Data on the pharmacokinetics of cannabidiol in pediatric patients are lacking, and the proper dose for titration and optimization of safety is unclear. |
Pharmaceutical-grade synthetic cannabidiol oral solution was generally safe and well tolerated; common adverse events were somnolence, anemia, and diarrhea. The study showed that systemic cannabidiol exposure generally increased linearly with increases in dose. |
Close monitoring of plasma concentrations of antiepileptic drugs and their clinical effects may be needed in pediatric patients receiving clobazam concomitantly with cannabidiol, particularly at higher doses, as drug–drug interactions have been observed with increased exposure to cannabidiol, clobazam, and norclobazam. |
1 Introduction
2 Methods
2.1 Patient Population
2.2 Study Design
2.3 Study Assessments
Morning dose | Day 1 serial sampling | Day 6a | Day 8a | Day 9a | Day 10 serial sampling | ||||
---|---|---|---|---|---|---|---|---|---|
1 to < 2 years | 2 to < 6 years | 6 to ≤ 17 years | 12 to ≤ 17 years | 2 to ≤ 17 years | 6 to ≤ 17 years | 1 to < 2 years | 2 to < 6 years | 6 to ≤ 17 years | |
Pre-dose (0)b | X | X | X | X | X | X | X | X | |
1 h | X | X | X | X | |||||
2 h | X | X | X | X | X | X | |||
3 h | X | X | X | X | |||||
4 h | X | X | X | X | X | X | |||
6 h | X | X | |||||||
8 h | X | X | X | X | X | X | |||
12 h | X | X | X | X | X | X | |||
16 h | X | X | |||||||
24 h (day 2) | X | X | X | X | |||||
36 h | X | ||||||||
48 h (day 3) | X | X | |||||||
72 h (day 4)b | X |
2.4 Data Analyses
3 Results
Characteristic | Cohort 1 10 mg/kg/day (n = 20) | Cohort 2 20 mg/kg/day (n = 20) | Cohort 3 40 mg/kg/day (n = 21) | All cohorts (N = 61) |
---|---|---|---|---|
Age, mean (SD), years | 7.5 (5.3) | 7.7 (5.2) | 7.8 (5.4) | 7.6 (5.2) |
Infants (n = 5) | 1.0 (0.0) | 1.0 (0.0) | 1.0 (0.0) | |
Children (n = 9) | 6.9 (3.1) | 7.2 (2.4) | 7.2 (2.7)a | |
Adolescents (n = 6) | 13.7 (1.8) | 13.8 (1.5) | 14.5 (1.6) | |
Male sex, n (%) | 10 (50.0) | 13 (65.0) | 10 (47.6) | 33 (54.1) |
Race, n (%) | ||||
White | 16 (80.0) | 16 (80.0) | 18 (85.7) | 50 (82.0) |
Black or African American | 1 (5.0) | 1 (5.0) | 1 (4.8) | 3 (4.9) |
Otherb | 3 (15.0) | 3 (15.0) | 2 (9.5) | 8 (13.1) |
Weight, mean (SD), kg | 24.3 (12.5) | 26.6 (18.4) | 29.7 (20.6) | 26.9 (17.4) |
Infants (n = 5) | 12.1 (2.3) | 10.7 (1.0) | 10.9 (1.5) | |
Children (n = 9) | 23.3 (9.2) | 21.7 (6.7) | 24.9 (12.3)a | |
Adolescents (n = 6) | 35.8 (12.1) | 47.2 (20.2) | 53.4 (18.5) | |
Seizures/d during 14–28 days before day 0, mean (SD) | 13.7 (23.5)c | 10.4 (16.6) | 23.7 (31.4) | 16.1 (25.0)d |
3.1 Pharmacokinetics
3.1.1 Cannabidiol
Cannabidiol oral solution cohort | Day 1 (single dose) | Day 10 (multiple dose) | ||||||
---|---|---|---|---|---|---|---|---|
Tmax, h: median (range) | t1/2, ha | AUC(0–12), ng·h/mLa | Cmax, ng/mLa | Tmax, h: median (range) | AUC(0–τ), ng·h/mLa | Cmax, ng/mLa | CLss/F, L/h/kga | |
