Bioequivalence Study of 40 mg Furosemide Tablets Manufactured by PT. Bernofarm in Comparison with 40 mg Lasix® Tablets Manufactured by PT. Aventis Pharma, Indonesia.
| 1. Background | |
|---|---|
| Registration Number | INA-QLM2BQB |
| Date of registry approval | 15-11-2023 |
| Registration Date | 13-06-2023 |
| Secondary identifiers | No |
| Name of issuing authority (for example protocol number, other registries, etc) | |
| Secondary identifier number | |
| Scientific study title | Bioequivalence Study of 40 mg Furosemide Tablets Manufactured by PT. Bernofarm in Comparison with 40 mg Lasix® Tablets Manufactured by PT. Aventis Pharma, Indonesia. |
| Public (popular study title) | Bioequivalence Study of 40 mg Furosemide Tablets Manufactured by PT. Bernofarm in Comparison with 40 mg Lasix® Tablets Manufactured by PT. Aventis Pharma, Indonesia. |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT. Bernofarm |
| Source(s) of monetary or material support | PT. Bernofarm |
| Other partners | PT. Pharma Metric Labs |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | Arini Setiawati, Pharm, PhD |
| City | Jakarta |
| Country | Indonesia |
| Principal investigator's affiliation | PT. Pharma Metric Labs |
| Principal Investigator's email address | arinisetiawati@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 Tel : +62 21 4265310 Fax : +62 21 4210302 |
| 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 | +62 21 4265310 |
| 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 Tel : +62 21 4265310 Fax : +62 21 4210302 Email : gusti.virgo@pharmametriclabs.com |
| 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-345/UN2.F1/ETIK/PPM.00.02/2022 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia - RSUPN Dr. Cipto Mangunkusumo |
| Date of Ethic approval | 11-04-2022 |
| Contact details of Ethic Committee (phone, email, and office) | Gedung Fakultas Kedokteran UI Jl. Salemba Raya No.6, Jakarta 10430 Phone : +62213912477 Email : humas@fk.ui.ac.id |
| Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB) | RG.01.02.321.06.22.00940/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT. Pharma Metric Labs |
| Recruitment status | Complete |
| Date of first enrollment | 22-06-2022 |
| Targeted Sample size | 00024 - |
| Number of enrolled participants | 24 |
| Date of study completion (last participant, last visit) | 01-08-2022 |
| 6. Study Design & Purpose | |
| Primary health condition(s) or problem(s) studied (e.g., depression, breast cancer,medication error) | healthy subjects |
| Purpose of the study | Treatment |
| 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) | subjects were given a single dose of 40 mg Furosemide of test drug or of reference drug with 240 mL of water. Subjects were administered the drug products in sitting posture. Subjects were asked to maintain upright position (standing or sitting) for 1 hour after dosing. The subjects should remain in a comfortable recumbent position for up to 8 hours after dosing and remain under medical surveillance for up to 12 hours after dosing. Before they were allowed to ambulate, they should sit up with legs in a dependent position for one minute prior to standing up. While standing immobile, they should be closely observed for blood pressure changes and/or orthostatic symptoms, including nausea, dizziness, or faintness for at least three minutes. |
| Control intervention (control arm) | 40 mg Lasix® tablets manufactured by PT. Aventis Pharma, Indonesia. The study was conducted following an oral administration of one tablet of the test drug (40 mg Furosemide tablets) or one tablet the reference drug (40 mg Lasix® tablets). Blood samples were drawn prior to study drug administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours after drug administration. Following a washout period of one week, this procedure was repeated using the alternate drug. |
| Intervention assignment | Crossover |
| 7. Eligibility Criteria | |
| Gender inclusion criteria | Female |
| Minimum age | 18 |
| Maximum age | 42 |
| Inclusion criteria | The inclusion criteria were healthy subjects who/with:
- had read the subject information and signed informed consent documents - healthy male and female - age range from 18 – 55 years - body mass index between 18 – 25 kg/m2 - had a normal electrocardiogram - had the blood pressure within normal range (systolic 90 - 120 mmHg and diastolic 60 - 80 mmHg) - had the heart rate within normal range (60 – 100 bpm) - had absence of significant disease or clinically significant abnormal laboratory values on laboratory evaluation, medical history or physical examination during screening. - had passed electrolyte screening related to sodium and potassium - had acceptance to use protection (condom) during intercourse with their spouse during study |
