Effects of Metabolic Enzymes and Transporter Gene Polymorphisms on the Pharmacokinetics and Metabolism of Oral Abiraterone Acetate in Healthy Chinese Adults

1. To explore the relationship between the changes of plasma concentration of abiraterone acetate after taken orally on fasting or postprandial and gene polymorphism.
2. Study of drug Metabolite profiling after oral administration of abiraterone acetate on fasting and postprandial in Chinese adults.

Study Overview

• Status: Active, not recruiting
• Conditions: Pharmacokinetic; Abiraterone Acetate; Plasma Concentration; Gene Polymorphism; Metabolic Analysis
• Intervention / Treatment: Drug: Abiraterone acetate tablets

Detailed Description

Prostate cancer is the most common malignancy in men currently, second only to lung cancer in China. And in Europe and America, it has already overtaken lung and bowel cancer and become the greatest threat of of men's health. After the diagnosis of high-risk prostate cancer patients, endocrine therapy is still the main treatment. It is effective for most patients who receive androgen deprivation therapy at first. However, after the remission whose median time is 18 to 24 months through endocrine therapy, most patients will turn to castration resistant prostate cancer (CRPC). The treatment of CRPC has always been a difficult point , and now it has become the emphasis of new endocrine drug development for prostate cancer.

Abiraterone acetate tablets in combination with prednisone apply to the treatment of metastatic castration-resistant prostate cancer. It has been approved by the US Food and Drug Administration in 2011 and gotten listing license in China. Abiraterone acetate is an effective irreversible inhibitor CYP17 enzyme and can be converted into abiraterone in vivo. Abiraterone is an androgen biosynthesis inhibitor with a high affinity and selectivity to CYP17. The inhibitory activity of abiraterone for CYP17 was 10-30 times higher than that of ketoconazole. Androgen biosynthesis is inhibited by inhibiting CYP17. The results of many large-scale clinical trials showed that abiraterone acetate could effectively prolong survival time of the patients .

In this study, Blood and plasma samples, urine and faeces samples in 72h from healthy Chinese adult volunteers who have taken abiraterone acetate tablet orally on an empty stomach or after meals were collected for metabolite analysis, the relationship between plasma concentration and gene polymorphism, and identifying the major metabolites in metabolic biological samples to reveal the pharmacokinetic characteristics of abiraterone acetate tablets，demonstrate the pharmacodynamic mechanism，and explore the effect of different genotypes Pharmacokinetic characteristics in healthy Chinese adults.

The result provides theoretical basis for clinical rational drug use.

• Study Type: Interventional
• Enrollment (Anticipated): 81
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Zhongnan Hospital of Wuhan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Age: Healthy male subjects aged 18 to 65 years
• Weight: weight ≥50.0kg, 19 ≤ BMI ≤ 26 kg/m2, BMI=weight (kg) / height2(m2)
• Fully aware of the purpose, nature, method and possible adverse reactions of the study, and sign informed consent prior to the commencement of any study procedure on a voluntarily base.
• Be able to communicate well with the investigator and understand and abide by the terms of the study requirements.

Exclusion Criteria:

