Bioequivalence Study of Atenolol 50 mg Tablet (Internolol® 50 Tablet) Manufactured by PT Interbat in Comparison with Tenormin® 50 mg Film-Coated Tablet Manufactured by Astrazeneca AB, Swedia
| 1. Background | |
|---|---|
| Registration Number | INA-NZ052EP |
| Date of registry approval | 04-03-2024 |
| Registration Date | 01-03-2024 |
| Secondary identifiers | Yes |
| Name of issuing authority (for example protocol number, other registries, etc) | 739/STD/PML/2023 |
| Secondary identifier number | 739/STD/PML/2023 |
| Scientific study title | Bioequivalence Study of Atenolol 50 mg Tablet (Internolol® 50 Tablet) Manufactured by PT Interbat in Comparison with Tenormin® 50 mg Film-Coated Tablet Manufactured by Astrazeneca AB, Swedia |
| Public (popular study title) | Bioequivalence Study of Atenolol 50 mg Tablet (Internolol® 50 Tablet) Manufactured by PT Interbat in Comparison with Tenormin® 50 mg Film-Coated Tablet Manufactured by Astrazeneca AB, Swedia |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT Interbat |
| Source(s) of monetary or material support | PT Interbat |
| Other partners | PT. Pharma Metric Labs |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | FD Suyatna, MD, PhD, SpFK |
| City | Jakarta Pusat |
| Country | Indonesia |
| Principal investigator's affiliation | PT. Pharma Metric Labs |
| Principal Investigator's email address | fransdsuyatna@yahoo.com |
| Public Queries | |
| Contact person name for public queries | Nabila Mudin S |
| Address for public queries | PT. Pharma Metric Labs Gedung Indra Sentral Cempaka Putih Unit R-U Jalan Letjen Suprapto Kav. 60 Central Jakarta, 10520 Indonesia |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation for public queries | PT. Pharma Metric Labs |
| Email address for public queries | nabila.pmlabs@gmail.com |
| Phone number for public queries | +62214265310 |
| Scientific Queries | |
| Name of Contact for scientific queries | I Gusti Putu Bagus Diana Virgo, Pharm |
| Address for scientific queries | PT. Pharma Metric Labs Gedung Indra Sentral Cempaka Putih Unit R-U Jalan Letjen Suprapto Kav. 60 Central Jakarta, 10520 Indonesia |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation of scientific queries contact | PT. Pharma Metric Labs |
| Email address for scientific queries | gusti.virgo@pharmametriclabs.com |
| 4. IRB & Regulatory | |
| Ethical Approval number | KET-1308/UN2.F1/ETIK/PPM.00.02/2023 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia |
| Date of Ethic approval | 06-10-2023 |
| Contact details of Ethic Committee (phone, email, and office) | Gedung H Fakultas Kedokteran UI, Jalan Salemba Raya No. 6 Jakarta 10430 Phone : (021) 3157008 website : https://komite-etik.fk.ui.ac.id/ |
| Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB) | RG.01.02.321.11.23.02223/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT Pharma Metric Labs |
| Recruitment status | Complete |
| Date of first enrollment | 20-12-2023 |
| Targeted Sample size | 00024 - |
| Number of enrolled participants | 24 |
| Date of study completion (last participant, last visit) | 12-01-2024 |
| 6. Study Design & Purpose | |
| Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error) | healthy human volunteers |
| Purpose of the study | Bioequivalent study |
| Study type | Interventional |
| Interventional Study category | Bioequivalence study |
| Method of allocation | |
| Description of the allocation concealment mechanism and sequence generation | |
| Masking | |
| Study intervention (study arm) | Internolol® 50 mg tablet batch no ZT0287202 (Formula A) and Internolol® 50 mg tablet batch no ZT0287203 (Formula B) |
| Control intervention (control arm) | Tenormin® 50 mg film-coated tablet |
| Intervention assignment | Crossover |
| 7. Eligibility Criteria | |
| Gender inclusion criteria | Male, Female |
| Minimum age | 18 |
| Maximum age | 55 |
| Inclusion criteria | Subjects had read the subject information and able to give written informed consent for participation in the study and comply with the study protocol/procedures, Subjects healthy male and female, Subjects’ age ranges from 18 – 55 years, Subjects’ body mass index between 18 – 25 kg/m2, Subjects had a normal electrocardiogram, Subjects had resting vital signs (after 10 – 15 minutes of resting) were within the following range : Systolic blood pressure: 110 – 129 mmHg, Diastolic blood pressure: 70 – 84 mmHg, Pulse/Heart rate: 60 – 100 beats per minute, Subjects had no significant disease or clinically significant abnormal laboratory values on laboratory evaluation, medical history or physical examination during screening |
| Exclusion criteria | those who were pregnant and/or nursing condition,those with a history of hypersensitivity or contraindication to atenolol, or allied drugs, or other ingredients in the study products, or a history of serious allergic reaction to any drug, a significant allergic disease, or allergic reaction, those with a history or presence of medical condition which might significantly influence the pharmacokinetics of the study drug, e.g. chronic gastrointestinal disease, diarrhea, gastric surgery, renal insufficiency, hepatic dysfunction or cardiovascular disease
