TABLE 4.
Summary of selected pharmacokinetic parameters in part A a of the study (pharmacokinetic population b )
| PK parameter | Treatment | n/N | GSK3358699 | GSK3206944 (metabolite) | ||
|---|---|---|---|---|---|---|
| Geometric mean (%CVb) | 95% CI | Geometric mean (%CVb) | 95% CI | |||
| AUC(0‐t), h*ng/mL | 1 mg SD | 5/5 | 0.8 (38.5) | (0.5, 1.3) | 15.1 (34.0) | (10.0, 22.8) |
| 3 mg SD | 3/3 | 2.2 (23.3) | (1.3, 4.0) | 28.4 (12.0) | (21.1, 38.3) | |
| 10 mg SD | 6/6 | 10.1 (44.0) | (6.5, 15.7) | 101.2 (27.4) | (76.3, 134.1) | |
| 20 mg SD | 6/6 | 23.0 (20.4) | (18.6, 28.4) | 221.9 (29.9) | (163.3, 301.6) | |
| 25 mg SD | 12/12 | 33.9 (22.5) | (29.4, 39.0) | 367.1 (13.9) | (336.2, 401.0) | |
| 30 mg SD | 6/6 | 76.7 (38.6) | (51.9, 113.4) | 494.7 (21.9) | (394.2, 620.9) | |
| 40 mg SD | 6/6 | 63.7 (30.8) | (46.5, 87.3) | 625.8 (32.7) | (448.0, 874.2) | |
| AUC(0‐∞), h*ng/mL | 1 mg SD | 0/5 | … | … | 17.1 (−) | … |
| 3 mg SD | 0/3 | … | … | 28.9 (−) | … | |
| 10 mg SD | 5/6 | 11.0 (45.7) | (6.4, 18.8) | 103.4 (25.8) | (79.3, 135.0) | |
| 20 mg SD | 6/6 | 23.5 (19.7) | (19.2, 28.9) | 192.6 (11.6) | (160.1, 231.6) | |
| 25 mg SD | 9/12 | 36.9 (23.2) | (31.0, 44.0) | 356.0 (13.7) | (317.8, 398.8) | |
| 30 mg SD | 4/6 | 76.9 (37.0) | (43.5, 135.9) | 511.8 (27.3) | (334.1, 784.1) | |
| 40 mg SD | 5/6 | 67.0 (33.1) | (44.9, 100.0) | 636.1 (31.9) | (458.9, 881.7) | |
| AUC(0‐24), h*ng/mL | 1 mg SD | 0/5 | … | … | 16.4 (−) | … |
| 3 mg SD | 0/3 | … | … | 28.1 (−) | … | |
| 10 mg SD | 5/6 | 11.0 (45.7) | (6.4, 18.8) | 98.8 (31.0) | (71.9, 135.9) | |
| 20 mg SD | 6/6 | 23.5 (19.7) | (19.1, 28.8) | 219.8 (28.8) | (163.4, 295.7) | |
| 25 mg SD | 10/12 | 34.5 (24.8) | (29.0, 41.0) | 348.7 (14.7) | (317.9, 382.6) | |
| 30 mg SD | 5/6 | 71.5 (34.8) | (47.0, 108.9) | 479.4 (22.8) | (378.5, 607.1) | |
| 40 mg SD | 6/6 | 64.1 (30.7) | (46.8, 87.8) | 599.5 (35.0) | (419.7, 856.5) | |
| C max, ng/mL | 1 mg SD | 5/5 | 0.9 (69.8) | (0.4, 1.9) | 3.1 (33.2) | (2.1, 4.7) |
| 3 mg SD | 3/3 | 1.9 (26.3) | (1.0, 3.6) | 6.0 (20.5) | (3.6, 9.9) | |
| 10 mg SD | 6/6 | 6.5 (48.2) | (4.0, 10.4) | 17.8 (49.9) | (10.8, 29.1) | |
| 20 mg SD | 6/6 | 15.0 (45.9) | (9.5, 23.7) | 48.5 (41.6) | (31.9, 73.7) | |
| 25 mg SD | 12/12 | 16.2 (39.6) | (12.7, 20.7) | 67.9 (31.3) | (55.9, 82.4) | |
| 30 mg SD | 6/6 | 49.8 (83.9) | (23.2, 107.2) | 106.7 (52.3) | (63.7, 178.7) | |