10 mg/kg/day (n = 20) | 2.6 (1.0–8.0) | 26.4, 31.3 (74.9) | 122, 173.9 (103.3) | 29.12, 59.03 (169.4) | 3.0 (1.0–4.2) | 507.0, 581.6 (48.7) | 91.0, 119.6 (87.8) | 9.9, 12.1 (88.0) |
20 mg/kg/day (n = 20) | 4.0 (1.0–8.1) | 29.6, 33.5 (44.7) | 243.6, 507.1 (135.6) | 47.19, 110.5 (128.8) | 2.0 (0.0–6.0) | 836.0, 1098 (88.9) | 126.0, 220.0 (134.0) | 12.3, 15.3 (63.9) |
40 mg/kg/day (n = 21) | 3.2 (1.0–24.0) | 19.5, 21.6 (48.7) | 473.5, 914.5 (126.3) | 103.7, 256.9 (136.9) | 3.0 (0.0–6.0) | 2108, 2708 (66.1) | 314.5, 426.8 (76.8) | 9.5, 13.2 (97.5) |
3.1.2 7-OH Cannabidiol
Cannabidiol oral solution cohort | Day 1 (single dose) | Day 10 (multiple dose) | ||||||
---|---|---|---|---|---|---|---|---|
Tmax, h: median (range) | t1/2, ha | AUC(0–12), ng·h/mLa | Cmax, ng/mLa | Tmax, h: median (range) | AUC(0–τ), ng·h/mLa | Cmax, ng/mLa | MRAUC(0–τ)a | |
10 mg/kg/day (n = 20) | 2.6 (1.0–6.1) | 18.4, 19.7 (38.8) | 104.0, 124.4 (64.4) | 22.03, 28.71 (93.1) | 2.1 (1.0–4.1) | 428.3, 513.4 (52.4) | 65.6, 79.4 (51.4) | 0.80, 0.88 (46.4) |
20 mg/kg/day (n = 20) | 4.0 (1.0–12.0) | 25.6, 31.8 (76.3) | 202.4, 329.8 (122.1) | 34.56, 61.89 (117.8) | 2.0 (1.0–6.0) | 658.8, 832.8 (81.1) | 97.1, 136.6 (103.1) | 0.75, 0.79 (30.0) |
40 mg/kg/day (n = 21) | 3.1 (1.0–12.1) | 14.2 14.8 (29.5) | 381.9, 646.7 (137.1) | 71.7, 140.9 (149.0) | 2.0 (0.0–5.9) | 1688, 2165 (64.9) | 217.7, 286.1 (70.6) | 0.76, 0.87 (49.5) |
3.1.3 Age Assessment
Cohort | Geometric LS mean | Pairwise comparison | Ratio, % (90% CI) |
---|---|---|---|
AUC(0–τ), ng·h/mL (95% CI) | |||
Cohort 1, 10 mg/kg/day | |||
Infants (n = 5) | 335.7 (197.8–569.8) | Infants vs. children | 52.73 (30.26–91.87) |
Children (n = 8) | 636.8 (419.2–967.3) | Infants vs. adolescents | 63.64 (35.29–114.79) |
Adolescents (n = 6) | 527.5 (325.5–854.9) | Children vs. adolescents | 120.71 (71.33–204.26) |
Cohort 2, 20 mg/kg/day | |||
Infants (n = 4)a | 746.1 (345.6–1611) | Infants vs. children | 113.65 (51.46–250.99) |
Children (n = 7) | 656.5 (366.9–1175) | Infants vs. adolescents | 62.39 (27.59–141.08) |
Adolescents (n = 6) | 1196 (637.9–2242) | Children vs. adolescents | 54.90 (27.17–110.91) |
Cohort 3, 40 mg/kg/day | |||
Infants (n = 5) | 1068 (545.4–2090) | Infants vs. children | 42.36 (21.48–83.53) |
Children (n = 10) | 2520 (1567–4053) | Infants vs. adolescents | 38.67 (18.26–81.93) |
Adolescents (n = 6) | 2761 (1495–5097) | Children vs. adolescents | 91.30 (48.13–173.18) |
Cmax, ng/mL (95% CI) | |||
---|---|---|---|
Cohort 1, 10 mg/kg/day | |||
Infants (n = 5) | 55.89 (27.21–114.8) | Infants vs. children | 47.74 (22.78–100.07) |
Children (n = 9) | 117.1 (68.47–200.2) | Infants vs. adolescents | 59.70 (26.73–133.33) |
Adolescents (n = 6) | 93.61 (48.53–180.6) | Children vs. adolescents | 125.06 (62.15–251.66) |
Cohort 2, 20 mg/kg/day | |||
Infants (n = 4)a | 128.0 (41.81–392.0) | Infants vs. children | 127.54 (40.30–403.64) |
Children (n = 7) | 100.4 (43.08–233.9) | Infants vs. adolescents | 78.68 (24.02–257.73) |
