Single dose Fasting In-Vivo Bioequivalence study of Dolutegravir Sodium Dispersible Tablet 10 mg(Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir 5mg dispersible tabletsmanufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human malesubjects.

Study Title: Single dose Fasting In-Vivo Bioequivalence study of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir 5mg dispersible tablets manufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human male subjects. Study Design: An open label, balanced, analyst blind, randomized, two-treatment, two-period, two-sequence, single dose, crossover bioequivalence study on 24 healthy, adult, human male subjects under fasting condition. Objective: i) Pharmacokinetic: To evaluate the comparative oral bioavailability of single dose of Dolutegravir Sodium Dispersible Tablet 10 mg (Macleods Pharmaceuticals Ltd., India) with two tablets of Dolutegravir Dispersible Tablet 5 mg Dolutegravir 5mg dispersible tablets manufactured by GlaxoSmithKline, UK on behalf of ViiV Healthcare, UK in healthy, adult, human male subjects under fasting condition. ii) Safety: To monitor the safety and tolerability of a single oral dose of Dolutegravir Sodium Dispersible Tablet 1 O mg and two tablets of Dolutegravir 5mg dispersible tablets when administered in healthy, adult, human male subjects under fasting condition. Number of Subjects- 24 Study Duration - Total 12 days approximately for each group with 7 days washout. If period II is scheduled later the duration of study will change accordingly. Diagnosis and main Criteria for Inclusion- Healthy human male subjects within the age range of 18 to 45 years with body-mass index (BMI) between 18.50 kg/m2 and 29.99 kg/m2 (both inclusive) with body weight not less than 50 kg and having absence of significant disease, laboratory values within normal range, absence of clinically significant medical history and normal physical examination during the screening and complying with inclusion and exclusion criteria. lnvestigational Product Administration: An oral dose of Reference product (R) or Test product (T) will be administered as per the randomization schedule. Subjects will receive the alternate ’treatment’ in both the periods in such a way that each subject will receive both the treatment test and reference each, by the end of the study. Note: Test and Reference tablets will be dispersed one minute prior to dosing in 50 ml of drinking water. Allow the tablets to disintegrate and stir gently and keep ready solution for dosing. lnvestigational 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 tablets will be dispersed in 50 ml of water and will be administered to the subjects, followed by rinsing of the administration device with an additional 50 ml of water and will be administered to the subjects. ii) Reference Formulation (R) : Dolutegravir (GSK1349572) Dispersible Tablet 5 mg Lot No: N/AV Mfg. Date: N/AV Exp. Date: N/AV Manufactured for: ViiV Healthcare UK limited, 980 Great West Road , Brentford, TW8 9GS Manufactured by: GlaxoSmithKline Research & Development Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS, Tel. +44 2080475000 Manufacturing site: Glaxo Operations UK Limited (trading as Glaxo Wellcome Operations), Priory Street, Ware, Hertfordshire, SG12 ODJ, Tel. +44 1920 56933 Dose: 2 Dispersible Tablets Mode of administration: The dispersible tablets will be dispersed in 50 ml of water and will be administered to the subjects, followed by rinsing of the administration device with an additional 50 ml of water and will be administered to the subjects. Dietary Plan- The dose will be administered after an overnight fast of at least 10 hours in each period. Fasting will continue for at least four hours post-dose, then meals will be provided approximately at 4.00, 8.00 and 13.00 hours post-dose on dosing day (day 1) and at 24.50, 28.50, 32.00 and 37.00 hours post dose on day 2 of each period. Study Restriction- Drinking water will be disallowed for 1.00 hour prior to dosing and until 2.00 hour post-dose except 100 ml of water at the time of dosing. Also, no food will be permitted until about 4 hours post-dose. Record should be maintained for timing, duration and amount of food and fluid consumed. Subjects will be dosed while in upright sitting posture and will be instructed to remain seated or be ambulatory (avoiding any strenuous activity and during recording of vitals) for first two hours following the investigational product administration. During this interval, under supervision, subjects will be permitted to use the washroom facilities. Thereafter the subjects will be allowed to engage only in normal activities while avoiding severe physical exertion. However should any adverse event occur at any time during housing the subjects will be placed in an appropriate posture. Collection Schedules               : Blood samples (1x 5 mL) will be collected in 5mL blood collection tube containing K2EDTA as anticoagulant duringeach period. The venous blood samples will be withdrawn pre-dose and at 0.08,0.17, 0.33, 0.50, 0.75, 1.00, 1.33, 1.67, 2.00, 2.50, 3.00, 4.00, 6.00,8.00, 10.00, 14.00, 18.00, 24.00, 36.00, 48.00 and 72.00 hours post dose (time points beingrelative to the investigational product dosing).

