DHEA and androstenedione are precursors of testosterone. The administration of abiraterone may potentiate mineralocorticoid production by the adrenal glands via inhibition of CYP Increased mineralocorticoid synthesis occurs as a result of enhanced deoxycorticosterone conversion from pregnenolone.
This may potentially lead to fluid retention, hypertension, and hypokalemia. The pharmacokinetic properties of abiraterone acetate have been studied in healthy subjects and in patients with CRPC. In dose-ranging studies, the median time to reach maximum plasma concentrations C max of abiraterone was 2 hours. There is significant variability in the absorption of abiraterone acetate, depending on whether it is administered with or without food.
In clinical trials, patients taking abiraterone with high-fat meals had a 4. Based on the extent of variability in exposure when abiraterone is taken with a high-fat food content, and given the normal variations in the content and composition of meals that cannot be controlled outside of the clinical trial setting, the FDA has requested that the product labeling reflect that abiraterone has to be administered 2 hours before meals.
Abiraterone acetate has been studies in phase 2 and phase 3 clinical trials. Of 47 patients, 45 had bone metastases at trial initiation. All patients in the study previously received luteinizing hormone—releasing hormone LHRH agonists and experienced disease progression. Patients received abiraterone acetate 1, mg four capsules of mg each in day cycles. Because of an accumulation of mineralocorticoids, some patients experienced hypertension, hypokalemia, and fluid retention.
These patients were managed with eplerenone Inspra, Pfizer 50 to mg or with low-dose glucocorticoids. Bone scans and computed tomography CT were performed at baseline and at 3 and 6 months.
PSA, albumin, liver and renal function tests, and alkaline phosphatase levels were monitored at baseline and then every 4 weeks. The median time to PSA progression was 24 weeks. Most of the patients received the study drug for 12 to 48 weeks. Three patients died during the study, but these deaths were not attributed to the medication. The promising results of this trial led to the development of a phase 3 clinical study. The second phase 2 trial was a multicenter, open-label, single-arm study of abiraterone plus prednisone in patients with docetaxel-treated CRPC.
The investigators anticipated phase 3 progression of abiraterone acetate and designed the trial to address the outcome of the number and type of prior hormone treatments, mainly ketoconazole Nizoral, Janssen. Patients received abiraterone acetate 1, mg four mg tablets in the morning on an empty stomach plus prednisone 5 mg by mouth twice daily for day cycles a minimum of 12 cycles.
Complete blood count, basic metabolic panel, and PSA and androgen levels were evaluated monthly. Men were enrolled in seven study centers from June to November In the ketoconazole subgroup, the median time to PSA progression was approximately No deaths or major adverse reactions were reported throughout the study period.
As with the previous phase 2 study, it was concluded that there was enough evidence to progress to a phase 3 trial. The investigators also determined that co-administration of prednisone 5 mg twice daily with abiraterone acetate decreased mineralocorticoid-related adverse events.
The phase 3 trial was a randomized, double-blind, placebo-controlled study of abiraterone acetate plus prednisone or placebo that evaluated prolongation of overall survival among patients with metastatic CRPC. Enrollees received abiraterone acetate for day cycles until the PSA level, radiography, or clinical findings showed disease progression.
The median age of the patients was 69 years. Patients received treatment for a median time of 8 months and 4 months in the abiraterone acetate and placebo groups, respectively. N Engl J Med ;— Abiraterone acetate therapy resulted in increased survival in all treatment groups, compared with placebo, and was associated with a low frequency of treatment-related adverse events. There were no significant differences in fatal cardiac events between the two groups.
The other events were considered not to be attributable to abiraterone acetate and occurred with a frequency similar to that of placebo Table 3. Abiraterone acetate is contraindicated in pregnancy and should be used with caution in patients with cardiac disease.
The dosage for abiraterone acetate is 1, mg once daily administered as four mg tablets. With median follow-up of 72 months , there were metastasis-free survival events in the combination-therapy groups and in the control groups. Seven grade 5 adverse events were reported: none in the control groups, three in the abiraterone acetate and prednisolone group one event each of rectal adenocarcinoma, pulmonary haemorrhage, and a respiratory disorder , and four in the abiraterone acetate and prednisolone with enzalutamide group two events each of septic shock and sudden death.
Interpretation: Among men with high-risk non-metastatic prostate cancer, combination therapy is associated with significantly higher rates of metastasis-free survival compared with ADT alone.
Abiraterone acetate with prednisolone should be considered a new standard treatment for this population. Abstract Background: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy ADT for 3 years, often combined with radiotherapy.
Associated data ClinicalTrials. Evidence that abiraterone may be an effective hormonal treatment for prostate cancer first emerged from a phase I trial in 21 men with HRPC. These changes were also accompanied by symptomatic improvements, such as reduced pain. Subsequent phase II trials have confirmed these encouraging early findings. A second phase II trial investigated the effects of abiraterone in men with HRPC who had also failed standard chemotherapy with docetaxel and whose PSA levels had started to rise.
Treatment with abiraterone again produced a reduction in PSA levels and no evidence of tumour progression over a week treatment period. The trial enrolled 1, patients across hospitals in North America, Europe and Australia. Patients in the trial were randomised to treatment with abiraterone plus prednisone or prednisone plus placebo.
The trial was an open label, dose escalating trial to assess the safety and efficacy of abiraterone in UK women suffering from advanced breast cancer. Xtandi enzalutamide is an androgen receptor inhibitor indicated for the treatment of metastatic castration-resistant prostate cancer mCRPC. It is jointly developed and manufactured by Medivation and Astellas Pharma. The results indicated that patients who were administered abiraterone demonstrated significant improvements in secondary end points compared to the placebo group and those who were administered prednisone or prednisolone.
The trial is assessing the safety and efficacy of abiraterone in combination with prednisolone in prostate cancer patients who have undergone hormone therapy but not chemotherapy. The study is being carried out on asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer. The trial includes 1, patients across study centres in North America, Europe and Australia.
The entire study is expected to be completed by April
0コメント