| Exclusion criteria | This study was not eligible for:
- those who were pregnant and/or nursing condition - those with a history of contraindication or hypersensitivity to furosemide or other diuretics 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 with a history or presence of any coagulation disorder or clinically significant hematology abnormalities - those who were using any medication (prescription or non-prescription drug, food supplement, herbal medicine), particularly the medication known to affect the pharmacokinetic of the study drug, within one week prior to the drug administration day - those who had participated in any clinical study within 3 months prior to the study (< 90 days). - those who had donated or lost 300 ml (or more) of blood within 3 months prior to the study. - those who were smoker - those with a history of travelling to another city within the last 14 days - those with a history of direct contact with a COVID-19 positive person in the subject’s neighborhood - those with a history or present of sore throat, fever (with temperature more than 37°C) or dyspnea with in the last 14 days - those who were positive to SARS CoV-2 antigen test - those who were positive to HIV, HBsAg, and HCV tests (to be kept confidential). - those with a 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 | comparison of Pharmacokinetic parameters (Cmax and AUC) between the test and reference drugs. |
| Metric/method of measurement | Plasma concentrations of furosemide were measured using a validated UPLC method. Plasma was first spiked with diclofenac sodium as internal standard solution, then further mixed using vortex. The drug was then extracted with an organic solvent. The organic layer was then transferred to a clean glass tube and evaporated to dry under nitrogen stream in a water bath. The residue was then reconstituted with an organic solvent and an aliquot is injected into the UPLC system. The LLOQ was 4.99 ng/mL. |
| Timepoint(s) of measurement | Blood samples for furosemide assay (approximately 6 mL) were drawn into tubes containing anticoagulant (EDTA) prior to study drug administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 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 40 mg Furosemide tablets manufactured by PT. Bernofarm was bioequivalent towards its reference product, 40 mg Lasix® tablets manufactured by PT. Aventis Pharma, Indonesia.
This study was designed as a randomized, single blind, three-period, two-treatment, three-sequence, single dose, semi-replicate design study with one week 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 (40 mg Furosemide tablets) or one tablet the reference drug (40 mg Lasix® tablets). Blood samples were drawn prior to study drug administration (0 h) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours after drug administration. Following a washout period of one week, this procedure was repeated using the alternate drug. The plasma concentrations of furosemide were determined by means of with LC-MS/MS system with the LLoQ was 4.99 ng/mL. From a total of 24 enrolled subjects, all subjects completed the study and statistically evaluated. The applied pharmacokinetic parameters in this study were area under the concentration-time curve of furosemide 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). Results from this bioequivalence study of 40 mg Furosemide tablets (test product) in comparison with 40 mg Lasix® tablets (reference drug) were as following: 90.00% confidence intervals of geometric means ratio of the two bioavailability parameters of furosemide were 86.67% – 113.35% for Cmax and 90.31% – 106.65% for AUCt. These results showed that 40 mg Furosemide tablets was bioequivalent towards its reference product, 40 mg Lasix® tablets. |
| Date of results summaries | 01-08-2022 |
| Participant flow | |
| Baseline characteristic | |
| Adverse events | |
| Outcome measures | |
| 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 | The results of this study showed that 40 mg Furosemide tablets manufactured by PT. Bernofarm was bioequivalent towards its reference product, 40 mg Lasix® tablets manufactured by PT. Aventis Pharma, Indonesia. |