Adolescents (n = 6) | 162.7 (65.25–405.8) | Children vs. adolescents | 61.69 (22.19–171.54) |
Cohort 3, 40 mg/kg/day | |||
Infants (n = 5) | 162.0 (78.57–334.0) | Infants vs. children | 39.17 (18.85–81.38) |
Children (n = 10) | 413.6 (248.0–689.9) | Infants vs. adolescents | 46.80 (20.85–105.05) |
Adolescents (n = 6) | 346.1 (178.8–670.0) | Children vs. adolescents | 119.49 (59.96–238.12) |
3.1.4 Influence of Clobazam Use
PK parameters | Day 1 serial sampling (geometric mean, mean, CV%) | Day 10 serial sampling (geometric mean, mean, CV%) | ||||
---|---|---|---|---|---|---|
10 mg/kg/day | 20 mg/kg/day | 40 mg/kg/day | 10 mg/kg/day | 20 mg/kg/day | 40 mg/kg/day | |
With clobazam | ||||||
Cmax (ng/mL) | 41.6, 93.3 (144.6)b | 52.9, 117.9 (129.1)b | 90.6, 241.5 (148.3)f | 91.5, 104.6 (55.1)b | 127.6, 221.9 (121.4)g | 453.7, 563.1 (61.4)h |
AUC(0–τ) (ng·h/mL)a | 171.2, 246.4 (93.1)b | 342.6, 650.9 (124.8)d | 446.8, 960.5 (138.7)f | 521.2, 575.2 (45.5)d | 867.1, 1093 (71.4)g | 3130, 3533 (49.1)h |
Cl/F (L/h/kg) | 19.2, 24.2 (61.2)c | 18.8, 30.6 (101.5)e | 18.2, 32.8 (109.7)g | 9.6, 10.7 (51.7)d | 12.1, 15.2 (74.7)g | 6.4, 7.2 (55.4)h |
Without clobazam | ||||||
Cmax (ng/mL) | 20.4, 24.8 (68.2)b | 42.1, 103.1 (135.2)b | 124.1, 277.6 (131.1)d | 90.5, 134.7 (103.6)b | 124.7, 218.3 (152.0)d | 192.9, 245.1 (80.7)d |
AUC(0–τ) (ng·h/mL)a | 86.9, 101.4 (61.2)b | 179.2, 377.6 (149.8)b | 511.6, 853.2 (110.5)d | 494.5, 587.3 (53.7)b | 809.3, 1102 (106.3)d | 1245, 1608 (75.6)d |
Cl/F (L/h/kg) | 35.9, 38.1 (41.0)c | 10.0, 11.6 (47.9)b | 22.2, 28.3 (67.2)e | 10.1, 13.3 (105.0)b | 12.6, 15.3 (57.3)d | 16.1, 21.0 (77.8)d |
Ratio of geometric means | ||||||
Cmax | 2.04 | 1.26 | 0.73 | 1.01 | 1.02 | 2.35 |
AUC(0–τ) | 1.97 | 1.91 | 0.87 | 1.05 | 1.07 | 2.51 |
Cl/F | 0.53 | 1.88 | 0.82 | 0.95 | 0.96 | 0.40 |
3.2 Safety
AE, n (%)a | Cannabidiol oral solution | |||
---|---|---|---|---|
All doses (N = 61) | 10 mg/kg/day (n = 20) | 20 mg/kg/day (n = 20) | 40 mg/kg/day (n = 21) | |
Any AE | 39 (63.9) | 13 (65.0) | 9 (45.0) | 17 (81.0) |
Somnolence | 13 (21.3) | 3 (15.0) | 3 (15.0) | 7 (33.3) |
Anemia | 11 (18.0) | 2 (10.0) | 5 (25.0) | 4 (19.0) |
Diarrhea | 10 (16.4) | 1 (5.0) | 2 (10.0) | 7 (33.3) |
Flatulence | 5 (8.2) | 0 | 2 (10.0) | 3 (14.3) |
Psychomotor hyperactivity | 5 (8.2) | 0 | 2 (10.0) | 3 (14.3) |
Abdominal pain upper | 4 (6.6) | 2 (10.0) | 1 (5.0) | 1 (4.8) |
Catheter site pruritus | 3 (4.9) | 0 | 2 (10.0) | 1 (4.8) |
Decreased appetite | 3 (4.9) | 2 (10.0) | 0 | 1 (4.8) |
Seizure | 3 (4.9) | 1 (5.0) | 1 (5.0) | 1 (4.8) |
Vomiting | 3 (4.9) | 2 (10.0) | 1 (5.0) | 0 |
Weight increased | 3 (4.9) | 0 | 1 (5.0) | 2 (9.5) |
Ataxia | 2 (3.3) | 0 | 0 | 2 (9.5) |
Cough | 2 (3.3) | 1 (5.0) | 1 (5.0) | 0 |
Contact dermatitis | 2 (3.3) | 0 | 2 (10.0) | 0 |
Dehydration | 2 (3.3) | 0 | 0 | 2 (9.5) |
Ecchymosis | 2 (3.3) | 0 | 1 (5.0) | 1 (4.8) |
Insomnia | 2 (3.3) | 0 | 1 (5.0) | 1 (4.8) |
Metabolic acidosis | 2 (3.3) | 0 | 0 | 2 (9.5) |
Pyrexia | 2 (3.3) | 1 (5.0) | 0 | 1 (4.8) |