those who had history or presence of any coagulation disorder or clinically significant hematology abnormalities, those who had history or presence of any metabolic acidosis condition those who had history or presence of asthma or chronic obstructive pulmonary disease or other health problems with symptoms of difficulty breathing, those who disagree to use non-hormonal contraceptives methods (condom) before any intercourse with their spouse throughout study period those who using any medication (prescription or non-prescription drug, food supplement, herbal medicine), particularly the medication known to affect the pharmacokinetics of the study drug, within one week prior to the drug administration day, those who had participated in any clinical study within the past 90 days prior to the study, those who had donated or lost 300 mL (or more) of blood within 3 months prior to the study, those who had smoking habit with more than 10 cigarettes a day, those who not receiving the complete primary SARS CoV-2 vaccine, those who were positive result of SARS CoV-2 antigen test (for those who has not received the first booster vaccine), those with history of direct contact with a COVID-19 positive person in the subject’s neighborhood within the last 14 days, those who with history or present of sore throat, fever (with temperature more than 37°C), cough, cold, anosmia/loss of smell, or dyspnea within the last 14 days, those who positive result for HIV, HbsAg, and HCV tests (to be kept confidential), those who had history of drug or alcohol abuse within 12 months prior to screening for this study, those who were unlikely to comply with the protocol, e.g. uncooperative attitude, inability to return for follow up visits, poor venous access |
| 8. Study Outcome | |
| Primary Outcome | |
| Name of primary outcome | Cmax, AUCt |
| Metric/method of measurement | The plasma concentrations of atenolol were determined by means of a validated LC-MS/MS method with the LLoQ was 4.99 ng/mL. |
| Timepoint(s) of measurement | Blood samples were drawn prior to study drug administration (0 h/blank), and at 20 and 40 minutes, and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours after drug administration |
| 9. Study Results | |
| Brief summary of study results | This study was performed to investigate whether Atenolol 50 mg tablet (Internolol® 50 Tablet) manufactured by PT Interbat is bioequivalent to its reference product, Tenormin® 50 mg film-coated tablet manufactured by Astrazeneca AB, Swedia.
This study was designed as a randomized, single blind, three-period, three-treatment, two-sequence, single dose, three-way crossover study with at least 7 days washout period in 24 healthy subjects under fasted condition. The subjects were informed about the study procedure and signed the informed consent form. This study protocol was approved by the Ethics Committee of the Medical Faculty, University of Indonesia and the Indonesian National Agency of Drug and Food Control. The study was conducted following an oral administration of one tablet of the test drug (Internolol® 50 Tablet for Formula A and Formula B) or one tablet of the reference drug (Tenormin® 50 mg Film-Coated Tablet). Blood samples were drawn prior to study drug administration (0 h/blank), and at 20 and 40 minutes, and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16 and 24 hours after drug administration. Following a washout period of at least 7 days, this procedure was repeated using the alternate drug. The plasma concentrations of atenolol were determined by means of a validated LC-MS/MS method with the LLoQ was 4.99 ng/mL. Of a total of 24 (twenty-four) enrolled subjects, only 23 (twenty-three) subjects completed the study and were statistically evaluated. Subject Number (SN) 001 was dropped out due to indication of high blood pressure on period two vital signs monitoring prior to study drug administration. Recorded adverse events in this study was high blood pressure which occurred to SN 001 and headache which occurred to SN 012. It is listed in Table IV. Summary of Adverse Events of in Atenolol 50 mg Tablets Bioequivalence Study Bioequivalence Study page 23 - 25. Protocol deviation related to clinical phase was blood sampling deviation that occurred due to phlebotomist having difficulty to find subjects’ vena access. The details are listed in Table V. Summary of Study Protocol Deviations in Atenolol 50 mg Tablets Bioequivalence Study page 26. While protocol deviation related to analytical phase was instrument type for bioanalysis. It can be previewed in Table VI. Summary of Analytical Activity in Atenolol 50 mg Tablets Bioequivalence Study page 27. The applied pharmacokinetic parameters in this study were area under the concentration-time curve of atenolol from time zero to 24 hours (AUCt), area under the concentration-time curve from time zero to infinite (AUCinf), maximum concentration (Cmax), time required to reach the maximum concentration (tmax) and the elimination half-life (t½). The products are bioequivalent when the 90% confidence intervals of the atenolol geometric mean ratio between test and reference products fall within the range of 80.00-125.00% for AUCt and Cmax. Formula A/T1 (batch no ZT0287202) Cmax -GMR : 81.61% -90CI : 63.83% - 104.35% -CV : 48.38% AUCt -GMR : 82.10% -90CI : 62.63 - 107.62% -CV : 53.29% Formula B/T2 (batch no ZT0287203) Cmax -GMR : 106.63% -90CI : 97.14 - 117.04% -CV : 18.35% AUCt -GMR : 108.71% -90CI : 99.61 - 118.64% -CV : 17.21% The results of this study showed that, Internolol® 50 Tablet (Atenolol 50 mg tablet Formula B/T2, batch no ZT0287203) manufactured by PT Interbat was bioequivalent towards its reference product, Tenormin® 50 mg film-coated tablet manufactured by Astrazeneca AB, Swedia. Meanwhile for Internolol® 50 Tablets (Atenolol 50 mg tablet Formula A/T1, batch no ZT0287202) was not bioequivalent towards its reference product, Tenormin® 50 mg film-coated tablet manufactured by Astrazeneca AB, Swedia. |
| Date of results summaries | 30-01-2024 |
| Participant flow | Subject screening and selection took place prior to the sampling period and only after the subject agreed to participate in the study by signing off the Informed Consent Form.
