TABLE 3.
Summary of calculated doses resulting in comparable adult exposures with the approved dose and model-predicted QTc prolongation with the maximum calculated dosec
| Dosing interval, formulation, and age group | wt group (kg) | Calculated dose(s) comparable to adult exposure (mg) | Median AUC0–24,ss (ng · h/mL) | AUC ratio vs adult | Simulated median Cmax,ss of DM-6705 at highest dose (ng/mL) | Model-predicted ΔQTcBa (ms) (90% CI) |
|---|---|---|---|---|---|---|
| QD dosing | ||||||
| Film-coated tablet | ||||||
| ≤2 yrs | 10–20 | 35–40 | 6,620–7,570 | 0.883–1.01 | 63.4 | 3.89 (1.17–6.60) |
| >2 yrs | 10–20 | 35–50 | 6,160–8,800 | 0.821–1.17 | 87.8 | 5.38 (1.62–9.14) |
| 20–30 | 100 | 7,320 | 0.976 | 82.3 | 5.05 (1.52–8.57) | |
| 30–40 | Not achievable up to 100 mg | |||||
| 40–50 | ||||||
| ≥50 | ||||||
| Dispersible tablet | ||||||
| ≤2 yrs | 10–20 | 40–50 | 6,370–7,970 | 0.849–1.06 | 66.0 | 4.05 (1.22–6.87) |
| >2 yrs | 10–20 | 50 | 7,410 | 0.988 | 73.0 | 4.48 (1.35–7.60) |
| 20–30 | 100 | 6,160 | 0.821 | 68.6 | 4.21 (1.27–7.14) | |
| 30–40 | Not achievable up to 100 mg | |||||
| 40–50 | ||||||
| ≥50 | ||||||
| BID dosing | ||||||
| Film-coated tablet | ||||||
| ≤2 yrs | 10–20 | 20 | 7,570 | 1.01 | 61.5 | 3.77 (1.14–6.41) |
| >2 yrs | 10–20 | 20–25 | 7,040–8,800 | 0.939–1.17 | 84.9 | 5.21 (1.57–8.84) |
| 20–30 | 30, 75 (50 mg a.m. + 25 mg p.m.)b | 6,940, 8,670 | 0.925, 1.16 | 95.3 | 5.84 (1.76–9.92) | |
| 30–40 | 35–50 | 6,300–8,830 | 0.840–1.18 | 95.4 | 5.85 (1.76–9.94) | |
| 40–50 | 50 | 7,440 | 0.992 | 78.3 | 4.80 (1.45–8.15) | |
| ≥50 | 50–100 | 6,240–7,900 | 0.832–1.05 | 81.8 | 5.02 (1.51–8.52) | |
| Dispersible tablet | ||||||
| ≤2 yrs | 10–20 | 20–25 | 6,370–7,970 | 0.849–1.06 | 64.4 | 3.95 (1.19–6.71) |
| >2 yrs | 10–20 | 25–30 | 7,410–8,890 | 0.988–1.19 | 85.3 | 5.23 (1.58–8.88) |
| 20–30 | 35–40, 75 (50 mg a.m. + 25 mg p.m.)b | 6,810–7,780, 7,300 | 0.908–1.04, 0.973 | 84.3 | 5.17 (1.56–8.78) | |
| 30–40 | 40–50 | 6,060–7,580 | 0.808–1.01 | 81.2 | 4.98 (1.50–8.46) | |
| 40–50 | 50–100 | 6,260–7,920 | 0.835–1.06 | 83.1 | 5.10 (1.54–8.65) | |
| ≥50 | 100 | 6,650 | 0.887 | 68.5 | 4.20 (1.27–7.13) | |
a
ΔQTcB is simulated by using the developed linear regression model and the simulated Cmax,ss of DM-6705 after administration of the maximum dose, which provides exposure comparable to that in adults with the approved dose.
b
Considering the availability of the tablet formulation, an additional dosing scenario, 50 mg (morning dose) plus 25 mg (evening dose), was simulated.
c
QD, once a day; BID, twice a day. Given the limited number of participants in the <10-kg weight category (n = 5) in the analysis data set, dose calculations for participants weighing <10 kg are not provided.