Characterization and prediction of OATP1B activity in prostate cancer patients on abiraterone acetate using endogenous biomarker coproporphyrin I.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are important hepatic transporters. We previously identified OATP1B3 being critically implicated in the disposition of abiraterone. We aimed to further investigate the effects of abiraterone on the activities of OATP1B1 and OATP1B3 utilizing a validated endogenous biomarker coproporphyrin I (CP-I). We utilized OATP1B-transfected cells to characterize the inhibitory potential of abiraterone against OATP1B-mediated uptake of CP-I. Inhibition constant (Ki) was incorporated into our physiologically based pharmacokinetic (PBPK) modeling to simulate the systemic exposures of CP-I among cancer populations receiving either our model-informed 500 mg or clinically approved 1000 mg abiraterone acetate (AA) dosage. Simulated data were compared with clinical CP-I concentrations determined among our 9 metastatic prostate cancer patients receiving 500 mg AA treatment. Abiraterone inhibited OATP1B3- but not OATP1B1-mediated uptake of CP-I in vitro, with an estimated Ki of 3.93 µM. Baseline CP-I concentrations were simulated to be 0.81 {plus minus} 0.26 ng/mL, and determined to be 0.72 {plus minus} 0.16 ng/mL among metastatic prostate cancer patients, both of which were higher than those observed for healthy subjects. PBPK simulations revealed an absence of OATP1B3-mediated interaction between abiraterone and CP-I. Our clinical observations confirmed that CP-I concentrations remained comparable to baseline levels up to 12 weeks post 500 mg AA treatment. Using CP-I as an endogenous biomarker, we identified the inhibition of abiraterone on OATP1B3 but not OATP1B1 in vitro, which was predicted and observed to be clinically insignificant. We concluded that the interaction risk between AA and substrates of OATP1Bs is low. Significance Statement We utilized the endogenous biomarker coproporphyrin I (CP-I) and identified abiraterone as a moderate inhibitor of organic anion transporting polypeptide (OATP) 1B3 in vitro. Subsequent physiologically based pharmacokinetic (PBPK) simulations and clinical observations suggested an absence of OATP1B-mediated interaction between abiraterone and CP-I among prostate cancer patients. This multi-pronged study concluded that the interaction risk between abiraterone acetate and substrates of OATP1Bs is low, demonstrating the application of PBPK-CP-I modelling in predicting OATP1B-mediated interaction implicating abiraterone.

Hospital readmissions for patients with prostate cancer are higher after radiotherapy than after prostatectomy.

PURPOSE: To compare hospital readmissions, biochemical recurrence rates, incidence of metastasis, and cancer-specific and overall mortality for prostate cancer patients undergoing radiotherapy vs. radical prostatectomy. The secondary outcome was to identify patient and disease characteristics affecting physician's choice of either therapy. MATERIALS AND METHODS: A total of 297 patients diagnosed with prostate cancer between 2008 and 2014 were identified from a single academic center's cancer database. Clinical information including age, ethnicity, comorbidities, prostate-specific antigen, Gleason score, stage, National Comprehensive Cancer Network (NCCN) risk group, biochemical recurrence, hospital readmissions, and survival outcomes were gathered and analyzed from ambulatory medical records until 2018. RESULTS: Patients selected for radiotherapy were older and had more comorbidities and NCCN high-risk disease. Biochemical recurrence was higher after radical prostatectomy for locally advanced disease, 59.3% vs. 20.0% (p<0.001), favoring radiotherapy. Hospital readmission was higher for patients with locally advanced disease undergoing radiotherapy, 48.6% vs. 18.5% (p=0.002), and 35.2% vs. 19.7% (p=0.044) for those with localized disease, with most of these readmissions occurring 24 months after the initial therapy. Radiation proctitis and colitis were the most common complications after radiotherapy and accounted for 46.3% of readmissions. CONCLUSIONS: Selection of patients for radiotherapy instead of surgery was influenced by age, significant comorbidities, and NCCN high-risk disease. The incidence of treatment- or cancer-related hospital readmissions was significantly higher for patients undergoing radiotherapy compared with radical prostatectomy, especially for those with locally advanced prostate cancer. This information may be useful in guiding a patient's choice of therapy.

NRAMP1 and hGPX1 gene polymorphism and response to bacillus Calmette-Guérin therapy for bladder cancer.

BACKGROUND: The natural resistance-associated macrophage protein 1 (NRAMP1) gene is associated with susceptibility to Mycobacterium tuberculosis in humans and to bacillus Calmette-Guérin (BCG) in mice. The detoxification enzyme, human glutathione peroxidase 1 (hGPX1), is associated with recurrence of bladder cancer (BCa). OBJECTIVE: To determine whether NRAMP1 and hGPX1 gene polymorphisms correlate with response to BCG immunotherapy for non-muscle-invasive BCa (NMIBC). DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from the peripheral blood of 99 NMIBC patients who were prospectively randomized to receive postresection intravesical BCG (81 mg [n=50] or 27 mg [n=19]) or BCG (27 mg) with interferon alpha (IFN-α; n=30). The median follow-up time was 60 mo. INTERVENTION: Intravesical BCG or BCG-IFN-α. MEASUREMENTS: Restriction fragment length polymorphism (RFLP) analysis was performed to identify polymorphisms in the NRAMP1 promoter region (GT repeat number) and at position 543 (aspartate [D] and/or asparagine [N] expression) within the NRAMP1 protein (D543N) and position 198 (proline and/or leucine expression) within the hGPX1 protein (Pro198Leu). Data were analyzed using χ(2) analysis, multivariate analysis, and Kaplan-Meier curves. RESULTS AND LIMITATIONS: On univariate analysis, the NRAMP1 D543N G:G genotype had decreased cancer-specific survival (CSS; p=0.036). The hGPX1 CT genotype (Pro-Leu) had decreased recurrence time (p=0.03) after BCG therapy. On multivariate analysis, patients with the NRAMP1 D543N G:G genotype and allele 3 (GT)n polymorphism had decreased recurrence time (p=0.014 and p=0.03) after BCG therapy. The limitation of this study was its small sample size. CONCLUSIONS: Polymorphisms of the NRAMP1 and hGPX1 genes may be associated with recurrence of BCa after BCG immunotherapy.