Bioequivalence Study of Fluoxetine 20 mg Tablets Manufactured by PT LAPI Laboratories, Cikande - Serang in Comparison with Prozac® 20 mg Capsules Manufactured by Patheon France S.A.S for Eli Lilly and Company, Indianapolis, USA, Imported by PT Pyridam Farma Tbk, Cianjur, Indonesia.
| 1. Background | |
|---|---|
| Registration Number | INA-XBTHN2D |
| Date of registry approval | 29-10-2024 |
| Registration Date | 11-10-2024 |
| Secondary identifiers | Yes |
| Name of issuing authority (for example protocol number, other registries, etc) | 684/STD/PML/2022 |
| Secondary identifier number | 684/STD/PML/2022 |
| Scientific study title | Bioequivalence Study of Fluoxetine 20 mg Tablets Manufactured by PT LAPI Laboratories, Cikande - Serang in Comparison with Prozac® 20 mg Capsules Manufactured by Patheon France S.A.S for Eli Lilly and Company, Indianapolis, USA, Imported by PT Pyridam Farma Tbk, Cianjur, Indonesia. |
| Public (popular study title) | Bioequivalence Study of Fluoxetine 20 mg Tablets Manufactured by PT LAPI Laboratories, Cikande - Serang in Comparison with Prozac® 20 mg Capsules Manufactured by Patheon France S.A.S for Eli Lilly and Company, Indianapolis, USA, Imported by PT Pyridam Farma Tbk, Cianjur, Indonesia. |
| 2. Sponsor and Funding | |
| Primary Sponsor | PT. LAPI Laboratories |
| Source(s) of monetary or material support | PT. LAPI Laboratories |
| Other partners | PT Pharma Metric Labs |
| 3. Contact details | |
| Principal Investigator | |
| Principal investigator | FD Suyatna, MD, PhD, SpFK |
| City | Jakarta |
| 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 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 | +62214265310 |
| Scientific Queries | |
| Name of Contact for scientific queries | Venska Hendriana Wilda, 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 |
| City | Jakarta |
| Country | Indonesia |
| ZIP | 10520 |
| Affiliation of scientific queries contact | PT. Pharma Metric Labs |
| Email address for scientific queries | venska.wilda@pharmametriclabs.com |
| 4. IRB & Regulatory | |
| Ethical Approval number | KET-147/UN2.F1/ETIK/PPM.00.02/2024 |
| Name of Ethics committee | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia |
| Date of Ethic approval | 26-01-2024 |
| Contact details of Ethic Committee (phone, email, and office) | Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia-RSUPN Dr. Cipto Mangunkusumo Gedung H Fakultas Kedokteran UI, Jalan Salemba Raya No.6 Jakarta, 10430 Telp : (021) 3157008 https://komite-etik.fk.ui.ac.id/ |
| Number of Persetujuan Pelaksanaan Uji Klinik (PPUK)/Persetujuan Protokol Uji BE (PPUB) | RG.01.02.321.06.24.02714/UB |
| 5. Status | |
| Countries of recruitment | Indonesia |
| Study sites in Indonesia | PT Pharma Metric Labs |
| Recruitment status | Complete |
| Date of first enrollment | 12-07-2024 |
| Targeted Sample size | 00020 - |
| Number of enrolled participants | 20 |
| Date of study completion (last participant, last visit) | 05-09-2024 |
| 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 | Bioequivalence 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) | Fluoxetine 20 mg Tablets |
| Control intervention (control arm) | Prozac® 20 mg Capsules |
| 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 were 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: 90 – 129 mmHg, Diastolic blood pressure: 60 – 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, Subjects had received the complete primary SARS CoV-2 vaccine, Subjects had negative result of SARS CoV-2 antigen test (for those who has not received the first booster vaccine) |
| Exclusion criteria | those who were pregnant and/or nursing women (for women), those with history of contraindication or hypersensitivity to fluoxetine 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 pharmacokinetic of the study drug, e.g. chronic gastrointestinal disease, diarrhea, gastric /intestinal surgery, renal insufficiency, hepatic dysfunction or any cardiovascular disease, those with history or presence of any coagulation disorder or clinically significant hematology abnormalities, those who were disagreed to use non-hormonal contraceptives methods (condom) before any intercourse with their spouse within 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 two weeks prior to the drug administration day, those who participated in any clinical study within the past 90 days prior to the study, those who donated or losing 300 mL (or more) of blood within 3 months prior to the study, those who were smoker, those who had history of direct contact with a COVID-19 positive person in the subject’s neighborhood within the last 14 days prior to screening, those who had 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 had 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 fluoxetine were determined by means of with LC-MS/MS system and the LLoQ was 0.5 ng/mL. |
| Timepoint(s) of measurement | Blood samples were drawn prior to study drug administration (0 h/blank), and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48 and 72 hours after drug administration. |
| 9. Study Results | |
| Brief summary of study results | A bioequivalence study was conducted to investigate whether Fluoxetine 20 mg Tablets manufactured by PT. LAPI Laboratories, Cikande - Serang was bioequivalent towards its reference product, Prozac® 20 mg Capsules manufactured by Patheon France S.A.S for Eli Lilly and Company, Indianapolis, USA, imported by PT. Pyridam Farma Tbk, Cianjur, Indonesia.
