Cardiovascular events among patients with prostate cancer treated with abiraterone and enzalutamide.

BACKGROUND AND PURPOSE: There is growing concern about the adverse metabolic and cardiovascular effects of abiraterone acetate (AA) and enzalutamide (ENZ), two standard hormonal therapies for prostate cancer. We analysed the risk of cardiovascular adverse events among patients treated with AA and ENZ. PATIENTS AND METHODS: We used Kythera Medicare data from January 2019 to June 2023 to identify patients with at least one pharmacy claim for AA or ENZ. The index date was the first prescription claim date. Patients were required to have 1 year of data pre- and post-index date. New users excluded those with prior AA or ENZ claims and pre-existing cardiovascular comorbidities. Demographic and clinical variables, including age, socioeconomic status (SES), comorbidity score, prostate-specific comorbidities, and healthcare costs, were analysed . Propensity score matching was employed for risk adjustment. RESULTS: Of the 8,929 and 8,624 patients in the AA and ENZ cohorts, respectively, 7,647 were matched after adjusting for age, sociodemographic, and clinical factors. Between the matched cohorts (15.54% vs. 14.83%, p < 0.05), there were no statistically significant differences in any cardiovascular event after adjusting for these factors. The most common cardiovascular event in both cohorts was heart failure (5.20% vs. 4.49%), followed by atrial fibrillation (4.42% vs. 3.60%) and hypotension (2.93% vs. 2.48%). INTERPRETATION: This study provides real-world evidence of the cardiovascular risk of AA and ENZ that may not appear in clinical trial settings. Adjusting for age, baseline comorbidities, and SES, the likelihood of a cardiovascular event did not differ between treatment groups.

Polymorphic ventricular tachycardia and cardiac arrest from abiraterone-induced hypokalemia: a case report.

BACKGROUND: Polymorphic ventricular tachycardia (PMVT) is an unstable and often fatal cardiac tachyarrhythmia. While there are many causes of this rhythm, including electrolyte imbalances, ischemia, and genetic disorders, iatrogenic etiologies are important to recognize. Abiraterone is an androgen synthesis antagonist effective in treating prostate cancer, but here we describe a case of severe hypokalemia secondary to abiraterone resulting in polymorphic ventricular tachycardia and cardiac arrest. While this is a potential adverse effect of the medication, severe hypokalemia causing polymorphic ventricular tachycardia and cardiac arrest, as seen in our patient's case, has not been described. CASE PRESENTATION: A 78-year-old African-American man with history of prostate cancer presents with polymorphic ventricular tachycardia and cardiac arrest. After resuscitation, he was found to be severely hypokalemic and refractory to large doses of repletion. Evaluation of secondary causes of hypokalemia identified the likely culprit to be adverse effects from prostate cancer treatment. CONCLUSION: A broad differential diagnosis for polymorphic ventricular tachycardia is essential in identifying and treating patients presenting in this rhythm. Here we present a case of iatrogenic polymorphic ventricular tachycardia secondary to oncologic treatment.

DHODH inhibition represents a therapeutic strategy and improves abiraterone treatment in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) is an aggressive disease with poor prognosis, and there is an urgent need for more effective therapeutic targets to address this challenge. Here, we showed that dihydroorotate dehydrogenase (DHODH), an enzyme crucial in the pyrimidine biosynthesis pathway, is a promising therapeutic target for CRPC. The transcript levels of DHODH were significantly elevated in prostate tumors and were negatively correlated with the prognosis of patients with prostate cancer. DHODH inhibition effectively suppressed CRPC progression by blocking cell cycle progression and inducing apoptosis. Notably, treatment with DHODH inhibitor BAY2402234 activated androgen biosynthesis signaling in CRPC cells. However, the combination treatment with BAY2402234 and abiraterone decreased intratumoral testosterone levels and induced apoptosis, which inhibited the growth of CWR22Rv1 xenograft tumors and patient-derived xenograft organoids. Taken together, these results establish DHODH as a key player in CRPC and as a potential therapeutic target for advanced prostate cancer.

An overlooked compound contributing to boar taint and consumer rejection of meat products: 2-Aminoacetophenone.

