterone acetate has minimal effect on hepatic drug metabolism (CYP3A4), glucocorticoid biosynthesis(CYP11B1), and mineralocorticoid synthesis (CYP11B2).[1]

Pharmacodynamic Properties

Abiraterone, the active metabolite of abiraterone acetate,irreversibly inhibits CYP17 (17α-hydroxylase/C17,20-lyase), an essential enzyme in androgen biosynthesis that is expressed in testicular, adrenal and prostatic tumour tissues. CYP17 levels are significantly (p=0.0005) higher(≈17-fold) in CRPC metastases than in primary prostate tumours. As reviewed previously , pregnenolone and progesterone are converted to 17 α-hydroxy derivatives by 17a-hydroxylase and subsequently by C17,20-lyase to dehydroepiandrosterone and androstenedione (precursors of androgens and testosterone).In phase 1 or 2 trials (reviewed previously), abiraterone acetate 250-2000mg once daily was associated with antitumor effects, including reduced prostate-specificantigen (PSA) levels (a biomarker in patients with mCRPC) and circulating tumour cell (CTC) counts. Abiraterone acetate also suppressed serum testosterone levels to undetectable or near undetectable levels after ≤28 days’therapy in patients with progressive CRPC, and in combination with prednisone, suppressed blood and bone marrow aspirate testosterone levels to below pg/mL levels inpatients with mCRPC, with this suppression maintained at disease progression. In vivo, phenotypes that exhibited ultra, intermediate and minimal responses to abiraterone acetate treatment were identified in a mouse model utilizing patient-derived PC xenograft. The ultra responsive phenotype was characterized by reduced AR signalling with the development of abiraterone acetate resistance,suggesting an AR-independent pathway to sustain survival;whether this translates into a biomarker to predict sustainability of clinical responses remains to be fully elucidated.

Concomitant use of a corticosteroid with abiraterone acetate therapy ameliorated the adverse symptoms associated with abiraterone acetate-induced mineralocorticoid excess in phase 1 and 2 trials; all participants in phase 3trials received concomitant prednisone.In patients with mCRPC, the QT/QTc interval does not appear to be affected by therapeutic dosages of abiraterone acetate (+prednisone). Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering abiraterone acetate with drugs known to prolong the QT interval or drugs that induce torsades de pointes (e.g class ⅠA and III antiarrhythmic drugs;methadone, moxifloxacin, antipsychotics).[2]

Pharmacokinetic Properties

Oral abiraterone acetate is rapidly absorbed and converted to its active metabolite abiraterone, with maximum plasma concentrations of abiraterone attained in a median time of 2 h in the fasted state. Systemic exposure of abiraterone is increased to a clinically relevant extent when abiraterone acetate is administered with food; thus, the drug should be taken 2 h after or at least 1 h before meals. At steady state, accumulation of abiraterone was observed, with exposure increasing twofold with multiple 1000 mg doses versus a single dose. Abiraterone is highly bound ([99%) to the human plasma proteins albumin and a-1 acid glycoprotein and appears to be extensively distributed into peripheral tissues (steady-state mean apparent volume of distribution 19,669 L). Metabolism of abiraterone predominantly occurs in the liver and involves hydroxylation, oxidation and sulphation, and is most likely mediated via esterase activity, with no involvement of CYP enzymes. After a radiolabeled dose, ≈92% of circulating radioactivity is present as metabolites of abiraterone, with ≈88% of the radioactivity excreted in the faeces and ≈5% in urine. The major components in the faeces are unchanged abiraterone acetate (≈55%) and abiraterone (≈22%). In patients with mCRPC, the mean terminal half-life of abiraterone in the plasma is 12 h.

There was no clinically relevant impact on the pharmacokinetics (PKs) of abiraterone acetate in patients with renal impairment or end-stage renal disease on haemodialysis; in the EU, caution is advised in patients with severe renal impairment due to a lack of clinical data. Mildhepatic impairment (Child-Pugh class A) had minimal effects on the PKs of abiraterone acetate, with no dosage adjustments required in these patients. Given that the drug is primarily metabolized in the liver and eliminated in the faeces, moderate or severe hepatic impairment (ChildPugh class B and C) increased exposure to abiraterone and prolonged elimination to a clinically relevant extent; local prescribing information should be consulted for use in these patient populations. In vitro, the major metabolites of abiraterone acetate inhibited the hepatic uptake transporter OAT1B1; no clinical data are available to confirm transporter based interaction. In vitro, in addition to inhibiting CYP17,abiraterone is a strong inhibitor of CYP2D6 and CYP2C8. In men with mCRPC, the PKs of theophylline (a strong CYP1A2 substrate) were not altered when it was coadministered with abiraterone acetate. Abiraterone acetate is potentially associated with clinically relevant drug-drug interactions when coadministered with strongCYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampicin, rifabutin), CYP2C6 substrates (e.g. dextromethorphan) and drugs that are predominantly eliminated byCYP2C8 (e.g. pioglitazone). When coadministered with ketoconazole (strong CYP3A4 inhibitor), there was no clinically meaningful effect on the PKs of abiraterone in healthy volunteers. Local prescribing information should be consulted for comprehensive information on potential drug-drug interactions associated with abiraterone acetate use.[2]

References

[1]Thakur A, Roy A, Ghosh A, Chhabra M, Banerjee S. Abiraterone acetate in the treatment of prostate cancer. Biomed Pharmacother. 2018;101:211-218. doi:10.1016/j.biopha.2018.02.067

[2]Scott LJ. Abiraterone Acetate: A Review in Metastatic Castration-Resistant Prostrate Cancer. Drugs. 2017;77(14):1565-1576. doi:10.1007/s40265-017-0799-9