Single dose Fed oral bioequivalence study of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404 in healthy adult males and non-pregnant, non-lactating females under fed conditions.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Cmax and AUC0-t
研究概览
简要总结
| Protocol Title |
Single dose Fed oral bioequivalence study of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404 in healthy adult males and non-pregnant, non-lactating females under fed conditions.
|Protocol No.
TAED-TBP-1003 Version No:03 Dated: 07 May 2025
|Product
Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension
|Study Type
Pilot Fed Bioequivalence
|Version
03
|Protocol Date
07 May 2025
|General Description
This protocol describes an open labelled, balanced, single dose, randomized, two-treatment, four-period, two-sequence, crossover, full replicate study to investigate the bioequivalence of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404.
Single dose fed pharmacokinetics will be characterized in Twenty-four (24) healthy adult males and non-pregnant, non-lactating females following administration of a single oral dose of either test product (T) or reference product (R=R1+R2) as per randomization schedule. The detailed administration process is given in the section 7.5. Treatment procedure of the protocol.
For Period 01 & 02: For Emtricitabine, Tenofovir Alafenamide, Tenofovir and Dolutegravir:
In each study period, Six milliliter (1 × 6 mL) blood samples (23) will be collected in K3EDTA Vacutainers at pre-dose (0.00 hour) and the following times after dosing: 0.083, 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00 and 72.00 hours.
For Period 03 & 04: For Tenofovir Alafenamide:
In each study period, four milliliter (1 × 4 mL) blood samples (15) will be collected in K3EDTA Vacutainers at pre-dose (0.00 hour) and the following times after dosing: 0.083, 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00 hours.
The Collected blood samples will be placed in an ice batch and centrifuged under refrigeration as soon as possible. Two aliquots (Aliquot 1 of 2, & Aliquot 2 of 2) of plasma will be extracted and stored in suitably labeled tubes at -70°C or colder with an acceptable operating range within -55°C to -90°C at the clinical site until transferred on dry ice to analytical site (refer Appendix-I: Bioanalytical sample handling instruction of the protocol).
For the determination of the pharmacokinetic disposition of the formulations, there will be a total of 76 (46 blood samples from period-1 & 2 and and 30 samples from period -3 & 4) blood samples involving a total of 396 mL of blood collected for pharmacokinetic analysis from each subject in the study. There will be at least 07 days gap between dosing times for the treatment periods.
The bioequivalence of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of: Gilead Sciences, Inc. Foster City, CA 94404 will be assessed by a statistical comparison of various pharmacokinetic parameters derived from the plasma concentration-time curves of the drug.
|OBJECTIVES
Primary Objective: To investigate the bioequivalence of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404 in healthy adult males and non-pregnant, nonlactating females.
Secondary Objective: To evaluate the safety of the subjects (i.e. monitor adverse events) under fed conditions.
|STUDY DRUG
Test product (T): Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension.
Manufactured by: Mylan Laboratories Limited, India.
Reference product (R=R1+R2):
Reference product (R1): TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension
Manufactured for: ViiV healthcare, Durham, NC 27701.
Reference Product (R2): DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension
Manufactured by: Cambrex (Mirabel, Quebac, Canada), 17800 Lapointe, Mirabel, Quebec, J7J0W8- Canada.
Distributed by: Gilead Sciences, Inc. Foster City, CA 94404.
|STUDY CONDUCT
This is an open labelled, balanced, single-dose, randomized, two-treatment, four-period, two sequence, crossover, full replicate study to investigate the bioequivalence of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral Suspension (T) of Mylan Laboratories Limited, India with that of Reference product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 g and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404 in healthy adult males and nonpregnant, non-lactating females.
Single dose fed pharmacokinetics will be characterized in Twenty-four (24) healthy adult males and non-pregnant, non-lactating females following administration of a single oral dose of either test product (T) or reference product (R=R1+R2).
Subjects will be housed the evening prior to drug dosing of period-1, period-2 and until at least 72.00 hours after investigational drug administration. Blood samples will be collected prior to dosing and for up to 72.00 hours after period-1 and period-2 dosing. Subjects will be housed the evening prior to drug dosing of period-3, period-4 and until at least 24.00 hours after investigational drug administration. Blood samples will be collected prior to dosing and for up to 4.00 hours after period-3 and period-4 dosing. There will be at least 07 days gap between dosing times of each treatment periods. Individual subjects should be dosed at approximately the same time of day in each dosing period. It is the sponsor’s intent to complete all subjects simultaneously. Thus, it is anticipated that all subjects will be completed in a single cohort within approximately 24 days following the initiation of dosing. If multiple cohorts are necessary to enroll the required number of subjects, no two cohorts can be dosed on the same day.
|Screening Procedures
Each prospective subject must agree to participate in screening procedures by signing the most recent Institutional Review Board/Independent Ethics Committee approved Informed Consent Document (ICD) before any screening procedure is initiated. The Principal Investigator or Medical Sub-Investigator will review the inclusion and exclusion criteria to confirm eligibility of each subject prior to enrollment.
