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Dantrolene is the only drug proven effective for prevention and treatment of malignant hyperthermia (MH). Current dosing recommendations are based on noncompartmental analyses and are largely empiric. They are also divergent, as evidenced by differing recommendations from the Malignant Hyperthermia Association of the United States (MHAUS) and European Sources. We determined the compartmental pharmacokinetics of dantrolene, simulated the concentration time course based on currently recommended dosing, and suggest an optimal regimen. Nine volunteers (55–89 kg) received IV infusions of dantrolene (5 mg/kg over 30 min followed by 0.05 mg · kg−1 · h−1 for 5 h). Venous blood samples were drawn for up to 60 h, and dantrolene plasma concentrations were determined by reverse phase, high-performance liquid chromatography. One, two, and three compartmental models were fitted to the data, and a covariate analysis was performed. All calculations were performed with NONMEM using the population approach. The data were adequately described by a two-compartment model with the following typical variable values (median ± se): volumes of distribution V1 = 3.24 ± 0.61 L; V2 = 22.9 ± 1.53 L; plasma clearance CLel = 0.03 ± 0.003 L/min; and distributional clearance CLdist = 1.24 ± 0.22 L/min. All parameters were scaled linearly with weight. Simulations of European recommendations for treatment of MH lead to plasma concentrations converging to 14–18 mg/L within 24 h. Simulating MHAUS guidelines (intermittent bolus administration) yielded peak and trough plasma concentrations ranging from 6.7–22.6 mg/L. Based on our findings, we propose an infusion regimen adjusted to the initial bolus dose(s) required to control symptoms. This strategy maintains the individualized therapeutic concentrations and improves stability of plasma concentrations.