Mainly skatole and androstenone have so far been considered causative for boar taint. Using a mixed methods approach it is shown herein that 2-aminoacetophenone (AAP) affects human perception of pork, too. We explored the importance of AAP in four trials: (1) chemical analyses of 221 fat samples from boar carcasses revealed that AAP occurs, on average, in similar quantities as skatole while the levels of androstenone being four-fold. (2) ranking tests with mixtures of androstenone and/or skatole with AAP presented on smell strips to trained sensory assessors showed that AAP amplifies boar odour. In order to study AAP's importance in meat products, four experimental variants of Lyon type sausage were then produced: a control, a product with added skatole (0.075 µg/g fat tissue), with added AAP (0.075 µg/g fat tissue), and with addition of both compounds. (3) results of a consumer discrimination test panel (n = 71) showed that, when added to a sausage system, APP causes a sensory difference of similar size as skatole while the methodology chosen affects the effect size: tetrad tests proved to be more sensitive than duo trio difference tests, in the tetrad test a sensory difference expressed as d' (d-prime) of 1.0 was reached. (4) a hedonic consumer test (n = 121) finally revealed that APP decreased consumer liking of the APP-spiked sausage - even to a stronger extent than skatole. APP caused significant drops in smell, taste, mouth-feel, after-taste and overall liking in Lyoner. Overall the findings suggest that, in the context of pork meat, AAP is of similar olfactory importance as skatole.

Dual inhibition of CYP17A1 and HDAC6 by abiraterone-installed hydroxamic acid overcomes temozolomide resistance in glioblastoma through inducing DNA damage and oxidative stress.

Glioblastoma (GBM) is a highly aggressive and treatment-resistant brain tumor, necessitating novel therapeutic strategies. In this study, we present a mechanistic breakthrough by designing and evaluating a series of abiraterone-installed hydroxamic acids as potential dual inhibitors of CYP17A1 and HDAC6 for GBM treatment. We established the correlation of CYP17A1/HDAC6 overexpression with tumor recurrence and temozolomide resistance in GBM patients. Compound 12, a dual inhibitor, demonstrated significant anti-GBM activity in vitro, particularly against TMZ-resistant cell lines. Mechanistically, compound 12 induced apoptosis, suppressed recurrence-associated genes, induced oxidative stress and initiated DNA damage response. Furthermore, molecular modeling studies confirmed its potent inhibitory activity against CYP17A1 and HDAC6. In vivo studies revealed that compound 12 effectively suppressed tumor growth in xenograft and orthotopic mouse models without inducing significant adverse effects. These findings highlight the potential of dual CYP17A1 and HDAC6 inhibition as a promising strategy for overcoming treatment resistance in GBM and offer new hope for improved therapeutic outcomes.

Cost-effectiveness and budget impact analysis of enzalutamide in comparison to abiraterone in treatment of metastatic prostate cancer resistant to castration in Iran.

INTRODUCTION: In recent years, enzalutamide and abiraterone have been widely used as treatments for metastatic castration-resistant prostate cancer (mCRPC). However, the cost-effectiveness of these drugs in Iran is unknown. This study evaluated the cost-effectiveness of enzalutamide for the treatment of metastatic prostate cancer resistant to castration in Iran. METHODS: A 3-state Markov model was developed to evaluate the cost-effectiveness of enzalutamide and abiraterone from a social perspective over 10 years. The clinical inputs were obtained from the meta-analysis studies. The direct medical costs were obtained from the tariffs of the healthcare system, while the direct non-medical and indirect costs were collected from the patients. The data of utilities were derived from the literature. In addition, sensitivity analyses were conducted to assess the uncertainties. RESULTS: Compared with Abiraterone, enzalutamide was associated with a high incremental cost-effectiveness ratio (ICER) of $6,260 per QALY gained. According to the one-way sensitivity analysis, ICER was most heavily influenced by the prices of enzalutamide and Abiraterone, non-medical costs, and indirect costs. Regardless of the variation, enzalutamide remained cost-effective. The budget impact analysis of enzalutamide in the health system during 5 years was estimated at $6,362,127. CONCLUSIONS: At current prices, adding enzalutamide to pharmaceutical lists represents the cost-effective use of the healthcare resources in Iran for the treatment of metastatic castration-resistant prostate cancer.

The Impact of Circulating Tumor Cell HOXB13 RNA Detection in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide.

