Multiple Dose, Bioequivalence Study of Generic Alfuzosin Hydrochloride 10 mg Prolonged-release Tablets Under Fed Conditions

Objectives:

To determine and compare the rate and extent of absorption of a test formulation with that of a reference innovator formulation when given as equal labeled dose after multiple oral dose administration in healthy subjects under fed conditions and To evaluate safety of test and reference formulations

Study Design:

An open label, randomized, two-treatment, two-period, two-sequence, multiple oral dose, crossover bioequivalence study in healthy Thai male volunteers under fed conditions with at least 7 days washout period between last dosing of Period 1 and first dosing of Period 2.

Each subject will receive a single dose of Alfuzosin Hydrochloride 10 mg Prolonged-release Tablets, as a test formulation (T) or a single dose of Alfuzosin Hydrochloride 10 mg Prolonged-release Tablets, Xatral® XL 10 mg, as a reference formulation (R), with 240±2 mL of ambient temperature drinking water at 30 minutes after the start of standardized HFHC breakfast. Investigational product will be provided to subject in stainless steel cup and subject will be dosed without touching the tablet. This activity will be followed by a mouth check using a tongue depressor and a flashlight to assess the compliance of dosing. The formulations will be given in a crossover fashion as per the randomization schedule. The dosing processes will be conducted under normal light condition.

In each period, total of 21 blood samples will be collected from 21 sampling time points. Blood samples (6 mL each) will be collected as per the following schedule:

* Pre-dose blood sample collection (Day 1, Day 4, Day 5 and Day 6) Total of 4 pre-dose blood samples (6 mL each) will be collected from 4 pre-dose sampling time points on Day 1, Day 4, Day 5 and Day 6.
* Post-dose blood sample collection (Day 6 and Day 7) Total of 17 post-dose blood samples (6 mL each) will be collected from 17 post-dose sampling time points at 0.50, 1.00, 2.00, 3.00, 4.00, 5.00, 6.00, 7.00, 8.00, 9.00, 10.00, 11.00, 12.00, 13.00, 14.00, 16.00 and 24.00 hours post-dose.

Eligibility Criteria:
Inclusion Criteria:

1. Healthy Thai male subjects between the ages of 18 to 55 years
2. Body mass index between 18.5 to 30.0 kg/m2
3. Normal laboratory values, including vital signs and physical examination, for all parameters in clinical laboratory tests at screening. Any abnormalities from the normal or reference range will be carefully considered clinically relevant by the physician as individual cases, documented in study files prior to enrolling the subject in this study.
4. Male subjects who are willing or able to use effective contraceptive e.g. condom or abstinence after check-in in Period 1 until 7 days after the end of study in Period 2.
5. Have voluntarily given written informed consent (signed and dated) by the subject prior to participating in this study

Exclusion Criteria:

1. History of allergic reaction or hypersensitivity to alfuzosin or any of the other components of this product.
2. History or evidence of clinically significant renal, hepatic, gastrointestinal (e.g. intestinal occlusion), hematological, endocrine (e.g. hyper-/hypothyroid), pulmonary or respiratory (e.g. allergic rhinitis, asthma), cardiovascular (e.g. hyper-/hypotension), psychiatric (e.g. depression), neurologic (e.g. convulsant), allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing) or any significant ongoing chronic medical illness.
3. Have high risk for coronavirus infection based on risk assessment questionnaire or diagnosed as confirmed case of COVID-19.
4. History about administration of COVID-19 vaccine within 30 days prior to check-in in each Period.
5. History or evidence of regular faintness, dizziness, headache or postural hypotension.
6. History or evidence of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
7. History of problems with swallowing tablet or capsule.
8. History of sensitivity to heparin or heparin-induced thrombocytopenia.
9. Any condition possibly affecting drug absorption e.g. gastrectomy, enterectomy, gastritis or duodenal or gastric ulceration other than appendectomy.
10. History of diarrhea or vomiting within 24 hours prior to check-in in each period.
11. History or evidence of drug addict or investigation with urine sample shows a positive test for drug of abuse (morphine, marijuana or methamphetamine).
12. Have sitting systolic blood pressure of less than 90 mmHg or more than 139 mmHg and diastolic blood pressure of less than 60 mmHg or more than 89 mmHg on screening day and on the check-in day. If abnormal blood pressure detects, the measurement should be repeated two more times after take a rest for at least 5 minutes each. The last measurement value should be used to determine the subject's eligibility.
13. Investigation of vital signs shows pulse rate less than 60 or more than 100 beats per minute on screening day and on the check-in day. If abnormal pulse rate detects, the measurement should be repeated two more times after take a rest for at least 5 minutes each. The last measurement value should be used to determine the subject's eligibility.

