TABLE 1.
Everolimus dosage, exposure, and safety for the overall population, by sex, and across age groups.
| Category | Overall | By sex | By age at consent, years | ||||
|---|---|---|---|---|---|---|---|
| N = 179 (100%) | Female N = 106 | Male N = 73 | ≤2 N = 7 (100%) | >2 to ≤9 N = 27 (100%) | >9 to <18 N = 27 (100%) | ≥18 N = 118 (100%) | |
| Pharmaceutical formulation a , n (%) | |||||||
| Tablets | 172 (96.1) | 101 (95.3) | 71 (97.3) | 6 (85.7) | 25 (92.6) | 23 (85.2) | 118 (100.0) |
| Dispersible tablets | 13 (7.3) | 8 (7.5) | 5 (6.8) | 3 (42.9) | 5 (18.5) | 5 (18.5) | 0 |
| Dosage a , n (%) | |||||||
| 2 mg | 3 (1.7) | 2 (1.9) | 1 (1.4) | 1 (14.3) | 0 | 0 | 2 (1.7) |
| 2.5 mg | 28 (15.6) | 19 (17.9) | 9 (12.3) | 3 (42.9) | 8 (29.6) | 3 (11.1) | 14 (11.9) |
| 3 mg | 5 (2.8) | 4 (3.8) | 1 (1.4) | 2 (28.6) | 2 (7.4) | 1 (3.7) | 0 |
| 5 mg | 156 (87.2) | 92 (86.8) | 64 (87.7) | 5 (71.4) | 20 (74.1) | 22 (81.5) | 109 (92.4) |
| 10 mg | 28 (15.6) | 16 (15.1) | 12 (16.4) | 1 (14.3) | 6 (22.2) | 9 (33.3) | 12 (10.2) |
| Other | 54 (30.2) | 33 (31.1) | 21 (28.8) | 4 (57.1) | 14 (51.9) | 13 (48.1) | 23 (19.5) |
| Daily dose, mg | |||||||
| Average (SD) | 7.3 (3.1) | 7.4 (3.5) | 7.2 (2.6) | 4.1 (2.0) | 6.2 (2.4) | 7.9 (2.3) | 7.7 (3.3) |
| Median (min–max) | 7.3 (1–20) | 7.3 (1–20) | 7.3 (3–15) | 4.5 (1–7) | 5.6 (3–10) | 7.5 (4–13) | 7.4 (1–20) |
| Patients with dose changes a , n (%) | 116 (64.8) | 68 (64.2) | 48 (65.8) | 7 (100.0) | 19 (70.4) | 19 (70.4) | 71 (60.2) |
| Interruptions | 69 (38.5) | 39 (36.8) | 30 (41.1) | 5 (71.4) | 12 (44.4) | 8 (29.6) | 44 (37.3) |
| Increases | 98 (54.7) | 57 (53.8) | 41 (56.2) | 7 (100.0) | 18 (66.7) | 17 (63.0) | 56 (47.5) |
| Reductions | 57 (31.8) | 34 (32.1) | 23 (31.5) | 3 (42.9) | 11 (40.7) | 13 (48.1) | 30 (25.4) |
| Reasons for changes a , n (%) | |||||||
| Side effect | 50 (27.9) | 30 (28.3) | 20 (27.4) | 4 (57.1) | 9 (33.3) | 8 (29.6) | 29 (24.6) |
| Dosing error | 5 (2.8) | 3 (2.8) | 2 (2.7) | 1 (14.3) | 0 | 1 (3.7) | 3 (2.5) |
| Lab test abnormality | 7 (3.9) | 4 (3.8) | 3 (4.1) | 0 | 1 (3.7) | 4 (14.8) | 2 (1.7) |
| Concomitant medication affecting drug exposure | 4 (2.2) | 3 (2.8) | 1 (1.4) | 2 (28.6) | 1 (3.7) | 0 | 1 (0.8) |
| Other | 78 (43.6) | 43 (40.6) | 35 (47.9) | 7 (100.0) | 18 (66.7) | 12 (44.4) | 41 (34.7) |
| Duration of exposure b , days | |||||||
| Mean (SD) | 1146.4 (503.9) | 1113.7 (468.1) | 1194.0 (551.7) | 1482.6 (971.7) | 1728.4 (599.2) | 1200.6 (422.0) | 981.0 (324.6) |
| Median (min–max) | 1026.0 (36–2652) | 1033.5 (83–2368) | 1016.0 (36–2652) | 1824.0 (83–2368) | 1919.0 (216–2652) | 1141.0 (490–2135) | 982.0 (36–1743) |
| Overall blood levels of everolimus, ng/ml | |||||||