PURPOSE: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide. EXPERIMENTAL DESIGN: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide. CTC detection and HOXB13 complementary DNA (cDNA) expression was measured using a modified Adnatest, grouping patients into 3 categories: CTC 0 (undetectable); CTC+ HOXB13 CTC low (<4 copies); or CTC+ HOXB13 CTC high. The HOXB13 threshold was determined by maximally selected rank statistics for prognostic associations with overall survival (OS) and progression-free survival (PFS). RESULTS: We included 102 men with sufficient CTC HOXB13 cDNA, identifying 25%, 31%, and 44% of patients who were CTC 0, CTC+ HOXB13 low, and CTC+ HOXB13 high, respectively. Median OS were 25.7, 27.8, and 12.1 months whereas the median PFS were 9.0, 7.7, and 3.8 months, respectively. In subgroup analysis among men with CellSearch CTCs ≥5 copies/mL and adjusting for prior abi/enza treatment and Halabi clinical risk score, the multivariate HR for HOXB13 CTC detection was 2.39 (95% CI, 1.06-5.40) for OS and 2.78 (95% CI, 1.38-5.59) for PFS, respectively. Low HOXB13 CTC detection was associated with lower CTC PSA, PSMA, AR-FL, and AR-V7 detection, and more liver/lung metastases (41% vs. 25%). CONCLUSIONS: Higher CTC HOXB13 expression is associated with AR-dependent biomarkers in CTCs and is adversely prognostic in the context of potent AR inhibition in men with mCRPC.

A phase I/II study evaluating the pharmacokinetics, pharmacodynamics, and safety of drospirenone as an oral contraceptive in Japanese women.

AIM: Drospirenone (DRSP) is a synthetic progestogen approved as a progestin-only pill for contraception in both the United States and Europe. Herein, we conducted a phase I/II study to evaluate the pharmacokinetics, pharmacodynamics, and safety of DRSP in Japanese women. METHODS: Single and multiple doses of 4 mg of DRSP were orally administered to healthy premenopausal Japanese women. In the multiple-dose period, 4 mg of DRSP was administered once daily for 24 days. Pharmacokinetics, hormone levels, and adverse events (AEs) were investigated. RESULTS: Twelve Japanese women participated in this study. The single- and multiple-dose pharmacokinetics of DRSP was similar to that reported in previous studies in Caucasians. In the multiple-dose period, no subject displayed a progesterone level of more than 5.03 ng/mL. AEs were observed in 11 (91.7%) subjects. The most common AE was genital hemorrhage, which was observed in six (50.0%) subjects, followed by diarrhea and acne in four (33.3%) subjects each. All AEs resolved or improved at the end of the study, and complete recovery was confirmed in all subjects at follow-up. CONCLUSIONS: The pharmacokinetics of DRSP in Japanese women was similar to that of previous studies performed in Caucasian women. Repeated administration of DRSP maintained low plasma progesterone levels indicating effective inhibition of ovulation. No notable safety concerns were observed. In this phase I/II study, DRSP had no obvious pharmacokinetic, pharmacodynamic, or safety issues to consider in Japanese women.

Hospitalizations Among Veterans Treated for Metastatic Prostate Cancer With Abiraterone or Enzalutamide.

BACKGROUND: Abiraterone and enzalutamide are second generation androgen receptor pathway inhibitors (ARPIs) used to treat advanced or metastatic prostate cancer. Without head-to-head comparative studies identifying 1 agent as preferred initial therapy, physician preferences guide initial ARPI choice. This study compares hospitalizations among patients treated initially with abiraterone versus enzalutamide. PATIENTS AND METHODS: United States veterans treated with abiraterone or enzalutamide between May 13, 2011 and December 31, 2019; then compared hospitalization rate during first treatment with ARPI in the Veterans Healthcare Administration. Baseline incidence rate of hospitalization was determined from data 1 year prior to ARPI. Incidence Rate Difference (IRD) was calculated using χ2 test and difference in IRD using Poisson Regression. RESULTS: 19,775 veterans were identified; 13,527 (68.4%) were initially treated with abiraterone and 6248 (31.6%) initially with enzalutamide. The enzalutamide cohort was older (75.8 vs. 74.5 years, P < .001) and had higher baseline comorbidities at ARPI initiation (4.4 vs. 4.0, P < .001). Patients were treated with enzalutamide longer than abiraterone (median 9.0 vs. 8.0 months, P < .001). Total hospitalizations increased from 465 per 1000 person-years in the year prior to treatment with abiraterone to 567 during treatment. Total hospitalizations increased from 417 per 1000 person-years in the year prior to treatment with enzalutamide to 430 during treatment. Total rate of hospitalization increased 22% for abiraterone compared to a 3% increase for enzalutamide in the 12 months after ARPI initiation (P < .0001). Abiraterone was associated with greater increase in rates of acute heart failure, atrial fibrillation, acute kidney injury, urinary tract infections, sepsis, and pneumonia. CONCLUSION: By comparing the rate of hospitalization before vs. during treatment, real world analyses identified a 22% versus 3% increase in hospitalizations with abiraterone compared to enzalutamide respectively, despite being used in a younger population with less comorbid disease. Abiraterone was also associated with higher risk of infections, a novel finding.

