Table 4.
Pharmacokinetic parameters of micafungin in adolescents, children, and neonates
| Population | Dose (mg/kg) | No. of subjects, SD or SS | Mean pharmacokinetic parameters (% coefficient of variation) [range] | |||||
|---|---|---|---|---|---|---|---|---|
| Weight (kg) | C max (mg/L) | C max at SS (mg/L) | C 24h (mg/L) | C 24h at SS (mg/L) | AUC24 (mg h/L) | |||
| Neonates <1 kg | 0.75 | 4 SD | 0.8 (21) | NR | NR | NR | NR | NR |
| 1 | 12 SD | 0.9 (14) [0.62–0.99] | NR | NR | NR | NR | NR | |
| 10 | 6 SS | 0.7 (16) [0.54–0.85] | NR | 28.1 (33) [19.2–40] | NR | NR | NR | |
| 15 | 7 SS | NR | NR | 38.6 (30) | NR | NR | NR | |
| Neonates >1 kg | 0.75 | 6 SD | 1.4 (12) [1.17–1.56] | 2.5 (36) [1.6–3.6] | NR | 0.1b | NR | 19 (38) [10.3–28.3] |
| 1 | 13 SD | 1.2 (12) [1.03–1.48] | NR | NR | NR | NR | NR | |
| 1.5 | 6 SD | 1.7 (17) [1.26–2.01] | 4.2 (26) [2.6–5.6] | NR | 0.4b | NR | 34.5 (16) [29.7–42.1] | |
| 3 | 6 SD | 1.5 (26) [1.08–1.95] | 9.3 (57) [2.1–15.4] | NR | 0.6b | NR | 69.0 (28) [48.9–93.1] | |
| 7 | 6 SS | 2.1 (65) [1.2–4.5] | NR | 26.6 (41) [17.4–48.1] | NR | NR | NR | |
| 15 | 5 SS | NR | NR | 38.2 (9) | NR | NR | NR | |
| Neonates <1.5 kgd | 1 | 25 SD | 1.1 (20) [0.62–1.48] | 1.3 (67) [0.39–3.1]h | NR | 0.2 (75) [0.076–0.62]i | 0.26 (62) [0.1–0.73]g | 16.4 (56) [4.2–40.2]f |
| Neonates <2 kgd | 15 | 12 SS | 1.0 (33) [0.54–1.62] | NR | 38.4 (23) | NR | NR | NR |
| 4–24 months | 1.5 | 11 SS | 8.1 (21) [5.2–9.8] | NR | 8.1 (35) [5.6–15.3] | NR | NR | NR |
| 3 months–4 years | 2 | 5 SS | 5.17 [1.67–9.63] | 6.71 (71) | 4.66 (47) | 1b | 1b | 52.84 (42) |
| 4–24 months | 4.5 | 8 SS | 7 (29) [4–9] | NR | 32.8 (69) [18.2–84.8] | NR | 5b | NR |
| 2–5 years | 1.5 | 11 SS | 14.8 (30) [9.3–22.6] | NR | 8.6 (57) [6.0–23.1] | NR | NR | NR |
| 4.5 | 8 SS | 14 (14) [9–19] | NR | 21.1 (29) [8.4–28.7] | NR | 6b | NR | |
| 6–11 years | 1 | 6 SS | 34.2 (11) [30.8–42.0] | NR | 6.7 (14) [5.5–7.7] | NR | NR | NR |
| 1.5 | 3 SS | 23.4 (7) [22.2–25.2] | NR | 8.7 (15) [7.2–9.7] | NR | NR | NR | |
| 3 | 4 SS | 32 (19) [25–44] | NR | 20.8 (20) [16.8–24.8] | NR | 6b | NR | |
| 4.5 | 3 SS | 19 (21) [12–24] | NR | 20.7 (15) [17.9–24] | NR | 5b | NR | |
| 11–15 years | >40 kg, 100 mg; < 40 kg, 2 mg/kg | 5 SS | 39.1 [25.2–46.7] | 8.08 (53) | 11.01 (68) | 1b | 1.5b | 73.7 (22) |
| 12–16 years | 1 | 9 SS | 59.8 (22) [37–75.1] | NR | 5.6 (21) [4.3–8.1] | NR | NR | NR |
| 3 | 8 SS | 54 (28) [26–74] | NR | 20.5 (50) [12.2–44.5] | NR | 4b | NR | |
| 4.5 | 1 SS | 23 | NR | 24.9 | NR | 10b | NR | |
| 1–13 years | 2 | 10 SS | 21 (57) | NR | 9.63 (38) | NR | 3.04 (40)j | NR |
| 7 months –10 years | 3 | 15 SD | NR | 12.5 (22) [8.3–18.7] | NR | 2.5b | NR | 128.5 (28) [79.3–229.2] |