14.12-lead ECG demonstrating QTc \>450 msec, a QRS interval \>120 msec or with an abnormality considered clinically significant at screening. If QTc exceeds 450 msec, or QRS exceeds 120 msec, the ECG will be repeated two more times and the average of the three QTc or QRS values will be used to determine the subject's eligibility.

15.Investigation with blood sample shows positive test for HBsAg. 16.Abnormal liver function, ≥1.5 times of upper normal limit of reference range for ALT, AST or bilirubin levels at screening laboratory test.

17.Have eGFR (CKD-EPI) \< 30 mL/min/1.73 m2 based on serum creatinine results, at the screening laboratory test or during enrollment.

18.History or evidence of habitual use of tobacco or nicotine containing products and cannot abstain for at least 48 hours prior to check-in in Period 1 and continued for entire duration of the study.

19.History or evidence of alcoholism or harmful use of alcohol (less than 2 years) i.e., alcohol consumption of more than 14 standard drinks per week for men (A standard drink is defined as 360 mL of beer or 150 mL of wine or 45 mL of 40% distilled spirits, such as rum, whisky, brandy, etc.).

20.History or evidence of alcohol consumption or alcohol-containing products and cannot abstain for at least 48 hours prior to check-in in Period 1 and continued for entire duration of the study or alcohol breath test shows positive result. In case of alcohol breath test result represents the alcohol concentration range of 1 - 10 mg% BAC and the physician carefully considers that the value came from other reasons, not from the alcohol drinking behavior of subjects, the test will be repeated two times separately, not more than 10 minutes. The result of the last time should be used for subject's eligibility which must be 0 mg%BAC.

21.History or evidence of habitual consume of tea, coffee, xanthine or caffeine containing products and cannot abstain for at least 48 hours prior to check-in in Period 1 and continued for entire duration of the study.

22.Consume or drink juice of grapefruit or orange or pomelo or its supplement / containing products and cannot abstain for at least 7 days prior to check-in in Period 1 and continued for entire duration of the study.

23.Use of prescription or nonprescription drugs (e.g. nitrates, paracetamol, erythromycin, clarithromycin, ketoconazole, itraconazole, prazosin, urapidil or minoxidil etc.), herbal medications or supplements (e.g. St. John's wort), vitamins or mineral (e.g. iron) or dietary supplements within 14 days prior to check-in in Period 1 and continued for entire duration of the study.

24.Participated in other clinical trials within 90 days prior to check-in in Period 1 (except for the subjects who drop out or withdrawn from the previous study prior to Period 1 dosing) or still participates in the clinical trial or participates in other clinical trials during enrollment in this study.

25.Blood donation or blood loss ≥ 1 unit (1 unit is equal to 350-450 mL of blood) within 90 days prior to check-in in Period 1 or during enrollment.

26.Subjects with poor venous access or intolerant to venipuncture. 27.Unwilling or unable to comply with schedule visit, treatment plan and other study procedures until end of study.

28.Inability to communicate well (i.e. language problem, poor mental development, psychiatric illness or poor cerebral function) that may impair the ability to provide written informed consent or cooperate with clinical team.

29.Subjects who are employees of International Bio Service Co., Ltd., Pharma Nueva Co., Ltd. or Siam Pharmaceutical Co., Ltd.