Subject screening was conducted with limited of number of people/subject candidates, with maximum 5 subjects per session. Study team in charge used medical personal protective equipment that consisted of surgical pants, head cap, face shield, N95 mask, goggles, hand gloves, and shoes’ cover. Beside the study team, the subjects were also instructed to wear face mask, washed their hands properly prior to registration/consenting procedures, wore the provided hand gloves, and implement physical distancing with a minimal of 1 meter distance among each other during the screening process. Informed consent was obtained from each subject before the screening process and the participation must be voluntary. All subjects were informed of possible side effects or adverse events and advised that they were free to withdraw from the study at any stage. The subject information sheet and consent form was provided in the subjects' first language (Bahasa Indonesia). The investigator informed all subjects about the details of the study, i.e. the objective and the procedure, as well as the study rules or restrictions to be followed during the study and the possible adverse effects of the drug. Medical history, physical examination, laboratory tests (routine hematology, blood biochemistry and urinalysis), electrocardiograph, pregnancy test and HIV, HBsAg, HCV tests were carried out to screen and obtain eligible subjects who met the inclusion and exclusion criteria. The Study Coordinator or Study Physician documented the subjects' demographic data which included full name, gender, date of birth, age, address, race, height, weight, and smoking and alcohol consumption habit. The medical history was taken includes systemic review of allergies, family history, and surgical history. The physical examination includes overall appearance, eyes, ears, nose, throat, head and neck, heart, lung, abdomen (including liver and spleen), lymph nodes, skin, musculoskeletal, and nervous system examination. The vital signs were also be measured, which included blood pressure, pulse rate, respiration rate and body temperature. The clinical laboratory examination covered routine hematology (hemoglobin, leucocyte, white blood cell differential counts, erythrocyte, platelet, hematocrit, and erythrocyte sedimentation rate), blood chemistry (alanine aminotransferase/ALT/SGPT, aspartate aminotransferase/AST/SGOT), alkaline phosphatase, bilirubin, blood glucose level, ureum, and creatinine), and urinalysis (density, pH, leucocyte, nitrite, albumin/protein, glucose, ketone (acetone), urobilinogen, bilirubin, and blood count) and serum electrolyte (potassium). A total of 15 mL of blood was drawn from each subject for the laboratory test, including HIV, HBsAg, HCV tests. All involved subjects should be received the complete primary SARS CoV-2 vaccine and the first booster. SARS CoV-2 antigen test was carried out for subjects who had not received the first booster vaccine. SARS CoV-2 antigen test was performed on the screening day and on 1 day prior to the study day on period 1 and 2, by swabbing the subject nasopharynx and examine the sample using provided test kit. If any subject showed positive result on the examination, the subject was withdrawn from the study and properly compensated. The subject was asked to perform isolation/quarantine for minimum 10 days and should remain in isolation/quarantine until 3 days after no more COVID-19 symptoms appeared, or another relevant procedure in accordance with the Indonesian health authority. Pregnancy test was carried out for female subjects in screening process and on the day of sampling just before drug administration. Women of childbearing potential were advised to take the necessary precaution to prevent pregnancy and to report to the Investigator or Study Physician if they suspected pregnancy. All included subjects met the inclusion and exclusion criteria. The screening data of all subjects were evaluated and subjects with any current or past medical conditions which might significantly affected the study results and assessment were excluded from the study. Investigator or Study Physician decision was needed to decide subject's eligibility if there was an abnormal result, whether it was clinically significant or not. The results of screening were recorded in the Case Report Form |
| Baseline characteristic | |
| Adverse events | Adverse events recorded in this study was High blood pressure that occurred to SN 001 and headache that occurred to SN 012 |
| Outcome measures | Formula A/T1 (batch no ZT0287202)
Cmax -GMR : 81.61% -90CI : 63.83% - 104.35% -CV : 48.38% AUCt -GMR : 82.10% -90CI : 62.63 - 107.62% -CV : 53.29% Formula B/T2 (batch no ZT0287203) Cmax -GMR : 106.63% -90CI : 97.14 - 117.04% -CV : 18.35% AUCt -GMR : 108.71% -90CI : 99.61 - 118.64% -CV : 17.21% |
| 10. Publication | |
| URL hyperlink(s) related to results and publications | |
| IPD sharing statement (Statement regarding the intended sharing of deidentified individual clinical trial participant-level data (IPD)) | No |
| Plan for IPD sharing (what IPD will be shared, when, by what mechanism, with whom, and for what types of analyses) | |
| Other important informations | Not available |