| 8 months–15 years | 1 | 7 SS | 23.5 (56) [7.0–45.6] | NR | 5.0 (46) [3.4–10.2] | NR | 1.3 (31) [1.0–2.0] | NR |
| 2 | 9 SS | 24.5 [9.2–48.0] | NR | 10.2 (43) [3.2–16.3] | NR | 2.8 (36) [1.7–4.7] | NR | |
| 3 | 9 SS | 25.3 (62) [7.0–48.0] | NR | 14.8 (37) [7.6–24.8] | NR | 5.1 (37) [2.3–7.4] | NR | |
| 6 | 1 SS | 25 | NR | 21.1 | 5.3 | NR | NR | |
| 2–17 years | 0.5 | 15 SS | 38.6 | 3.7 (27) | 6.4 (22)f | NR | 0.5b,f | 19.0 (10) |
| 1 | 11 SS | 45.9 | 10.8 (18)f | 16.2 (23) | NR | 1b | 40.3 (9)f | |
| 1.5 | 10 SS | 36.7 | 13.2 (23) | 16.3 (15) | NR | 1.5b | 79.4 (16) | |
| 2 | 11 SS | 29.5 | 15.3 (25) | 21.4 (45)k | NR | 2b,k | 83.0 (9) | |
| 3 | 9 SS | 30.9 | 35.8 (20) | 30.4 (29)l | NR | 3b,l | 162.9 (12) | |
| 4 | 7 SS | 28 | 30.3 (23) | 43.5 (21) | NR | 5b | 191.4 (11) | |
| Healthy adult subjects (Table 1) | 100 mg | 9.1 | ||||||
| 150 mg | 16 | ~4.5 | ||||||
| Population | Dose (mg/kg) | No. of subjects, SD or SS | Mean pharmacokinetic parameters (% coefficient of variation) [range] | References | |||
|---|---|---|---|---|---|---|---|
| AUC (mg h/L) | T ½ (h) | CL (mL/h/kg) | V d (L/kg) | ||||
| Neonates <1 kg | 0.75 | 4 SD | NR | 5.5 | 79.3 (16) | NR | [80] |
| 1 | 12 SD | NR | 6.3 (33) [2.9–11] | 98 (41) [45–160] | 0.81 (28) [0.42–1.1] | [81] | |
| 10 | 6 SS | 308 (33) [185.3–460.5] | 10.6 (30) [7.7–16.4] | 36 (33) [24–48] | 0.51 (15) [0.36–0.56] | [82] | |
| 15 | 7 SS | 412.7 (29) | NR | 37.3 (40) | 0.64 (58)a | [64] | |
| Neonates >1 kg | 0.75 | 6 SD | NR | 8.0c [5.6–10.3] | 39 (46) [22.4–69.1] | 0.40 (30) [0.28–0.57] | [80] |
| 1 | 13 SD | NR | 7.1 (31) [4–11] | 81 (65) [21–190] | 0.72 (43) [0.3–1.1] | [81] | |
| 1.5 | 6 SD | NR | 7.8c [6–11] | 38.6 (23) [27.7–46.7] | 0.44 (14) [0.39–0.53] | [80] | |
| 3 | 6 SD | NR | 8.2c [6.2–10.5] | 39.1 (27) [26.2–51.8] | 0.47 (32) [0.29–0.66 | [80] | |
| 7 | 6 SS | 307.6 (56) [162.6–643.2] | 11.4 (31) [6.9–15.4] | 24 (50) [12–36] | 0.39 (33) [0.24–0.59] | [82] | |
| 15 | 5 SS | 472.2 (11) | NR | 30.6 (11) | 0.58 (18)a | [64] | |
| Neonates <1.5 kgd | 1 | 25 SD | 18.8 (62) [9.4–49.1]e,f | 6.7 (33) [2.9–11] | 89 (53) [21–190] | 0.76 (37) [0.3–1.1] | [81] |
| Neonates <2 kgd | 15 | 12 SS | 437.5 (23) | NR | 34.5 (34) | 0.61 (46)a | [64] |
| 4–24 months | 1.5 | 11 SS | 77.3 (15) [59.6–99.3] | 11.5 (19) [7.9–16.0] | 19.7 (14) [14.6–24.1] | 0.32 (19) [0.24–0.45] | [84] |
| 3 months–4 years | 2 | 5 SS | 53.82 (43)e | 10.13 (17) | 42.72 (44) | NR | [87] |
| 4–24 months | 4.5 | 8 SS | 299.4 (47) [188–622.2] | NR | 16.7 (32) [7.3–24.2] | NR | [85] |
| 2–5 years | 1.5 | 11 SS | 76.0 (20) [62.8–106.7] | 11.1 (12) [8.9–13.8] | 20.4 (17) [14.2–24.0] | 0.32 (24) [0.15–0.42] | [84] |
