Bioequivalence study of methyldopa 250 mg tablets (Dopamet) produced by PT Actavis Indonesia in comparison with the comparator product (Aldomet® 250 mg Tablets, Aspen Pharmacare Australia Pty Ltd, Australia)


INA-OZQWN67
27-12-2023
19-12-2023
Yes
BE. 767/EQL/2022 Ver 2.0 (09 May 2023)
BE. 767/EQL/2022 Ver 2.0 (09 May 2023)
Bioequivalence study of methyldopa 250 mg tablets (Dopamet) produced by PT Actavis Indonesia in comparison with the comparator product (Aldomet® 250 mg Tablets, Aspen Pharmacare Australia Pty Ltd, Australia)
Bioequivalence study of methyldopa 250 mg tablets (Dopamet) produced by PT Actavis Indonesia in comparison with the comparator product (Aldomet® 250 mg Tablets, Aspen Pharmacare Australia Pty Ltd, Australia)
 
PT Actavis Indonesia
PT Actavis Indonesia
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PT Equilab International
Jakarta Timur
Indonesia
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Yetty Afnita
Jl. Raya Bogor Km. 28
Jakarta Timur
Indonesia
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021-8710311
Vicky Achmad Ginanjar
JL RS. Fatmawati Kav. 33, RT 002 / RW 005, Jakarta 12430-Indoensia
Jakarta
Indonesia
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vicky.achmad@equilab-int.com
 
KET-419/UN2.F1/ETIK/PPM.00.02/2023
Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia
10-04-2023
Danang Agung Yunaidi, MD
RG.01.02.321.07.23.01864/UB
 
Indonesia
Jakarta
Complete
19-12-2023
29080 -
36 orang
06-11-2023
 
Health
1.This study will assess the relative bioavailability of methyldopa 250 mg tablets, compared to that of Aldomet® 250 mg Tablets, following a single oral dose (1 × 250 mg tablet) in healthy adult subjects when administered under fasting conditions. 2.T
Observational
 
Male, Female
18 tahun
52 tahun
1. Able to participate, communicate well with the investigators and willing to provide written informed consent to participate in the study.
2. Healthy male and female aged between 18 to 55 years, inclusive, at the time of first signing of the informed consent.
3. Completed the screening process within 21 days prior to Period I dosing.
4. Body mass index (BMI) between 18.0 kg/m2 to 25.0 kg/m2, inclusive.
5. Judged by an investigator to be in good health as documented by the medical history, physical examination (including but may not be limited to an evaluation of the cardiovascular, gastrointestinal, respiratory and central nervous systems), vital sign assessments must be within the following ranges:
- Systolic blood pressure : 110–129 mmHg
- Diastolic blood pressure : 70–84 mmHg
- Pulse rate : 60–90 bpm
6. Normal result of 12-lead electrocardiogram (ECG) and clinical laboratory assessments. Any abnormalities or deviations outside the normal ranges for any of clinical testing (laboratory tests, ECG, vital signs) can be repeated at the discretion of the investigator(s) and judged to be not clinically significant for study participation.
7. Negative urine screen for drugs of abuse (benzodiazepines, cannabinoids, amphetamines, cocaine, barbiturates and opioids) and alcohol urine test at screening and check-in for each study period.
8. For female volunteers, one of the following must apply:
o Females of childbearing potential must practice one of the following acceptable methods of birth control as judged by the investigator(s), e.g.
o Abstinent for 14 days prior to the first dose and until end of study
o IUD in place for at least 3 months
- If the IUD was inserted less than 3 months prior to Period I dosing or proper documentation of the confirmation test is not provided, the volunteer must agree to use an additional non-hormonal medically acceptable method of birth control o Use of barrier methods (condom, diaphragm) with spermicide for at least 14 days prior to the first dose and until end of study.
o Use of hormonal contraceptives for at least 3 months prior to the first dose and until end of study.
o Naturally postmenopausal (no menses) for at least 1 year
o Surgically postmenopausal (bilateral oophorectomy or hysterectomy) or surgically sterile (bilateral tubal ligation) for at least 6 months
- Surgically sterile or surgically postmenopausal must provide documentation of the
bilateral tubal ligation, bilateral oophorectomy, or hysterectomy prior to Period I dosing or the volunteer must agree to use a medically acceptable non-hormonal method of birth control.
9. For male volunteers, one of the following must apply in order to avoid impregnating a female partner, from the first study dose until end of study:
o Abstinent
o Use of barrier method with spermicide.
o Documented vasectomy or congenitally sterile
10. Study allows enrollment of light smokers: Reports smoking of less than 10 cigarettes/day, use of less than 4 packets/day of tobacco products or use of nicotine products (patches, gums, etc.) corresponding to less than 10 cigarettes/day.
11. Subject who agrees to avoid donating blood (1 unit or 350 mL) other than blood for study purposes and donating plasma (e.g. plasmapheresis) throughout the study and until 30 days after completing the study.
Any of the following criteria excluded the subject from the study:
1. Reports receiving any investigational drug within 30 days prior to Period I dosing.
2. Participation in another clinical trial simultaneously.
3. Reports any presence or history of a clinically significant disorder involving the cardiovascular, respiratory, renal, urologic, gastrointestinal, hepatic, immunologic, hematologic, endocrine, or neurologic system(s) or psychiatric disease as determined by
the investigator(s).
4. Presence of any clinically significant results from laboratory tests, vital signs assessments, and electrocardiograms, as judged by the investigator(s).
5. Pregnant, lactating, breastfeeding, or intends to become pregnant over the course of the study.
6. Demonstrates a positive pregnancy test.
7. Demonstrates a positive screening for hepatitis B surface antigen, hepatitis C antibody or HIV antibody.
8. Reports a history of drug or alcohol addiction or abuse within the past 1 year.
a. Alcohol abuse defined as consumption of ≥7 units/week for females or ≥14 units/week for males
b. One unit of alcohol equals 360 mL of beer; 150 mL of wine; or 45 mL of 40 % alcohol
9. Demonstrates a positive urine screening for drug abuse or a positive alcohol urine test.
10. Reports a clinically significant illness during the 30 days prior to Period I dosing (as determined by the investigator(s)).
11. Reports a history of allergic response(s) to the methyldopa or related drugs.
12. Reports a history of clinically significant allergies including food or drug allergies.
13. Reports donating blood (1 unit or 350 mL) or plasma (e.g. plasmapheresis) or significant blood loss within 90 days prior to Period I dosing.
14. Demonstrates, in the opinion of study staff, veins unsuitable for repeated venipuncture (e.g. veins difficult to locate, access, or puncture; veins with a tendency to rupture during or after puncture).
15. Reports difficulty fasting or consuming standardized meals.
16. Difficulty in swallowing solids like tablets or capsules.
17. Use of any prescription drug therapy or over-the-counter (OTC) drugs 21 days prior to receiving the first dose of study medication or repeated use of drugs within last 21 days.
18. GGT values ≥2 × ULN.
19. Have had a tattoo or body piercing within 90 days prior to the first dose.
20. Presence of significant infection within 1 week prior to screening and check-in.
21. Have live virus vaccinations (exceptional for inactivated seasonal flu) within 90 days prior to the dosing date.
 
