Pharmacokinetics and clinical efficacy of midazolam in children with severe malaria and convulsions

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Abstract
To investigate the pharmacokinetics and clinical efficacy of intravenous (IV), intramuscular (IM) and buccal midazolam (MDZ) in children with severe falciparum malaria and convulsions. Thirty-three children with severe malaria and convulsions lasting ≥5 min were given a single dose of MDZ (0.3 mg kg−1) IV (n = 13), IM (n = 12) or via the buccal route (n = 8). Blood samples were collected over 6 h post-dose for determination of plasma MDZ and 1′-hydroxymidazolam concentrations. Plasma concentration–time data were fitted using pharmacokinetic models. Median (range) MDZ Cmax of 481 (258–616), 253 (96–696) and 186 (64–394) ng ml−1 were attained within a median (range) tmax of 10 (5–15), 15 (5–60) and 10 (5–40) min, following IV, IM and buccal administration, respectively. Mean (95% confidence interval) of the pharmacokinetic parameters were: AUC(0,∞) 596 (327, 865), 608 (353, 864) and 518 (294, 741) ng ml−1 h; Vd 0.85 l kg−1; clearance 14.4 ml min−1 kg−1, elimination half-life 1.22 (0.65, 1.8) h, respectively. A single dose of MDZ terminated convulsions in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration. Four children (one in the IV, one in the IM and two in the buccal groups) had respiratory depression. Administration of MDZ at the currently recommended dose resulted in rapid achievement of therapeutic MDZ concentrations. Although IM and buccal administration of MDZ may be more practical in peripheral healthcare facilities, the efficacy appears to be poorer at the dose used, and a different dosage regimen might improve the efficacy. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Midazolam (MDZ), a water-soluble benzodiazepine, can be administered via several routes, including intravenously (IV), intramuscularly (IM) and buccal routes to terminate convulsions. It may be a suitable alternative to diazepam to stop convulsions in children with severe malaria, especially at peripheral healthcare facilities. The pharmacokinetics of MDZ have not been described in African children, in whom factors such as the aetiology and nutritional status may influence the pharmacokinetics. WHAT THIS STUDY ADDS Administration of MDZ (IV, IM, or buccal) at the currently recommended dose (0.3 mg kg−1) resulted in rapid achievement of median maximum plasma concentrations of MDZ within the range 64–616 ng ml−1, with few clinically significant cardio-respiratory effects. A single dose of MDZ rapidly terminated (within 10 min) seizures in all (100%), 9/12 (75%) and 5/8 (63%) children following IV, IM and buccal administration, respectively. Although IM and buccal MDZ may be the preferred treatment for children in the pre-hospital settings the efficacy appears to be poorer.