• Clinical laboratory examination is abnormal and clinically significant.
• Vital signs examination is abnormal and clinically significant, or there are other diseases of clinical significance（Including but not limited to gastrointestinal tract, kidney, liver, nerve, blood, endocrine, tumor, lung, immune, mental or cardio-cerebrovascular disease）or other specific systemic disease.
• Electrocardiogram is abnormal and clinically significant.
• HbsAg, Anti - HCV, TPPA, or HIV antibody positive.
• History of allergy to abiraterone acetate tablets or its ingredients and analogs
• The number of daily smoking >5 during 3 months before the trial.
• Alcoholics or regular drinkers in the 6 months prior to the trial, that is drinking more than 14 units per week (1 Unit =360mL beer or 45mL 40% liquor or 150mL wine)
• Positive for drug, has a history of drug abuse in the past five years or has used drugs in the 3 months prior to the trial.
• Positive for alcohol screening or use of any alcoholic product within 24 hours prior to taking the study drug.
• Blood donation or massive blood loss within 3 months prior to taking the study drug (>450mL).
• Take any xanthine rich beverage, food, grapefruit fruit or products that contain grapefruit in 48 hours before the trial.
• Take in chocolate or any food or drink containing caffeine in 48 hours before the trial.
• A history of dysphagia or any gastrointestinal disease that affect drug absorption.
• Have taken the study drug or participated in the drug or medical device within three months before this trial.
• There are major changes in diet or exercise habits recently.
• Acute disease occurs during the study screening phase or prior to taking study drugs.
• There are drug combination of CYP3A4, P-GP, or Bcrp inhibitors or inducers (such as itraconazole, ketoconazole, dronedarone et al.), or any drugs that affect hepatic microsomal enzyme activity during the 28 days before taking the study drug.
• Accompanied by any coagulation disorders (such as Willebrand's disease or hemophilia) or history of hemorrhagic disease.
• Accompanied by any disease that increases the risk of bleeding, such as hemorrhoids, acute gastritis, stomach or duodenal ulcers, etc.
• Special requirements on diet and fails to comply with the diet provided and the corresponding regulations, especially for the lactose intolerant.
• History of asthma or seizures.
• Have a pregnancy plan in 6 months, sperm or egg donation, or reluctance to use one or more non-drug contraceptives during the trial.
• Taking any prescription drugs, nonprescription drug, over-the-counter, vitamin products, or herbal medicines in 14 days before taking the study drug.
• Patients with abnormal nucleic acid or antibody detection of COVID-19 and considered ineligible by the investigator.
• Pulmonary CT were abnormal and considered inappropriate to participate in the study by the investigator.
• Subjects considered to have poor compliance or have any factors that would make them inappropriate to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Fasting group; Subjects will take abiraterone acetate tablets (250 mg, produced by Patheon Ich, trade name: Zytiga®) orally on an empty stomach and their blood and plasma samples, urine and faeces samples in 72h will be collected for detection.	Drug: Abiraterone acetate tablets; Subjects will take abiraterone acetate tablets (250 mg, produced by Patheon Ich, trade name: Zytiga®) orally on an empty stomach or after meals and their blood and plasma samples, urine and faeces samples in 72h will be collected for detection.
Experimental: Postprandial group; Subjects will take abiraterone acetate tablets (250 mg, produced by Patheon Ich, trade name: Zytiga®)orally after meals and their blood and plasma samples, urine and faeces samples in 72h will be collected for detection.	Drug: Abiraterone acetate tablets; Subjects will take abiraterone acetate tablets (250 mg, produced by Patheon Ich, trade name: Zytiga®) orally on an empty stomach or after meals and their blood and plasma samples, urine and faeces samples in 72h will be collected for detection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentrations of abiraterone in plasma	-1h, 30min, 1h , 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h, 60h, 72h after administration for blood sampling	2 months
Cmax	peak concentration	2 months
AUC0-t	Area under curve. The linear trapezoid method is used to calculate the blood drug concentration from zero to the last measurable concentration area under the curve	2 months
AUC0-∞	The area under the blood concentration-time curve from zero to infinite blood concentration	2 months
λz	End phase elimination rate constant, the least square method is used to find the slope of the optimal curve for phase elimination And multiplied by 2.303	2 months
T1/2z	Elimination or final half-life, 0.693/λz	2 months
AUC_%Extra	[（AUC0-∞- AUC0-t）/ AUC0-∞]×100%, Percentage of residual area	2 months
Vz/F	apparent volume of distribution, Vz/F = CLz/F /λz	2 months
CLz/F	apparent clearance, CLZ /F= administration dose /AUC0-∞	2 months
the main metabolite of abiraterone	The plasma, urine and feces samples were collected to assay the metabolic profile of abiraterone in vivo by UFLC-Q-Exactive Orbitrap HRMS system	2 months
genotyping related to abiraterone metabolism	Mutation sites of transporter and metabolic enzyme related to abiraterone metabolism were detected through the gene detection technology service platform	10 months

Collaborators and Investigators

• Sponsor: Zhongnan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 5, 2020
• Primary Completion (Actual): August 20, 2020
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: November 16, 2020
• First Submitted That Met QC Criteria: January 29, 2021
• First Posted (Actual): February 3, 2021

Study Record Updates

• Last Update Posted (Actual): January 3, 2022
• Last Update Submitted That Met QC Criteria: December 30, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: pharmacokinetic; metabolites; gene polymorphism; Abiraterone; plasma
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; Abiraterone Acetate
• Other Study ID Numbers: 20201010

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No