Table 3.
Pharmacokinetic parameters of midazolam (MDZ) and 1′-hydroxymidazolam following administration of a single dose (0.3 mg kg−1) of MDZ intravenously (IV), intramuscularly (IM) or via the buccal cavity in children with severe malaria and convulsions
| Parameter | IV midazolam | IM midazolam | Buccal midazolam | 95% CI for the difference between means or ‡medians | ||
|---|---|---|---|---|---|---|
| IV vs. IM | IV vs. buccal | IM vs. buccal | ||||
| Number of children | 12 | 11 | 8 | |||
| Midazolam | ||||||
| Cmax (ng ml−1)‡ | 481 (358, 554) | 253 (145, 475) | 186 (64, 394) | 79, 322* | 135, 369* | −37, 220 |
| tmax (h)‡ | 0.167 (0.08, 0.167) | 0.25 (0.167, 0.67) | 0.27 (0.12, 0.50) | 0.0, 0.33 | −0.25, 0.0 | −0.16, 0.25 |
| t1/2 (elimination) (h) | 1.22 (0.65, 1.8) | – | – | |||
| AUC (0,∞) (ng ml−1 h) | 596 (327, 865) | 608 (353, 864) | 518 (294, 741) | −366, 340 | −433, 278 | −413, 233 |
| CL (ml−1 min−1 kg−1) | 14.4 (9.2, 19.7) | – | – | |||
| Vd (l kg−1) | 0.85 (0.49, 1.13) | – | – | |||
| Bioavailability (F) | Assume 100% | 102% | 87% | |||
| 1′-Hydoxymidazolam** | ||||||
| Cmax (ng ml−1)‡ | 64 (44, 103) | 82 (18, 116) | 46 (16, 102) | −29, 42 | −56, 20 | −24, 66 |
| tmax (h)‡ | 0.59 (0.167, 1.0) | 0.67 (0.5, 2.0) | 1.0 (0.5, 2.0) | −0.67, 0.33 | −0.33, 0.83 | −0.33, 0.50 |
| AUC(0,∞) (ng ml−1 h) | 197 (118, 276) | 270 (151, 389) | 189 (61, 317) | −56, 203 | −139, 123 | −87, 249 |
| AUC1–hydroxymidazolam : AUCmidazolam | 0.55 (0.11, 0.99) | 0.49 (0.27, 0.72) | 0.55 (0.07, 1.04) | −0.44, 0.55 | −0.63, 0.64 | 0.37, 0.49* |
Values are presented as mean (95% confidence interval, CI) or
‡
median (95% CI).
*
Statistically significantly different from the IV MDZ group.
**
n = 6 for buccal MDZ; calculation of pharmacokinetic parameters were possible in only these number of cases.