Phase 1
Completed N=14
Bioavailability Study of 10 Milligram (mg) and 5 mg Tablets Versus Conventional Tablets of Dolutegravir
Source: ClinicalTrials.gov NCT03095638 ↗Enrolled (actual)
14
Serious AEs
0.0%
Results posted
Dec 2018
Primary outcomePrimary: Area Under the Plasma Concentration-time Curve From Time of Dose Extrapolated to Infinite Time (AUC[0-infinity]) of DTG for Part 1 — 58900; 58400 hours*nanograms/mL (h*ng/mL)
Summary
The aim of this cross-over study is to compare the relative bioavailability and pharmacokinetic parameters of both 10 mg conventional tablets and 5 mg dispersible tablets of dolutegravir (DTG) with that of 25 mg or 50 mg conventional DTG tablets. The study will be carried out in 2 parts. Part 1 of the study will be open-label, 2 period designs with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 10 mg DTG tablets or one 50 mg DTG tablet in a crossover manner in the fasting state. Part 2 of the study will be a 3 period crossover design with a wash out period of at least 7 days between the dosing periods. Subjects will be randomized to receive either single dose of five 5 mg DTG tablets (administered as dispersed with water or directly to mouth) or one 25 mg DTG tablet in a crossover manner in the fasting state. Subjects will have a follow-up visit 7-10 days post last dose of study treatment. Approximately 14 healthy subjects will participate in Part 1 and approximately 24 healthy subjects will participate in Part 2 of the study. The total duration of Part 1 will be approximately 7 to 8 weeks and that of part 2 will be approximately 8 to 9 weeks.
TIVICAY® is a trademark of the GlaxoSmithKline group of companies.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Area Under the Plasma Concentration-time Curve From Time of Dose Extrapolated to Infinite Time (AUC[0-infinity]) of DTG for Part 1 |
58900; 58400 | — |
| PRIMARY Area Under the Plasma Concentration-time Curve From Time of Dose to Last Measurable Concentration AUC [0-t] of DTG for Part 1 |
55800; 55200 | — |
| PRIMARY Maximum Observed Concentration (Cmax) of DTG for Part 1 |
2780; 2700 | — |
| PRIMARY AUC (0-infinity) of DTG for Part 2 |
51300; 48800; 31600 | — |
| SECONDARY AUC (0-t) of DTG for Part 2 |
49000; 46700; 30100 | — |
| SECONDARY Cmax of DTG for Part 2 |
2690; 2700; 1500 | — |
| SECONDARY Plasma DTG Lag Time Before Observation of Drug Concentrations (Tlag) for Part 1 |
0.00; 0.00 | — |
| SECONDARY Time to First Occurrence of Cmax (Tmax) of DTG for Part 1 |
2.01; 2.00 | — |
| SECONDARY Terminal Phase Half-life (t1/2) of DTG for Part 1 |
15.81; 16.23 | — |
| SECONDARY Terminal-phase Rate Constant (Lambda z) of DTG for Part 1 |
0.0439; 0.0427 | — |
| SECONDARY Percentage of AUC (0-infinity) Obtained by Extrapolation (%AUCex) of DTG for Part 1 |
5.17; 5.52 | — |
| SECONDARY Area Under the Concentration-time Curve Over Time Zero (Pre-dose) to 24 Hours After Dose Administration (AUC[0-24]) of DTG for Part 1 |
37500; 36600 | — |
| SECONDARY Apparent Oral Clearance (CL/F) of DTG for Part 1 |
0.849; 0.856 | — |
| SECONDARY Apparent Volume of Distribution During the Terminal Phase (Vz/F) of DTG for Part 1 |
19.4; 20.0 | — |
| SECONDARY Last Observed Quantifiable Concentration (Ct) of DTG for Part 1 |
106; 114 | — |
| SECONDARY Observed Concentration at 24 Hours After Dose Administration (C24) of DTG for Part 1 |
912; 916 | — |
| SECONDARY Plasma DTG Tlag for Part 2 |
0.00; 0.00; 0.00 | — |
| SECONDARY Tmax of DTG for Part 2 |
1.00; 1.00; 1.75 | — |
| SECONDARY t1/2 of DTG for Part 2 |
15.66; 15.48; 15.78 | — |
| SECONDARY Lambda Z of DTG for Part 2 |
0.0443; 0.0448; 0.0439 | — |
| SECONDARY %AUCex of DTG for Part 2 |
4.37; 4.23; 4.66 | — |
| SECONDARY AUC (0-24) of DTG for Part 2 |
34000; 32300; 20400 | — |
| SECONDARY DTG CL/F for Part 2 |
0.487; 0.513; 0.792 | — |
| SECONDARY Vz/F of DTG for Part 2 |
11.0; 11.4; 18.0 | — |
| SECONDARY Ct of DTG for Part 2 |
89.3; 84.4; 58.2 | — |
| SECONDARY C24 of DTG for Part 2 |
770; 741; 493 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) for Part 1 |
1; 2; 0; 0 | — |
| SECONDARY Number of Participants With Adverse Events AEs and Serious Adverse Events SAEs for Part 2 |
2; 2; 3; 0; 0; 0 | — |
| SECONDARY Change From Baseline in Clinical Laboratory Parameters Serum Glucose, Serum Calcium, Serum Potassium, Serum Sodium, Serum Urea for Part 1 |
-0.091; 0.071; -0.178; 0.022; 0.001; -0.005 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Alanine Amino Transferase (ALT), Serum Alkaline Phosphatase, Serum Aspartate Amino Transferase (AST), Serum Creatine Kinase for Part 1 |
0.8; -1.1; -1.6; -1.0; 1.5; 0.8 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 1 |
0.3; 0.1; -1.2; -0.4; 2.3; 2.4 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatinine and Serum Direct Bilirubin for Part 1 |
3.29; 3.28; 0.10; 2.16; 9.91; 11.19 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Glucose, Serum Calcium, Serum Potassium, Serum Sodium, Serum Urea for Part 2 |
