Table 4.
Derived pharmacokinetic parameters following administration of a single dose and multiple doses of AZD5438
| AZD5438 dose (mg) |
||||||||
| Single dose (studies 1, 2 and 3) |
2.5 | 5 | 10 | 20 | 40 | 60 | 90 | |
| Study 3 only | Studies 2 + 3 | All studies | All studies | All studies | Study 1 only | Study 1 only | ||
| Cmax (ng/ml) | Median (range), n | 14.2 (2.9–24.9), 3 | 21.3 (12.5–37.5), 6 | 88 (10.7–182), 11 | 134 (30.9–301), 17 | 261 (25.1–754), 18 | 708 (239–1690), 6 | 438 (51.3–602), 3 |
| Tmax (h) | Median (range), n | 1.0 (1.0–2.0), 3 | 1.25 (1.0–3.0), 6 | 1.0 (0.5–2.0), 11 | 1.5 (0.5–3.25), 17 | 1.0 (0.5–4.0), 18 | 1.0 (0.5–1.5), 6 | 1.0 (0.5–2.0), 3 |
| AUC (ng h/ml) | Median (range), n | 62.9 (7.8–118), 2 | 89.3 (53.0–342), 5 | 256 (44.4–715), 9 | 411 (107–3246), 16 | 1028 (59.8–4550), 15 | 1655 (346–2964), 2 | 751 (109–1393), 2 |
| AUC(0–5) (ng h/ml) | Median (range), n | 38.8 (6.8–79.7), 3 | 44.9 (34.7–121), 6 | 169 (34.1–382), 10 | 303 (88.9–942), 17 | 724 (50.7–1607), 18 | 2220 (343–4510), 6 | 1179 (100–1272), 2 |
| Half-life (h) | Median (range), n | 2.32 (1.23–2.82), 3 | 2.54 (1.68–7.24), 6 | 2.09 (1.27–5.28), 9 | 2.0 (1.31–8.09), 17 | 2.60 (1.31–7.61), 15 | 1.27 (0.72–1.82), 2 | 1.18 (1.01–1.34), 2 |
| CL/F (l/h) | Median (range), n | 172 (21.2–322), 2 | 56 (14.6–94.4), 5 | 39.1 (14.0–225), 9 | 49 (6.2–188), 16 | 38.9 (8.8–669), 15 | 96.6 (20.2–173), 2 | 444 (64.6–824), 2 |
| Vdss/F (l) | Median (range), n | 511 (92.7–929), 2 | 321 (144–662), 5 | 113 (64.7–839), 9 | 168 (73.2–690), 16 | 136 (70.4–1851), 15 | 126 (61.8–190), 2 | 1203 (143–2262), 2 |
| Multiple doses (studies 2 and 3) |
2.5 | 5 | 5 | 10 | 10 | 20 | 20 | 40 | 40 | |
| Study 3 | Study 2 | Study 3 | Study 2 | Study 3 | Study 2 | Study3 | Study 2 | Study 3 | ||
| Cmax ss (ng/ml) | Median (range), n | 24.2 (3.6–49.8), 3 | 33.5 (33–41.2), 3 | 27.7 (22.1–36.8), 3 | 135 (22.3–284), 3 | 150 (97.3–202), 2 | 177 (86.9–197), 3 | 155 (72.4–171), 3 | 178.5 (173–184), 2 | 85.8, 1 |
| Tmax ss (h) | Median (range), n | 0.5 (0.5–1.5), 3 | 1.0 (0.5–1.5), 3 | 1.0 (0.5–1.0), 3 | 2.0 (0.5–2.0), 3 | 1.25 (1.0–1.5), 2 | 1.0 (1.0–3.0), 3 | 1.0 (1.0–2.0), 3 | 0.75 (0.5–1.0), 2 | 2, 1 |
| AUC(0–5) (ng h/ml) | Median (range), n | 58.7 (7.3–172), 3 | 94.9 (93.0–95.5), 3 | 62.2 (36.7–110), 3 | 422 (53.3–809), 3 | 411, 1 | 420 (309–531), 2 | 392 (115–426), 3 | 367, 1 | 245, 1 |
| Cmin ss (ng/ml)a | Median (range), n | <0.5–21.1 (5.39), 3 | 7.84 (7.32–9.96), 3 | 4.53 (2.19–15.1), 3 | 78.9 (7.09–92.9), 3 | 33.9, 1 | 71.3 (54.2–318), 3 | 32.8 (3.9–47.5), 3 | 16.3, 1 | 18, 1 |
| Predictabilityb | Median (range), n | 0.59 (0.25–0.94), 2 | 1.06 (0.72–1.72), 3 | 0.51 (0.32–0.69), 2 | 0.70 (0.59–1.46), 3 | 0.90, 1 | 1.68 (1.08–2.28), 2 | 0.89 (0.78–1.08), 3 | 0.82, 1 | 0.75, 1 |
| Accumulation ratio | Median (range), n | 1.51 (1.07–2.16), 3 | 2.65 (1.42–2.68), 3 | 0.91 (0.89–1.3), 3 | 1.1 (0.76–2.64), 3 | 1.11, 1 | 2.55 (1.61–3.48), 2 | 1.21 (1.08–1.40), 3 | 0.92, 1 | 0.86, 1 |
Concentration present at 5 h after dosing.
Assessment of how well predicted the multiple-dose exposure is from the single-dose data (ratio of day 14 AUC(0–5):day 1 AUC for study 2 and ratio of day 28 AUC(0-5):day 1 AUC for study 3).
AUC, area under the plasma concentration–time curve; AUC(0–5), area under the plasma concentration–time curve from time 0 to 5 h; CL/F, total apparent drug clearance; Cmax, maximum plasma drug concentration; Cmax ss, maximum plasma drug concentration at steady-state; Cmin ss, minimum plasma drug concentration at steady-state; tmax, time to reach maximum plasma drug concentration; tmax ss, time to reach maximum plasma drug concentration at steady-state; Vdss/F, apparent volume of distribution at steady-state.