Single Dose fed In-Vivo Bioequivalence Study of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects.
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.
研究概览
简要总结
Study Title:
SingleDose fed In-Vivo Bioequivalence Study of Dolutegravir Sodium Dispersible Tablet 10 mg (MacleodsPharmaceuticals Ltd., India)with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK)in healthy, adult, malesubjects.
Study Design:
An open label, balanced, analyst blind, randomized,two-treatment, two-period, two-sequence, single dose, crossover bioequivalencestudy on 12 healthy, adult, male subjects under fed condition.
Objective:
i) Pharmacokinetic: To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (MacleodsPharmaceuticals Ltd., India)with two tablets ofDolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.
ii) Safety: To monitor the safety and tolerability of single oral dose of Dolutegravir SodiumDispersible Tablet 10 mg whenadministered in healthy, adult, male subjectsunder fed condition.
Number of Subjects: 12
Study Duration: Total 12 daysapproximately with 7 days washout.
Investigational Products:
| i)Test Formulation (T) |
:
Dolutegravir Sodium Dispersible Tablet 10 mg
Batch number: N/AV
Mfg. Date: N/AV
Exp. Date: N/AV
Manufactured by: Macleods Pharmaceuticals Ltd., India
Dose: 1 Dispersible Tablet
Mode of administration: The dispersible tablet will be dispersed in 50 mL of water and will be administered to the subjects, followed by rinsing of the administration device thrice with an additional 190 mL of water and will be administered to the subjects.
ii) Reference
| Formulation (R) |
:
Dolutegravir Dispersible Tablet 5 mg
Lot No: N/AV
Mfg. Date: N/AV
Exp. Date: N/AV
Manufactured by: GSK, Priory Street, Ware, Hertfordshire, SG12 0DJ
Dose: 2 Dispersible Tablets
Mode of administration: The dispersible tablet will be dispersed in 50 mL of water and will be administered to the subjects, followed by rinsing of the administration device thrice with an additional 190 mL of water and will be administered to the subjects.
Note: Test andReference tablets will be dispersed one minute prior to dosing in 50 mL ofdrinking water. Allow the tablets to disintegrate and stir gently and keepready solution for dosing.
Dietary Plan:
Following an overnight fast of at least 10 hours, subjects will start therecommended high fat, high calorie, non-vegetarian breakfast (comprising of 800to 1000 kilocalories), 30 minutes prior to administration of theinvestigational product. Study subjects will eat this meal in 30 minutes or less. Fasting willcontinue for four hours post-dose, then meals will be provided at 5.00, 9.00and 13.00 hours post dose on dosing day (day 1) and 24.50, 28.00, 32.00 and37.00 hours post dose on day 2 during both the periods
Study Restriction:
Drinking water willbe disallowed for one hour pre-dose and one hour post-dose. Subsequently,drinking water will be provided ad libitum. Subjects will be dosed while inupright sitting posture and will be instructed to remain seated or beambulatory (avoiding any strenuous activity) for first two hours following theinvestigational product administration (except during recording of vitals andblood collection time point).
CollectionSchedules:
Blood samples (1 ´ 5 mL) will be collected in 5 mL bloodcollection tube containing K2EDTA as anticoagulant during eachperiod. The venous blood samples will be withdrawn pre-dose and at 0.50, 1.00,1.33, 1.67, 2.00, 2.33, 2.67, 3.00, 3.50, 4.00, 4.50, 5.00, 6.00, 7.00, 8.00,10.00, 14.00, 18.00, 24.00, 36.00, 48.00 and 72.00 hours post-dose (Time points being relative to the investigationalproduct dosing).
During each ambulatory visit blood sample will be collected -1.00 hour to+ 2.00 hours of the scheduled time.
During check out of period I, 6 mL blood will be collected in plain tubesfor liverfunction test (SGPT, SGOT and GGT).