| 40 mg SD | 6/6 | 42.3 (98.5) | (17.8, 100.4) | 133.4 (42.6) | (86.9, 204.7) | |
| t max, h* | 1 mg SD | 5/5 | 0.5 (0.3, 1.0) | … | 1.0 (1.0, 2.0) | … |
| 3 mg SD | 3/3 | 0.5 (0.5, 1.0) | … | 2.0 (1.0, 2.0) | … | |
| 10 mg SD | 6/6 | 0.5 (0.5, 0.5) | … | 2.0 (1.0, 2.0) | … | |
| 20 mg SD | 6/6 | 1.0 (0.3, 1.0) | … | 2.0 (1.0, 2.1) | … | |
| 25 mg SD | 12/12 | 1.0 (0.2, 2.0) | … | 2.0 (2.0, 4.0) | … | |
| 30 mg SD | 6/6 | 0.8 (0.5, 1.0) | … | 2.0 (1.0, 2.0) | … | |
| 40 mg SD | 6/6 | 0.5 (0.5, 1.1) | … | 2.0 (1.0, 2.0) | … | |
| t 1/2 (terminal), h* | 1 mg SD | 0/5 | … | … | 5.0 (2.8, 7.1) | … |
| 3 mg SD | 0/3 | … | … | 4.9 (4.8, 5.0) | … | |
| 10 mg SD | 5/6 | 2.4 (2.0, 2.8) | … | 4.1 (3.0, 14.5) | … | |
| 20 mg SD | 6/6 | 2.8 (2.0, 3.4) | … | 3.8 (3.5, 4.3) | … | |
| 25 mg SD | 9/12 | 6.0 (2.1, 18.4) | … | 7.8 (3.8, 11.6) | … | |
| 30 mg SD | 4/6 | 4.8 (3.5, 11.8) | … | 7.0 (4.1, 8.8) | … | |
| 40 mg SD | 5/6 | 6.9 (2.1, 11.1) | … | 6.8 (3.0, 15.2) | … | |
| t 1/2 (initial), h* | 1 mg SD | 4/5 | 0.7 (0.6, 0.8) | … | 2.9 (2.7, 3.3) | … |
| 3 mg SD | 3/3 | 1.0 (0.5, 1.1) | … | 2.3 (2.2, 2.5) | … | |
| 10 mg SD | 6/6 | 0.7 (0.6, 1.6) | … | 2.5 (2.1, 3.2) | … | |
| 20 mg SD | 4/6 | 1.0 (0.7, 1.2) | … | 2.4 (1.8, 3.2) | … | |
| 25 mg SD | 11/12 | 1.1 (0.8, 2.8) | … | 2.2 (1.7, 3.9) | … | |
| 30 mg SD | 4/6 | 0.9 (0.8, 1.1) | … | 2.2 (1.9, 3.1) | … | |
| 40 mg SD | 5/6 | 1.0 (0.8, 1.2) | ‐ | 2.1 (1.9, 2.5) | ‐ | |
Abbreviations: AUC(0‐t), area under the concentration‐time curve from time zero to the time of the last quantifiable concentration; AUC(0‐∞), area under the concentration‐time curve extrapolated to infinity; AUC(0‐24), area under the concentration‐time curve from time zero to 24 hours post‐dose; C max, maximum observed concentration; CI, confidence interval; CVb, coefficient of variation; PK, pharmacokinetic; T max, time to reach C max; t 1/2 (terminal), apparent terminal half‐life; t 1/2 (initial), actual initial half‐life.
Part A was a single ascending‐dose crossover study in two interlocking cohorts. Each participant received a maximum of two single ascending oral doses of GSK3358699 (1, 3, 10, 20, 40 or 30 mg) and one dose of placebo.
The pharmacokinetic population included all participants who received an active dose of the study drug and for whom pharmacokinetic samples were obtained and analysed.