Bioavailability of methyldopa 250 mg tablets, compared to that of Aldomet® 250 mg Tablets, following a single oral dose (1 × 250 mg tablet) in healthy adult subjects when administered under fasting conditions.
Bioequivalence study
Blood samples were drawn before taking the drug (control), and at 0.33, 0.66, 1.00, 1.33, 1.66, 2.00, 2.33, 2.66, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours after drug administration. These blood samples were used to investigate the pharmacokinetic parameters of methyldopa following single dose administration.
 
The aim of the present study was to compare the bioavailability of Methyldopa 250 mg tablets (produced by PT Actavis Indonesia, Indonesia) as the test drug with Aldomet® 250 mg Tablets (produced by Aspen Pharmacare Australia Pty Ltd, Australia) as the comparator drug.
This was an open-label, randomized, single-dose, two-treatment, two-period, two-way crossover design study under fasting conditions which included 36 healthy adult subjects. All of 36 subjects were analyzed for plasma concentration of methyldopa.
AUC0-t and Cmax of methyldopa were defined as the main parameters in order to assess possible bioequivalence between both preparations. Based on standard bioequivalence guideline, the criteria for bioequivalence were the 90% confidence interval of the test/comparator-geometric
means ratio in the range of 80.00 - 125.00% for the AUC0-t and Cmax.
The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug for methyldopa were 102.79% (93.41 – 113.10%) for AUC0-t and 100.90% (88.51 – 115.03%) for Cmax. The 90% confidence intervals of the test/comparator ratios for AUC0-t and Cmax of methyldopa were within the acceptance range for bioequivalence.
The AUC0-t value of methyldopa were more than 80% compared to the value of AUC0-inf, (range AUC0-t/AUC0-inf were 94.58% to 98.98% for the test drug; 94.21% to 99.21% for the comparator drug), indicating that the sampling time was sufficiently long to ensure an adequate description of the absorption phase for methyldopa.
The mean (SD) elimination half-lives (t½) of methyldopa for the test drug was 4.74 (1.70) hours and for the comparator drug was 4.24 (1.73) hours. The half-life values of the test and the comparator drug were calculated utilizing Student’s paired t-test and the result were significantly different, demonstrating a comparable rate of drug elimination from the body. Based on this result, elimination of test drug expected to be relatively longer than comparator drug.
The median (range) of the time to reach maximum methyldopa plasma concentration (tmax) of the test drug was 2.66 (1.66 – 6.00) hours and 3.00 (1.00 – 6.00) hours for the comparator drug.
The tmax values of the two drugs (test and comparator drugs) were calculated using Wilcoxon matched-pairs test on the original data and the result were not significantly different.
Based on the results of the single dose study above, it was concluded that the Methyldopa 250 mg tablets produced by PT Actavis Indonesia are bioequivalent to the Aldomet® 250 mg Tablets, Aspen Pharmacare Australia Pty Ltd, Australia.
In the present study, the intra-subject coefficient of variance (%CV) obtained from the ANOVA for methyldopa AUC0-t was 24.35%. Hence, the number of subjects in this study (36 subjects) was adequate to ensure that this study has an adequate power of the study to confirm a statistical conclusion.
Investigational products were well tolerated by the subjects and there was no safety concern after single dose administration of the drug in the study.
06-11-2023
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