Table 1.
Geometric mean (95% CI) pharmacokinetic parameters of ODN in healthy young males and postmenopausal females following single oral doses of ODN
| Dose | Panel | AUC0–24 h (μm h)† | AUC0–168 h (μm h)† | AUC0–∞ (μm h)† | C24 h (nm)† | C168 h (nm)† | Cmax day1 (nm)† | Cmax overall (nm)† | Tmax day1 (h)† | Tmax overall (h)‡ | Apparent terminal half-life (h)§ |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Study I | |||||||||||
| 2 mg | A | 0.7 (0.5, 0.9) | ND | ND | 28.0 (21.1, 37.1) | 2.9 (1.6, 5.2) | 40.7 (31.4, 52.8) | 40.5 (31.2, 52.6) | 6 (4, 6) | 6 (4, 6) | ND |
| 5 mg | B | 1.5 (1.2, 2.0) | ND | ND | 61.4 (46.3, 81.2) | 7.6 (4.3, 13.3) | 77.6 (59.9, 100.6) | 78.7 (60.7, 102.1) | 5 (4, 9) | 5 (4, 9) | ND |
| 10 mg | A | 2.5 (1.9, 3.1) | 8.8 (6.2, 12.5) | ND | 119 (90.3, 158.4) | 12.1 (6.9, 21.3) | 119.6 (92.2, 155.1) | 125.1 (96.5, 162.3) | 6 (4, 16) | 15 (4, 32) | ND |
| 25 mg | B | 3.2 (2.5, 4.1) | 14.2 (10.0, 20.2) | ND | 147 (111.3, 195.6) | 20.9 (11.8, 36.9) | 154.7 (119.2, 200.8) | 160.4 (123.6, 208.3) | 13 (6, 16) | 13 (6, 48) | ND |
| 25 mg fed* | B | 6.7 (5.2, 8.6) | ND | ND | 310.1 (233.9, 411.0) | ND | 344.7 (265.6, 447.4) | 378.6 (291.6, 491.5) | 6 (4, 12) | 18 (6, 48) | ND |
| 50 mg | A | 4.7 (3.7, 6.1) | 20.2 (14.2, 28.7) | ND | 221.1 (167.0, 292.8) | 29.0 (16.3, 51.4) | 254 (195.9, 329.3) | 258.8 (199.5, 335.7) | 6 (4, 9) | 6 (6, 24) | ND |
| 100 mg | B | 6.4 (5.0, 8.2) | 29.4 (20.7, 41.8) | ND | 210.8 (159.2, 279.1) | 44.4 (25.1, 78.6) | 353.5 (272.6, 458.3) | 349.8 (269.7, 453.7) | 4 (4, 16) | 4 (4, 6) | ND |
| 200 mg | A | 7.7 (6.0, 9.9) | ND | ND | 392.2 (248.7, 436.0) | ND | 425.4 (328.1, 551.5) | 425.4 (327.9, 551.7) | 5 (4, 6) | 5 (4, 6) | ND |
| 400 mg | A | 10.1 (7.9, 13.0) | 35.3 (25.3, 49.2) | 40.8 (24.4, 68.2) | 409.6 (309.1, 543.0) | 54.5 (31.5, 94.4) | 531 (409.2, 689.2) | 528.8 (407.3, 686.5) | 6 (4, 16) | 6 (4, 16) | 43.6 (11.0) |
| 600 mg | B | 9.4 (7.3, 12.0) | 33.8 (24.8, 46.0) | 43.9 (26.3, 73.4) | 392.8 (296.7, 520.2) | 53.2 (31.1, 91.0) | 477.3 (368.1, 618.9) | 482.2 (371.8, 625.4) | 3 (2, 4) | 4 (2, 24) | 59.2 (16.0) |
| 50 mg | C | 3.0 (2.2, 4.1) | ND | ND | 139.1 (93.6, 206.8) | ND | 176.7 (118.3, 263.9) | 183.0 (122.6, 273.2) | 12 (5, 16) | 20 (5, 72) | ND |
| 100 mg | C | 5.5 (4.1, 7.6) | 26.7 (21.7, 32.9) | 34.3 (26.1, 45.2) | 261.3 (175.9, 388.4) | 86.9 (57.2, 132.0) | 350.1 (234.4, 522.7) | 353.0 (236.5,527.0) | 2 (2, 5) | 2 (2, 5) | 77.5 (20.9) |
| 100 mg fed | D | 11.3 (10.0, 12.8) | 44.0 (37.7, 51.4) | 49.5 (40.1, 61.1) | 507.4 (442.3, 582.1) | 58.1 (34.6, 97.5) | 630.4 (533.3, 745.2) | 630.4 (533.2, 745.4) | 8 (5, 12) | 8 (5, 12) | 48.2 (11.7) |
| 200 mg fed | D | 13.6 (12.0, 15.3) | 53.8 (46.1, 62.9) | 61.7 (50.0, 76.2) | 571.0 (497.7, 655.1) | 82.5 (49.2, 138.4) | 738.5 (624.7, 873.0) | 738.5 (624.6, 873.2) | 6 (5, 12) | 6 (5, 12) | 50.5 (13.4) |
| 300 mg fed | D | 16.1 (14.2, 18.1) | 63.8 (54.6, 74.6) | 74.8 (60.6, 92.3) | 709.8 (618.7, 814.4) | 97.0 (57.8, 162.7) | 839.2 (709.8, 992.0) | 843.3 (713.2, 997.0) | 5 (4, 9) | 6 (4, 24) | 62.6 (12.0) |
| Study II | |||||||||||
| 100 mg fasted | E | 7.5 (6.2, 9.0) | 33.0 (26.9, 40.5) | 43.8 (27.7, 69.3) | 326.7, (268.3, 397.8) | 76.5 (50.2, 116.6) | 423.1 (325.0, 550.7) | 423.1 (325.0, 550.7) | 4 (2, 4) | 4 (2, 4) | 77.8 (26.2) |
| 100 mg fed low fat | E | 9.3 (7.7, 11.2) | 42.2 (34.4, 51.7) | 60.9 (38.0, 97.5) | 392.3 (322.2, 477.7) | 110.4 (72.4, 168.2) | 506.7 (389.2, 659.5) | 506.7 (389.2, 659.5) | 4 (3, 5) | 4 (3, 5) | 75.9 (36.9) |
Abbreviations are as follows: AUC0–24 h, area under the curve0-24 hours; AUC0–168 h, area under the curve0-168 hours; AUC0–∞, area under the curve0-infinity; CI, confidence interval; C24 h, Concentration at 24 hours; C168 h, Concentration at 168 hours; Cmax,overall, Maximum concentration, overall; ND, not determined; ODN, odanacatib.
Subjects were given a repeat oral dose of 25 mg ODN following a standard high-fat breakfast.
Back-transformed least-squares mean and 95% CI from mixed-effects model performed on natural log-transformed values. In young healthy males (panels A and B), the model included panel and treatment within panel as fixed effects and subject within panel as a random effect. In postmenopausal females (panel C), the model included treatment as a fixed effect and subject as a random effect. In young healthy males with treatments given with a high-fat breakfast (panel D), the model included treatment as a fixed effect and subject as a random effect.
Median; minimum, maximum.
Harmonic mean; jack-knife SD. The AUC0–168 h, C168 h values, apparent terminal half-life and AUC0–∞ could not be determined for subjects with insufficient PK sampling.