Each subject will undergo a screening procedure for health assessment, which consists of a complete medical history, physical examination with vital signs, clinical laboratory evaluations, 12-lead ECG and Chest X-ray PA view. The physical examination findings, ECG, and the laboratory tests can be considered as valid for maximum of 21 days prior to the dosing (drug administration) in first period of the study. Chest X-ray PA view will be taken within 6 months prior to dosing (drug administration) of period-1.
The physician in charge will assess abnormal values to determine if it is clinically significant.
|Housing
Enough subjects from the general population will be available in the clinic for Period-1 dosing in order to dose the required number of subjects. Subjects will be housed 11.00 hours prior until at least 72.00 hours after dosing for period-1 & period-2. Subjects will be housed 11.00 hours prior to dosing until at least 24.00 hours after dosing for period-3 and period-4. There will be at least 07 days gap between dosing times for the treatment periods.
|Toxicity Management
|Bioanalytical Method
A validated assay method will be employed for the analysis of Emtricitabine, Tenofovir Alafenamide, Tenofovir and Dolutegravir in plasma samples. Full validation of the method, including precision, accuracy and reproducibility will be included in the final report, along with a statement regarding the stability of frozen samples.
|Pharmacokinetic Parameter Determination
All concentration values below the lower limit of quantification (BLOQ) will be set to zero. Any missing samples will be reported as ‘M’ and will not be included for pharmacokinetic and statistical analysis.
The following pharmacokinetic parameters will be computed by using Phoenix® WinNonlin® version 8.0 or higher for Emtricitabine, Tenofovir Alafenamide, Tenofovir and Dolutegravir through non compartmental method. Pharmacokinetic data from tenofovir will be provided as supportive evidence of comparable therapeutic outcome. Subjects concentration data from the first two periods will be considered for the pharmacokinetic parameters estimation of Emtricitabine, Tenofovir & Dolutegravir:
For TAF: The pharmacokinetic parameters will be estimated by using the concentration data up to 04.00 hrs post dose.
|Statistical Analysis of the Pharmacokinetic
Parameters
Subjects who completed all periods of the study will be included in scaled average BE and with in reference variability estimation. All other scenarios where the subject didn’t completed all periods of the study will be considered in average bioequivalence evaluation as per IEC approved protocol using SAS version 9.4 or higher version. Descriptive statistics of all the pharmacokinetic parameters will be computed and reported for Emtricitabine, Tenofovir Alafenamide, Tenofovir and Dolutegravir. The below will be calculated and reported for Emtricitabine, Tenofovir Alafenamide, Tenofovir and Dolutegravir:
|APPENDIX VI: STUDY CONDUCT
INFORMATION
The clinical research organization conducting this study on behalf of Mylan Laboratories Ltd., India is required to complete this sheet and forward to Mylan prior to the enrollment of any subjects into the study. Any updates throughout the study conduct period must be reported on this sheet.
Protocol Number: TAED-TBP-1003
Protocol Title: Single dose Fed oral bioequivalence study of Emtricitabine, Tenofovir Alafenamide and Dolutegravir 15 mg/1.88 mg/5 mg Tablets for Oral
Suspension (T) of Mylan Laboratories Limited, India with that of Reference
product (R=R1+R2) R1: TIVICAY PD (Dolutegravir) 5 mg Tablets for oral suspension of ViiV healthcare, Durham, NC27701 and R2: DESCOVY® (emtricitabine and tenofovir alafenamide) 15 mg and 1.88 mg Tablets for oral suspension of Gilead Sciences, Inc. Foster City, CA 94404 in healthy adult males and non-pregnant, non-lactating females.
Principal Investigator: Dr. Anjum Jabeen, M.B.B.S., M.D.,
Address: Aizant Drug Research Solutions Pvt. Ltd., Clinical Pharmacology Unit-II,
Maitrivihar Commercial Complex, Block No. 101-107 & 201-206, Ameerpet
Hyderabad, Telangana, India - 500016.
Clinical Research Facility: Aizant Drug Research Solutions Pvt. Ltd.,
Maitrivihar Commercial Complex, Block No. 101-107 & 201-206, Ameerpet
Hyderabad, Telangana, India – 500016.
Stastical Investigator: Mr. Udaya Kumar Konda,
Pharmacokinetic & Statistical analysis,
Aizant Drug Research Solutions Pvt. Ltd.,
Survey No.: 172 &173, Apparel Park Road,
Dulapally Village, Dundigal Gandimaisamma Mandal, Medchal-
Malkhajgiri District - 500100, Telangana, India.