| Mean (SD) | 5.5 (4.0) | 5.7 (4.4) | 5.2 (3.3) | 4.5 (2.2) | 5.7 (3.4) | 6.8 (2.9) | 5.2 (4.4) |
| Median (min–max) | 4.5 (1.0–35.9) | 4.4 (1.0–35.9) | 4.7 (1.3–20.7) | 3.9 (1.9–8.2) | 4.7 (1.0–13.3) | 6.4 (2.5–12.3) | 4.2 (1.2–35.9) |
| Blood levels of everolimus by number of AEs, type of AEs, and concomitant AEDs, ng/ml | |||||||
| No AE | 73 | 40 | 33 | 1 | 5 | 12 | 55 |
| Mean (SD) | 5.5 (4.9) | 5.7 (5.8) | 5.4 (3.5) | 3.9 (-) | 4.8 (1.9) | 6.6 (2.7) | 5.4 (5.5) |
| Median (min–max) | 4.3 (1.3–35.9) | 4.1 (1.6–35.9) | 4.8 (1.3–20.7) | 3.9 (3.9–3.9) | 5.0 (2.0–7.0) | 6.7 (2.6–10.6) | 4.1 (1.3–35.9) |
| ≥1 AE | 102 | 65 | 37 | 6 | 21 | 14 | 61 |
| Mean (SD) | 5.6 (3.3) | 5.9 (3.4) | 4.9 (2.9) | 4.6 (2.4) | 6.3 (3.6) | 7.4 (3.3) | 5.0 (3.1) |
| Median (min–max) | 4.7 (1.0–15.2) | 4.9 (1.0–15.2) | 4.3 (1.0–13.0) | 4.6 (1.9–8.2) | 5.0 (1.0–12.3) | 6.1 (2.5–12.3) | 4.3 (1.0–15.2) |
| ≥1 grade 3/4 AE | 25 | 17 | 8 | 3 | 6 | 4 | 12 |
| Mean (SD) | 4.3 (1.9) | 4.3 (1.9) | 4.2 (2.0) | 3.0 (0.4) | 4.4 (2.3) | 5.8 (0.6) | 4.0 (2.0) |
| Median (min–max) | 4.2 (1.4–8.3) | 4.8 (1.4–8.3) | 3.2 (2.1–7.1) | 3.2 (2.5–3.2) | 4.0 (2.0–7.1) | 5.9 (5.3–6.3) | 4.1 (1.4–8.3) |
| ≥1 AESI | 73 | 47 | 26 | 5 | 17 | 12 | 39 |
| Mean (SD) | 6.4 (4.5) | 6.6 (3.4) | 6.2 (6.2) | 5.0 (2.4) | 7.7 (4.4) | 9.0 (7.1) | 5.3 (3.4) |
| Median (min–max) | 5.1 (1.0–29.0) | 5.6 (1.2–15.2) | 4.3 (1.0–29.0) | 5.6 (1.9–8.2) | 6.2 (1.8–18.3) | 6.5 (2.5–29.0) | 4.3 (1.0–15.2) |
| ≥1 grade 3/4 AESI | 16 | 10 | 6 | 2 | 3 | 3 | 8 |
| Mean (SD) | 4.3 (2.0) | 4.3 (2.2) | 4.3 (1.8) | 3.6 (0.5) | 4.0 (2.7) | 5.7 (0.6) | 4.0 (2.3) |
| Median (min–max) | 4.1 (1.4–8.3) | 4.5 (1.4–8.3) | 3.6 (2.7–7.1) | 3.6 (3.2–3.9) | 3.0 (2.0–7.1) | 5.4 (5.3–6.3) | 3.5 (1.4–8.3) |
| ≥1 concomitant AED | 67 | 39 | 28 | 6 | 20 | 14 | 27 |
| Mean (SD) | 6.5 (5.1) | 7.2 (6.0) | 5.5 (3.2) | 3.9 (1.6) | 6.0 (3.5) | 7.9 (3.0) | 6.7 (7.0) |
| Median (min–max) | 5.0 (1.0–35.9) | 5.1 (1.0–35.9) | 4.9 (1.3–15.9) | 3.7 (1.9–5.9) | 5.0 (1.0–13.3) | 8.4 (3.0–12.3) | 4.5 (1.2–35.9) |
| ≥1 AESI and ≥1 concomitant AED | 38 | 23 | 15 | 4 | 12 | 6 | 16 |
| Mean (SD) | 6.3 (5.1) | 6.9 (3.8) | 5.3 (6.7) | 4.2 (1.9) | 6.7 (3.6) | 11.7 (8.9) | 4.4 (3.4) |
| Median (min–max) | 5.1 (1.2–29.0) | 5.6 (1.2–15.2) | 4.0 (1.3–29.0) | 4.6 (1.9–5.9) | 5.3 (1.8–12.0) | 8.8 (5.3–29.0) | 4.1 (1.2–15.2) |
AE, adverse event; AED, antiepileptic drug; AESI, adverse event of special interest; SD, standard deviation.
a
A patient may have taken both formulations, multiple dosages, or may have had multiple reasons for dose changes.
b
Duration of exposure was “end date − start date + 1”.
Only data with collection date before or on study completion date were analyzed.