This study was designed as a randomized, single-blind, two-period, two-treatment, two-sequence, single dose, two-way cross-over study with at least 6 weeks washout period in 20 healthy subjects under fasting condition. The subjects age ranged from 18 to 47 years, with normal body weight (body mass index 18.13 – 24.46 kg/m2), normal or not clinically significant blood pressure range (systolic blood pressure within 95 – 128 mmHg and diastolic blood pressure within 60 – 84 mmHg), with normal heart rate (60 – 100 bpm) and normal electrocardiogram, with absence of significant disease or clinically significant abnormal laboratory values on laboratory evaluation, medical history or physical examination during screening, had received the complete primary SARS CoV-2 vaccine and had negative result of SARS CoV-2 antigen test (for those who had not received the first booster vaccine), had read the subject information and had signed the informed consent documents. The study was conducted following an oral administration of one tablet of the test drug (Fluoxetine 20 mg Tablets) or one capsule of the reference drug (Prozac® 20 mg Capsules). Blood samples were drawn before dosing (0 h/blank), and at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 24, 48 and 72 hours after drug administration. Following at least 6 weeks washout period (six weeks as the actual washout period), this procedure was repeated using the alternate drug. The plasma concentrations of fluoxetine were determined by means of a validated LC-MS/MS method with the LLoQ was 0.5 ng/mL. From a total of 20 healthy enrolled subjects, only 19 subjects completed the study and statistically evaluated. One subject (SN 010) was dropped out/withdrawn from the study at period two of the study due to personal reason. There was no adverse event recorded in this study. The detail is listed in Table IV. Summary of Adverse Events of Subjects in Fluoxetine 20 mg Tablets Bioequivalence Study page 14 – 15. The protocol deviation recorded in this study was sampling time deviation due to phlebotomist difficulties to access subject’s vena. It can be seen in Table V. Summary of Study Protocol Deviations in Fluoxetine 20 mg Tablets Bioequivalence Study page 16. Protocol deviation recorded related to analytical phase was reanalysis of SN009, SN011, SN012, and SN013 due to calibration curve and QC samples not meet the acceptance criteria and column diameter for bioanalysis. The detail is presented in Table VI. Summary of Analytical Activity in Fluoxetine 20 mg Tablets Bioequivalence Study page 17. The applied pharmacokinetic parameters in this study were area under the concentration-time curve of fluoxetine from time zero to 72 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 Fluoxetine 20 mg Tablets (test product) in comparison with Prozac® 20 mg Capsules (reference drug) were as following: 90.00% confidence intervals of geometric means ratio of the two bioavailability parameters of fluoxetine were 89.89% - 101.36% for Cmax and 94.35% - 103.16% for AUCt. These results showed that, Fluoxetine 20 mg Tablets was bioequivalent towards its reference product, Prozac® 20 mg Capsules |
| Date of results summaries | 01-10-2024 |
| 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 10 subjects per session. Study team in charge used medical personal protective equipment that consisted of lab coat, KN95 mask, and hand gloves. Beside the study team, the subjects were also instructed to wear face masks, washed their hands before entering the screening room, and practiced physical distancing among each other on 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 included 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). 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 3-5 days, 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 | There was no adverse event recorded in this study. |
| Outcome measures | 1. Cmax:
-GMR : 95.45% -90% CI : 89.89% - 101.36% -CV : 10.63% 2. AUCt: -GMR : 98.66% -90% CI : 94.35% – 103.16% -CV : 7.90% |
| 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 |