**Randomization Facility:**Pharmacokinetic & Statistical analysis
Aizant Drug Research Solutions Pvt. Ltd., Survey No.: 172 &173, Apparel Park Road, Dulapally Village, Dundigal Gandimaisamma Mandal, Medchal-
Malkhajgiri District - 500100, Telangana, India.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
入排标准
- 年龄范围
- 18.00 Year(s) 至 45.00 Year(s)（—）
- 性别
- All
入选标准
- •Subjects must fulfill all of the following criteria to be considered for inclusion into this study.
- •Normal healthy adult males and non-pregnant, non-lactating females, age between 18 to 45 years (inclusive of both).
- •Body mass index of (greater than or equal to) 18.5 kg/m2 and (less than and equal to) 30.0 kg/m2 and weight (greater than or equal to) 50.00 kg.
- •Healthy according to the laboratory results and physical examination, performed within 21 days prior to the commencement of the dosing in Period-
- •Subject whose clinical laboratory values are within normal limits or clinically insignificant as determined by physician or principal investigator to be of no clinical significance.
- •Have normal ECG, Chest X-ray and vital signs.
- •Non-smoker and Non-alcoholic.
- •Subject creatinine clearance (CrCl) should be more than 60 mL/min.
- •Willing to not to participate in clinical research study or blood donations till 90 days after the study completion.
- •Subject able to communicate effectively and provide written informed consent.
- •Subject willing to adhere to protocol requirements as evidenced by written informed consent approved by an Independent Ethics Committee (IEC).
- •If study subject is a female and is of child bearing potential practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s), such as condoms, foams, jellies, diaphragm, intrauterine device (IUD), or abstinence.
- •Or is postmenopausal for at least 1 year Or is surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy or tubectomy has been performed on the study subject).
排除标准
- •Subject candidates must not be enrolled in the study if they meet any of the following criteria.
- •Any history of allergy or hypersensitivity to Emtricitabine, Tenofovir Alafenamide and Dolutegravir or other related drugs.
- •Positive test result for hepatitis B surface antigen (HBs Ag), hepatitis C virus antibody (HCV Ab) or HIV-1 antibody or HIV Type 2 (HIV-2) antibody (HIV Ab) and VDRL / syphilis.
- •The study drug is contraindicated for medical reasons.
- •Any history or presence of significant cardiovascular, pulmonary, hepatic, renal, gastrointestinal, endocrine, dermatological, neurological, psychiatric diseases or disorders.
- •History or presence of drug abuse in the past one year.
- •Difficulty in swallowing tablets or suspension.
- •Any history of difficulty in donating blood.
- •Had clinically significant abnormal values of laboratory parameters.
- •Blood pressure is (less than) 90/60 and (greater than) 129/79 millimeters of mercury (Systolic blood pressure/ Diastolic blood pressure).
- •Any history or presence of fractures or decreases in bone density.
- •Any history evidence of Lactic acidosis and severe hepatomegaly.
- •Use of any prescription or over the counter (OTC) medications other than hormonal contraceptive or hormone replacement therapy within the 14 days prior to the initial administration of study medication.
- •A depot injection or implant of any drug within 3 months prior to initial administration of study medication.
- •Use of any medication, herbal supplement, or vitamin known to induce or inhibit hepatic enzyme activity within 28 days prior to the initial administration of study medication.
- •Liver function tests (ALT, AST and bilirubin) 1.1 times the upper limit of normal.
- •Amenorrhea or irregular menstrual periods (defined unable to predict within 7 days) during past 6 months for females.
- •Female subject who is currently breast feeding or a female study subject who is pregnant or who is likely to become pregnant during the study.
- •Female subject demonstrating positive for pregnancy test (performed at the time of each period check-in).
- •Subject positive for urine or breath alcohol test, urine screen for drugs of abuse [Cannabinoids (Marijuana / Tetra Hydro Cannabinoids-THC), Cocaine, Opiates (morphine), Amphetamine, Barbiturates and Benzodiazepines] at the time of each period check-in will be excluded from the study.
- •Participation in a drug research study/donation of blood within past 90 days.
结局指标
主要结局
Cmax and AUC0-t
时间窗: For Period 01 & 02: 0.00, 0.083, 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00, 6.00, 8.00, 10.00, 12.00, 24.00, 36.00, 48.00 and 72.00 hours. | For Period 03 & 04: 0.00, 0.083, 0.17, 0.33, 0.50, 0.75, 1.00, 1.25, 1.50, 1.75, 2.00, 2.50, 3.00, 3.50, 4.00 hours
次要结局
- To monitor the adverse events and to ensure the(safety of the subjects)
研究者
Anjum Jabeen MBBS MD
Aizant Drug Research Solutions Pvt. Ltd.,