Effect of food and polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on pharmacokinetics of abiraterone and its metabolites in Chinese volunteers.

AIMS: Abiraterone acetate, a prodrug of abiraterone (ABI), provides an efficient therapeutic option for metastatic castration-resistant prostate cancer patients. ABI undergoes extensive metabolism in vivo and is transformed into active metabolites Δ4 -abiraterone and 3-keto-5α-abiraterone as well as inactive metabolites abiraterone sulfate and abiraterone N-oxide sulfate. We aimed to examine the effect of polymorphisms in SLCO2B1, CYP3A4 and UGT1A4 on the pharmacokinetics of ABI and its metabolites. METHODS: In this study, 81 healthy Chinese subjects were enrolled and divided into 2 groups for fasted (n = 45) and fed (n = 36) studies. Plasma samples were collected after administering a 250 mg abiraterone acetate tablet followed by liquid chromatography-tandem mass spectrometry analysis. Genotyping was performed on a MassARRAY system. The association between SLCO2B1, CYP3A4, UGT1A4 genotype and pharmacokinetic parameters of ABI and its metabolites was assessed. RESULTS: Food effect study demonstrated high fat meal remarkedly increased systemic exposure of ABI and its metabolites. The geometric mean ratio and 90% confidence interval of area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t ) and maximum plasma concentration (Cmax ) of ABI in fed state vs. fasted state were 351.64% (286.86%-431.04%) and 478.45% (390.01%-586.94%), respectively, while the corresponding results were ranging from 145.11% to 269.42% and 150.10% to 478.45% for AUC0-t and Cmax of ABI metabolites in fed state vs. fasted state, respectively. The SLCO2B1 rs1077858 had a significant influence on AUC0-t and Cmax , while 7 other SLCO2B1 variants prolonged half-life of ABI under both fasted and fed conditions. As for ABI metabolites, the systemic exposure of Δ4 -abiraterone, abiraterone sulfate and abiraterone N-oxide sulfate as well as the elimination of 3-keto-5α-abiraterone were significantly affected by SLCO2B1 polymorphisms. Polymorphisms in CYP3A4 and UGT1A4 did not significantly affect pharmacokinetics of ABI and its metabolites. CONCLUSION: Polymorphisms in SLCO2B1 were significantly related to the pharmacokinetic variability of ABI and its metabolites under both fasted and fed conditions.

Predictive significance of inflammatory markers and mGPS in metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide.

BACKGROUND: Prostate cancer is a prevalent cancer in men worldwide, and castration-resistant prostate cancer (CRPC) is characterized by disease progression despite androgen deprivation therapy. While clinical and prognostic biomarkers have been identified in CRPC, the significance of serum inflammatory markers remains unclear. MATERIALS AND METHODS: This retrospective study included 79 CRPC patients treated with abiraterone or enzalutamide. Inflammatory markers, including the modified Glasgow prognostic score (mGPS), systemic immune-inflammation index (SII), and neutrophil-to-lymphocyte ratio (NLR), were assessed as predictive tools for treatment response. Patient data were obtained from medical charts, and statistical analyses were performed. RESULTS: The median age of the patients was 67 years, with most having a Gleason score of 8-10. The median values for NLR, PLR, and SII were 2.9, 168.5, and 713.5, respectively. The objective response rate (ORR) to abiraterone or enzalutamide therapy was 55.1%. mGPS showed a significant association with ORR, with the mGPS 0 group having the highest response rate (59.5%). Median progression-free survival (PFS) was 12.8 months, and median overall survival (OS) was 35.4 months. Palliative radiotherapy during therapy and PSA doubling time were independent prognostic factors for PFS. CONCLUSIONS: mGPS and PSA doubling time significantly impacted survival, and mGPS significantly predicted the treatment response in mCRPC, which may lead to further prospective studies.