-0.220; -0.223; -0.187; 0.130; -0.060; -0.150 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum ALT, Serum Alkaline Phosphate, Serum AST, Serum Creatine Kinase for Part 2 |
-0.4; -1.0; -1.1; 2.0; -1.0; 0.3 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Albumin and Serum Protein for Part 2 |
0.4; 1.1; 0.5; 2.0; -1.0; 1.7 | — |
| SECONDARY Change From Baseline in Clinical Chemistry Parameters Serum Bilirubin, Serum Creatine and Serum Direct Bilirubin for Part 2 |
2.26; 2.85; 2.91; 0.97; -0.80; 3.07 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocyte Mean Corpuscular Hemoglobin (MCH) for Part 1 |
0.08; -0.02; 0.00; -0.22 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocyte Mean Corpuscular Volume (MCV) for Part 1 |
-0.01; 0.26; -0.38; 0.26 | — |
| SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils, Blood Platelets for Part 1 |
-0.004; -0.013; -0.004; -0.004; 0.003; -0.014 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Hemoglobin for Part 1 |
4.9; 4.0; -0.8; -3.4 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 1 |
0.0137; 0.0131; -0.0042; -0.0058 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocytes for Part 1 |
0.182; 0.193; -0.024; -0.014 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocyte MCH for Part 2 |
0.12; 0.05; 0.05; 0.03; -0.25; 0.03 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocyte MCV for Part 2 |
-0.03; -0.13; 0.29; 0.07; -0.25; -0.20 | — |
| SECONDARY Change From Baseline in Hematology Parameters Blood Basophils, Blood Eosinophils,, Blood Leukocytes, Blood Lymphocytes, Blood Monocytes, Blood Neutrophils, Blood Platelets for Part 2 |
-0.004; -0.005; -0.004; 0.003; 0.000; 0.000 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Hemoglobin for Part 2 |
5.0; 6.3; 4.8; 3.7; 2.0; 3.7 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Hematocrit for Part 2 |
0.0126; 0.0172; 0.0158; 0.0113; 0.0090; 0.0103 | — |
| SECONDARY Change From Baseline in Hematology Parameter Blood Erythrocytes for Part 2 |
0.145; 0.209; 0.165; 0.123; 0.120; 0.117 | — |
| SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 1 |
2; 2; 0; 1; 0; 1 | — |
| SECONDARY Urine Potential of Hydrogen (pH) Analysis by Dipstick Method for Part 1 |
6.43; 6.25; 6.20; 6.00 | — |
| SECONDARY Urine Specific Gravity Analysis by Dipstick Method for Part 1 |
1.0131; 1.0177; 1.0180; 1.0150 | — |
| SECONDARY Number of Participants With Abnormal Values on Urinalysis by Dipstick Method for Part 2 |
1; 0; 0; 1; 1; 0 | — |
| SECONDARY Urine pH Analysis by Dipstick Method for Part 2 |
6.31; 6.21; 6.31; 5.33; 5.50; 6.83 | — |
| SECONDARY Urine Specific Gravity Analysis by Dipstick Method for Part 2 |
1.0143; 1.0148; 1.0141; 1.0207; 1.0165; 1.0117 | — |
| SECONDARY Number of Participants With Chemistry Toxicities of Grade 2 as Defined by Division of Acquired Immunodeficiency Syndrome (DAIDS) for Part 1 |
1; 0 | — |
| SECONDARY Number of Participants With Urinalysis Toxicities of Grade 2 as Defined by DAIDS for Part 1 |
1; 0 | — |
Eligibility Criteria
Inclusion Criteria
- Between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- Healthy as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac evaluation (history and electrocardiogram [ECG]). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the investigator in consultation with the Medical Monitor agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
- Body weight >= 50 kilogram (kg) for males and >= 45 kg for females and body mass index (BMI) within the range 18.5 - 31.0 kg per meter square (kg/m^2) (inclusive).
- Male or female. Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until 2 weeks after dosing with study medication and completion of the follow-up visit.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions.
Exclusion Criteria
- Alanine amino transferase (ALT) and bilirubin >1.5x Upper limit of normal (ULN) (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 450 Milliseconds (msec).
- Unable to refrain from the use of prescription [that is (i.e. or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and ViiV Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.
- History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 gram (g) of alcohol: 12 ounces (360 milliliters [mL]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
- Urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine- containing products within 1 month prior to screening.
- History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
- Creatinine clearance (CrCL) <90 mL/minute.
- A positive hepatitis B surface antigen (HBsAg) or a positive hepatitis B core antibody with a negative hepatitis B surface antibody, positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment.
- A positive pre-study drug/alcohol screen.
- A positive test for Human Immuno-deficiency Virus (HIV) antibody.
- Wh
Data sourced from ClinicalTrials.gov (NCT03095638). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.