BloodLoss:
For each subject,the total number of blood draws will be 46(23 per period). The total volume of blood withdrawn will not exceed 272 mL (including 13 mL for safety assessment, 6 mL blood forliver function test (SGPT, SGOT and GGT) and 23 mL discarded normalsaline blood).
Handling of Blood Samples:
The blood samplescollected at each time point will be centrifuged between 4±2 ºC (short termexcursion permitted up to 10°C) and at 4000 rpm for 10 minutes to separateplasma. [For ambulatory samples, the samples collected till the scheduled timeof last subject will be centrifuged together and the samples collected laterwill be centrifuged separately according to their collection time]. Bloodsamples will be centrifuged within 30 minutes after collection of last bloodsample. The separated plasma will be transferred in prelabelled polypropylenetubes during each period. These tubes willbe labelled with study number, period number, subject number, sample number,time point (hrs) and aliquot number.
These tubes willthen be transferred to a deep freezer for storage.
| Special condition: |
· During check out of period I at 48.00 hours liver function test (SGPT, SGOT and GGT) will be carried out. If any clinically significant liver chemistry elevations are observed, subject will be withdrawn from study.
· For post study safety assessment
o In the event of a suspected drug induced liver injury, or other clinically significant liver chemistry elevations, dolutegravir should be stopped and subjects should not be rechallenged with a dolutegravir-containing product due to the risk of a recurrent reaction.
§ Provision shall be made in the volunteer database to avoid such subjects to get enrolled in dolutegravir-containing product.
Safety Assessment:
In each period,subject questionnaire and vital signs (Blood Pressure, Temperature and PulseRate) will be done at the time of check-in, pre-dose and at 3.00, 6.00, 10.00, 26.00, 35.00, 48.00 and 72.00 hours post-dose (Timepoints being relative to the investigational product dosing).
Note: subject will be kept in supine position for at least 5 minutesbefore start of Blood Pressure recording on each time point.
During check out ofperiod I at 48.00 hours liver function test (SGPT, SGOT and GGT) will becarried out. If any clinically significant liver chemistry elevations areobserved, subject will be withdrawn from study.
If any adverseevents are observed by either clinical staff or reported by subjects at timesother than scheduled times will be recorded.
In each period, thebreath of the subject will be checked to see whether they have consumed alcoholor not at the time of check-in and during each ambulatory visit of the studyusing breath alcohol analyzer. (Note: If subjects found breath alcohol testpositive during ambulatory visit, further blood sample will not be taken forthe respective period but subject questionnaire and vital signs will be taken).
Medical examination,ECG and clinical laboratory tests will be performed to cater to the post-studysafety assessments after the last ambulatory blood sample collection of periodII.
Medical examinationwill be carried out during check-in, check-out and at 72.00 hrs ambulatoryvisit of each period of the study and whenever attending medical officer thinksnecessary.
Urine test fordrugs of abuse will be carried out at the time of check-in of both the studyperiods.
Risk Evaluation and Mitigation Strategies:
Risk evaluated:
The studyInvestigational product can bring out various adverse effects.
Mitigationstrategies:
· Ambulance will be made available before start of study.
· All medical staff including nurses and doctors will beinformed to be available at clinical site.
· ICU will be checked for availability of all emergencymedicines and other devices will be checked for proper functioning
· Toxicity Management
In the event of a discontinuation of dolutegravir forsuspected drug induced liver injury, other clinically significant liverchemistry elevations, severe skin reaction or hypersensitivity reaction,subjects should not be rechallenged with a dolutegravir-containing product dueto the risk of a recurrent reaction. These subjects should be withdrawn fromstudy. Further details on this are provided in Appendix III.
Clinical Residency:
Subject will beadmitted and housed in the facility sufficient time before to maintain 10 hoursfasting condition before the administration of dose and until 48 hourspost-dose, during each period of the study. The subjects will visit the centre forambulatory blood sample collection at 72.00 hours post dose.