Analysis on the therapeutic effect of Cangfu Daotan Decoction combined with drospirenone and ethinylestradiol tablets (II) on patients with polycystic ovary syndrome.

OBJECTIVE: This study was designed to investigate the therapeutic effect of Cangfu Daotan Decoction (CDD) combined with drospirenone and ethinylestradiol tablets (II) on patients with polycystic ovary syndrome (PCOS). METHODS: Patients with PCOS were gathered from September 2020 to September 2022 and divided into the experimental group (n = 36), treated with CDD combined with drospirenone and ethinylestradiol tablets (II), and the control group (n = 41), received only drospirenone and ethinylestradiol tablets (II). Levels of sex hormone, obesity, blood glucose, blood lipid were detected and compared between the two groups pre- and post-treatment. The treatment efficacy, Traditional Chinese Medicine (TCM) syndrome score, adverse drug reactions, and pregnancy rate were compared as well. RESULTS: After treatment, the experimental group had a higher treatment efficacy (94.44% vs 73.17%, P < 0.05) and a higher pregnancy rate (44.44% vs 21.95%, P < 0.05) than the control group, but the difference in the incidence of adverse drug reactions was not statistically significant (P > 0.05). Compared with control group, TCM syndrome score and levels of fasting blood glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), and waist circumference of the experimental group after treatment displayed remarkable reduction (P < 0.05), while the levels of estradiol (E2) and high-density lipoprotein cholesterol (HDL-C) showed a remarkable increase (P < 0.05). CONCLUSION: CDD in combination with drospirenone and ethinylestradiol tablets (II) may be effective in treating PCOS by improving obesity, glucose metabolism and lipid metabolism with no serious adverse events, making it a feasible clinical practice option.

FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

A new progestin-only pill (POP): the impact of drospirenone-only pill 4 mg 24 + 4 on coagulation markers and bleeding patterns.

PURPOSE: Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. The aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRSP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. MATERIALS AND METHODS: This is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F VIII, F V, INR, aPTT, Protein S and antithrombin III. A 'bleeding diary' was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. Thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. RESULTS: There was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F VII, F V and INR. A significant increase in aPTT (p = 0.01 at 3 cycles), Protein S (p = 0.0006 at 3 cycles) and antithrombin III (p < 0.0001 at 3 cycles) was recorded. This non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). CONCLUSIONS: DRSP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Contraception with DRSP 24 + 4 was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Combined oral contraceptive with estetrol plus drospirenone: from pharmacokinetics to clinical applications.

INTRODUCTION: Drospirenone/estetrol (DRSP/E4) is a combined oral contraceptive (COC) recently approved in several countries. It is composed of 15 mg of E4, a natural estrogen produced by human fetal liver throughout pregnancy, and 3 mg of DRSP, the first synthetic progestin used in oral contraception derived from 17-α-spirolactone. E4 and DRSP synergistically prevent pregnancy by inhibiting ovulation. E4 differs from 17-ß-estradiol or ethinylestradiol because it represents a native estrogen with selective action in tissues (NEST), therefore it displays both agonist and antagonist estrogenic effects in different tissues. AREAS COVERED: In this paper, we reviewed the scientific literature published in English prior to April 2023 and gathered information on the pharmacodynamics and pharmacokinetics of DRSP, E4 and their combination for contraception. We also proposed possible clinical applications based on the characteristics of the components of this COC. EXPERT OPINION: E4/DRSP-based COC has shown high tolerability, safety and satisfaction and may represent a viable choice in young girls in need of oral contraception and pill users who suffer from high cholesterol, breast tenderness or water retention. Moreover, this new COC shows higher scheduled bleeding rate compared to other pills containing natural estrogens. All the data are reassuring, permitting long-term use.

AKR1C3 Converts Castrate and Post-Abiraterone DHEA-S into Testosterone to Stimulate Growth of Prostate Cancer Cells via 5-Androstene-3ß,17ß-Diol.