| 4.5 | 8 SS | 248.9 (27) [110–335.4] | NR | 20.0 (45) [13.4–40.9] | NR | [85] | |
| 6–11 years | 1 | 6 SS | 77.9 (21) [60.8–107.6] | 14.7 (47) [9.8–28.4] | 13.2 (18) [9.31–16.0] | 0.26 (29) [0.21–0.41] | [84] |
| 1.5 | 3 SS | 113.6 (11) [101.1–127.1] | 15.2 (20) [12.6–18.5] | 13.3 (13) [11.6–14.9] | 0.29 (6) [0.27–0.30] | [84] | |
| 3 | 4 SS | 247.5 (19) [191.8–300.1] | NR | 12.3 (20) [10.0–15.4] | NR | [85] | |
| 4.5 | 3 SS | 278.4 (15) [245.7–325.2] | NR | 16.4 (14) [13.8–18.3] | NR | [85] | |
| 11–15 years | >40 kg, 100 mg; < 40 kg, 2 mg/kg | 5 SS | 81.70 (30)e | 13.81 (32) | 28.52 (28) | NR | [87] |
| 12–16 years | 1 | 9 SS | 65.4 (17) [51.4–84.4] | 13.1 (13) [10.5–16.2] | 13.0 (17) [10.2–16.7] | 0.24 (19) [0.20–0.34] | [84] |
| 3 | 8 SS | 193.3 (16) [158.9–240.1] | NR | 13.5 (23) [9.5–19.0] | NR | [85] | |
| 4.5 | 1 SS | 339 | NR | 13.3 | NR | [85] | |
| 1–13 years | 2 | 10 SS | NR | NR | NR | NR | [88] |
| 7 months –10 years | 3 | 15 SD | 180.8 (34) [104.2–352.9]e | 13 (16) [9.5–16.8] | 17.7 (33) [7.9–29.6] | 0.3 (33) [0.2–0.5] | [96] |
| 8 months–15 years | 1 | 7 SS | NR | 13.0 (14) [10.9–15.4] | NR | NR | [51] |
| 2 | 9 SS | NR | 12.3 (15) [9.9–15.5] | NR | NR | [51] | |
| 3 | 9 SS | NR | 14.4 (22) [11.2–20.1] | NR | NR | [51] | |
| 6 | 1 SS | NR | 11.3 | NR | NR | [51] | |
| 2–17 years | 0.5 | 15 SS | 27.9 (8)f | 12.3 (8)f | 19.4 (10)f | 0.32 (10)f | [86] |
| 1 | 11 SS | 52.4 (9) | 17.3 (9) | 20.6 (10) | 0.39 (17) | [86] | |
| 1.5 | 10 SS | 100.6 (10) | 12.9 (13) | 16.5 (15) | 0.28 (16) | [86] | |
| 2 | 11 SS | 94.3 (17)k | 12.2 (6)k | 24.3 (14)k | 0.31 (18)k | [86] | |
| 3 | 9 SS | 190.5 (13)l | 13.2 (9)l | 17.0 (15)l | 0.29 (12)l | [86] | |
| 4 | 7 SS | 301.9 (14) | 13.5 (11) | 14.2 (16) | 0.26 (17) | [86] | |
| Healthy adult subjects (Table 1) | 133 | 15.4 | 10.4 | 0.2 | |||
| 181.4 | |||||||
C max maximum plasma concentration, SD single dose, SS steady state, C 24h trough plasma concentration 24 h after dosing, AUC 24 area under the plasma concentration-time curve after a single dose from zero to 24 h, AUC area under the plasma concentration-time curve at steady state from zero to 24 h, t ½ terminal half-life, CL clearance, V d volume of distribution; average is weighted by the number of patients reported, NR not reported
a Vd in the elimination phase (Vβ). Steady-state volume of distributions are 1.64, 1.34 and 1.52 L for neonates <1, >1 and <2 kg, respectively
b Values not reported but extracted from figures with concentration versus time curves
c Median value
d The authors compiled the data of the groups above and below 1 kg into a single group
e AUC∞ after a single dose
f n = 16
g n = 17
h n = 19
i n = 21
j n = 13
k n = 8
l n = 5