BioanalyticalMethod:
Dolutegravir will be estimated in plasma using validated LC-MS/MS method.
Pharmacokinetic Parameters:
-
Primary parameters :Cmax, AUC0-t andAUC0-Â¥.
-
Secondary parameters :T1/2, Kel, Tmax,npoints, Ke_first and Ke_last.
All the above parameters will becalculated using SAS®.
Statistical Analysis:
Summary statistics, ANOVA, intra-subject variabilityand 90% confidence interval will be calculated using SAS®. Linear& semi log graphs will be plot using SAS®.
Criteriafor Bioequivalence**:**
The 90% confidence intervalfor Cmax, AUC0-t and AUC0-¥.of Dolutegravir will form the basis forconcluding the bioequivalence of Dolutegravir sodium in product R and T. If the 90%confidence intervals are entirely included in the range of 80.00 – 125.00% for Cmax, AUC0-t and AUC0-¥.of Dolutegravir log-transformedthen the treatments will be claimed to be bioequivalent.
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 18.00 Year(s) 至 45.00 Year(s)（—）
- 性别
- Male
入选标准
- •The subjects will be included based on the following criteria: 1.Healthy volunteers within the age range of 18 to 45 years.
- •2.Presently non-tobacco users (smokers and chewers).
- •3.Willingness to provide written informed consent to participate in the study.
- •4.Body-mass index (BMI) between 18.50 kg/m2 and 29.99 kg/m2 (both inclusive) with body weight not less than 50 kg.
- •5.Absence of significant disease or clinically significant abnormal laboratory values or laboratory evaluation, medical history or physical examination during the screening.
- •6.Have a normal 12-lead ECG or one with abnormality considered to be clinically insignificant.
- •7.Have a normal chest X-ray PA view or one with abnormality considered to be clinically insignificant.
- •8.Comprehension of the nature and purpose of the study and compliance with the requirement of the distributed ICF.
排除标准
- •The subjects will be excluded based on the following criteria: 1.Personal history of allergy or hypersensitivity to Dolutegravir or allied drugs or excipients.
- •2.Any major illness in the past 90 days or any clinically significant ongoing chronic medical illness 3.Presence of any clinically significant abnormal laboratory values during screening 4.Severe cardiac, renal or liver impairment, gastro-intestinal disease or other conditions, any other organ or system impairment.
- •5.History of seizures, epilepsy or any kind of Neurological disorders and history of head trauma.
- •6.Past history of Anaphylaxis or angioedema.
- •7.Presence of disease markers of HIV or Hepatitis B or Hepatitis C virus.
- •8.History of chronic consumption of any kind of alcoholic beverages or having consumed alcohol within 48 hours prior to dosing.
- •9.Consumption of products containing xanthine derivatives or tobacco products within 48 hours prior to dosing.
- •10.Consumption of grapefruit or grapefruit containing products or any cruciferous vegetables or char-broiled meat prior 7 days 11.Consumption of products containing Ca/Fe/Mg within 48 hours prior to dosing.
- •12.Use of any recreational drug or a history of drug addiction.
- •14.History of difficulty with donating blood or difficulty in accessibility of veins in left or right arm.
- •15.Donation of blood within 90 days prior to receiving the first dose of study medication.
- •16.Consumption of any other prescription drug or over the counter (OTC) drugs and receiving dofetilide within two weeks prior to receiving the first dose of study medication.
- •17.An unusual diet for whatever reason e.g. low sodium diet.
- •18.Recent history of dehydration from diarrhoea, vomiting or any other reason within a period of 48 hours prior to the study.
结局指标
主要结局
To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.
时间窗: To evaluate the comparative oral bioavailability of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg (ViiV Healthcare, UK) in healthy, adult, male subjects under fed condition.
次要结局
- To monitor the safety and tolerability of single oral dose of Dolutegravir Sodium Dispersible Tablet 10 mg when administered in healthy, adult, male subjects under fed condition.(Throughout the study period and 5 drug half life)