Androgen receptor signaling inhibitors (ARSI) are used to treat castration-resistant prostate cancer (CRPC) to stop a resurgence of androgen receptor (AR) signaling. Despite early success, patients on ARSIs eventually relapse, develop drug resistance, and succumb to the disease. Resistance may occur through intratumoral steroidogenesis mediated by upregulation of aldo-keto reductase family 1C member 3 (AKR1C3). Patients treated with leuprolide (castrate) and those treated with leuprolide plus abiraterone (post-Abi) harbor a reservoir of DHEA-S which could fuel testosterone (T) biosynthesis via AKR1C3 to cause a resurgence of prostate cancer cell growth. We demonstrate that concentrations of DHEA-S found in castrate and post-Abi patients are (i) converted to T in an AKR1C3-dependent manner in prostate cancer cells, and (ii) in amounts sufficient to stimulate AKR1C3-dependent cell growth. We observed this in primary and metastatic prostate cancer cell lines, CWR22PC and DuCaP, respectively. Androgen measurements were made by stable isotope dilution LC-MS/MS. We demonstrate AKR1C3 dependence using stable short hairpin RNA knockdown and pharmacologic inhibitors. We also demonstrate that free DHEA is reduced to 5-androstene-3ß,17ß-diol (5-Adiol) by AKR1C3 and that this is a major metabolite, suggesting that in our cell lines 5-Adiol is a predominant precursor of T. We have identified a mechanism of ARSI resistance common to both primary and metastatic cell lines that is dependent on the conversion of DHEA to 5-Adiol on route to T catalyzed by AKR1C3. SIGNIFICANCE: We show that reservoirs of DHEA-S that remain after ARSI treatment are converted into T in primary and metastatic prostate cancer cells in amounts sufficient to stimulate cell growth. Pharmacologic and genetic approaches demonstrate that AKR1C3 is required for these effects. Furthermore, the route to T proceeds through 5-Adiol. We propose that this is a mechanism of ARSI drug resistance.

Scale-Up of Phytosterols Bioconversion into Androstenedione.

Phytosterols, coming as a by-product of vegetable oils or wood pulp, contain the cyclopentanoperhydrophenanthrene nucleus and can be bioconverted into steroid intermediates by removing the C17 side chain. This chapter shows the scale-up, from flask to bioreactor, of phytosterols bioconversion into 4-androstene-3,17-dione (androstenedione; AD) using Mycolicibacterium neoaurum B-3805. Due to the fact that phytosterols and AD are nearly insoluble in water, two-phase systems and the use of chemically modified cyclodextrins have been described as methods to solve it. Here, we use a water-oil two-phase system that allows the bioconversion of up to 20 g/L of phytosterols into AD in 5 L and 20 L bioreactors.

Unraveling Complexities in the Absorption and Disposition Kinetics of Abiraterone via Iterative PBPK Model Development and Refinement.

BACKGROUND AND OBJECTIVE: Abiraterone is a first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1), and its pharmacokinetic (PK) profile is susceptible to intrinsic and extrinsic variabilities. Potential associations between abiraterone concentrations and pharmacodynamic consequences in prostate cancer may demand further dosage optimization to balance therapeutic outcomes. Consequently, we aim to develop a physiologically based pharmacokinetic (PBPK) model for abiraterone via a middle-out approach to prospectively interrogate the untested, albeit clinically relevant, scenarios. METHODS: To characterize in vivo hydrolysis of prodrug abiraterone acetate (AA) and supersaturation of abiraterone, in vitro aqueous solubility data, biorelevant measurements, and supersaturation and precipitation parameters were utilized for mechanistic absorption simulation. CYP3A4-mediated N-oxidation and sulfotransferase 2A1-catalyzed sulfation of abiraterone were subsequently quantified in human liver subcellular systems. Iterative PBPK model refinement involved evaluation of potential organic anion transporting polypeptide (OATP)-mediated abiraterone uptake in transfected cells in the absence and presence of albumin. RESULTS: The developed PBPK model recapitulated the duodenal concentration-time profile of both AA and abiraterone after simulated AA administration. Our findings established abiraterone as a substrate of hepatic OATP1B3 to recapitulate its unbound metabolic intrinsic clearance. Further consideration of a transporter-induced protein-binding shift established accurate translational scaling factors and extrapolated the sinusoidal uptake process. Subsequent simulations effectively predicted the PK of abiraterone upon single and multiple dosing. CONCLUSION: Our systematic development of the abiraterone PBPK model has demonstrated its application for the prospective interrogation of the individual or combined influences of potential interindividual variabilities influencing the systemic exposure of abiraterone.