Note:During each ambulatory visit blood sample will be collected  -1.00 hour to + 2.00 hours of thescheduled time.

Duringcheck out of period I, 6 mL blood will be collected in plain tubes for liverfunction test (SGPT, SGOT and GGT).

Blood Loss                               : For eachsubject, the total number of blood draws will be 44 (22 per period). The totalvolume of blood withdrawn will not exceed 260 mL (including 13 mL for safetyassessment, 6 mL blood for liver function test (SGPT, SGOT and GGT) and 21 mL discardednormal saline blood). Should circumstances arise, like breakage of tube aftercollection, adverse event (including abnormal laboratory values) where moreblood needs to be withdrawn, additional blood samples may be taken. The consentof the subject would be taken and the IEC would be informed and subject will becompensated accordingly.

Handling of Blood Samples     :     The blood samplescollected at each time point will be centrifuged between 4 to 8 °C (short term excursion permitted up to 10°C) and at 4000 rpm for10 minutes to separate plasma. For ambulatory samples, the samplescollected till the scheduled time of last subject will be centrifuged togetherand the samples collected later will be centrifuged separately according totheir collection time. Blood samples will becentrifuged within 30 minutes after collection of last blood sample; if thereis any delay in centrifugation then sample will be kept in cold condition. Theseparated plasma will be aliquoted in duplicate in prelabelled polypropylenetubes during each period. These tubes will be labelled with Study Number, Period Number, SubjectNumber, Sample Number, Time Point (hrs) and Aliquot Number.

Thesetubes will then be transferred to a deep freezer set at -75°C for storage.

                                                      Washout Period                       : There will bewashout period of at least 7 days from the completion of dosing between twoperiods.

Safety Assessment                   :     In each period, subjectquestionnaire and vital signs (Blood pressure, Temperature and PulseRate) will be done at the time of check-in, pre-doseand at 3.00, 6.00, 10.00, 26.00, 35.00, 47.00 and 72.00 hours post-dose (Time points being relative to the investigationalproduct dosing).

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 centrefor ambulatory blood sample collection at 72.00 hours post dose.

 Bioanalytical Method**:**     Dolutegravir will be estimated inplasma using validated LC-MS/MS method.

Pharmacokinetic

Parameters                              : 1) Primary parameters          :Cmax, AUC0-t and AUC0-inf.

2. Secondary parameters    : T1/2, Ke, Tmax,npoints, Residual area, Ke_first and Ke_last.

Both parameters will be calculated usingSAS®.

Statistical Analysis                   : Summarystatistics, ANOVA, Intra subject variability, and 90% confidence interval willbe calculated using SAS® Linear & semi log graphs will be plotusing SAS®.

 Criteria for Bioequivalence**:** The 90% confidence intervalfor Cmax, AUC0-t and AUC0-inf of Dolutegravirwillform the basis for concluding the bioequivalence of Dolutegravir Sodium in product R and T. If the90% confidence intervals are entirely included in the range of 80.00% – 125.00%for log-transformed Cmax, AUC0-tand AUC0-inf then the products will be claimed to bebioequivalent.