IntroductionOnly limited information exists on the pharmacokinetics of prolonged (> 24 hours) and high-dose dexmedetomidine infusions in critically ill patients. The aim of this study was to characterize the pharmacokinetics of long dexmedetomidine infusions and to assess the dose linearity of high doses. Additionally, we wanted to quantify for the first time in humans the concentrations of H-3, a practically inactive metabolite of dexmedetomidine.MethodsThirteen intensive care patients with mean age of 57 years and Simplified Acute Physiology Score (SAPS) II score of 45 were included in the study. Dexmedetomidine infusion was commenced by using a constant infusion rate for the first 12 hours. After the first 12 hours, the infusion rate of dexmedetomidine was titrated between 0.1 and 2.5 μg/kg/h by using predefined dose levels to maintain sedation in the range of 0 to -3 on the Richmond Agitation-Sedation Scale. Dexmedetomidine was continued as long as required to a maximum of 14 days. Plasma dexmedetomidine and H-3 metabolite concentrations were measured, and pharmacokinetic variables were calculated with standard noncompartmental methods. Safety and tolerability were assessed by adverse events, cardiovascular signs, and laboratory tests.ResultsThe following geometric mean values (coefficient of variation) were calculated: length of infusion, 92 hours (117%); dexmedetomidine clearance, 39.7 L/h (41%); elimination half-life, 3.7 hours (38%); and volume of distribution during the elimination phase, 223 L (35%). Altogether, 116 steady-state concentrations were found in 12 subjects. The geometric mean value for clearance at steady state was 53.1 L/h (55%). A statistically significant linear relation (r2 = 0.95; P < 0.001) was found between the areas under the dexmedetomidine plasma concentration-time curves and cumulative doses of dexmedetomidine. The elimination half-life of H-3 was 9.1 hours (37%). The ratio of AUC0-∞ of H-3 metabolite to that of dexmedetomidine was 1.47 (105%), ranging from 0.29 to 4.4. The ratio was not statistically significantly related to the total dose of dexmedetomidine or the duration of the infusion.ConclusionsThe results suggest linear pharmacokinetics of dexmedetomidine up to the dose of 2.5 μg/kg/h. Despite the high dose and prolonged infusions, safety findings were as expected for dexmedetomidine and the patient population.Trial RegistrationClinicalTrials.gov: NCT00747721

Background and ObjectivesAlthough the pharmacokinetics of dexmedetomidine in healthy volunteers have been studied, there are limited data about the pharmacokinetics of long-term administration of dexmedetomidine in critically ill patients.MethodsThis population pharmacokinetic analysis was performed to quantify the pharmacokinetics of dexmedetomidine in critically ill patients following infusions up to 14 days in duration. The data consisted of three phase III studies (527 patients with sparse blood sampling, for a total of 2,144 samples). Covariates were included in a full random-effects covariate model and the most important covariate relationships were tested separately. The linearity of dexmedetomidine clearance was evaluated by observing steady-state plasma concentrations acquired at various infusion rates.ResultsThe data were adequately described with a one-compartment model. The clearance of dexmedetomidine was 39 (95 % CI 37–41) L/h and volume of distribution 104 (95 % CI 93–115) L. Both clearance and volume of distribution were highly variable between patients (coefficients of variation of 62 and 57 %, respectively), which highlights the importance of dose titration by response. Covariate analysis showed a strong correlation between body weight and clearance of dexmedetomidine. The clearance of dexmedetomidine was constant in the dose range 0.2–1.4 μg/kg/h.ConclusionsThe pharmacokinetics of dexmedetomidine are dose-proportional in prolonged infusions when dosing rates of 0.2–1.4 μg/kg/h, recommended by the Dexdor® summary of product characteristics, are used.

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Nimodipine is a widely used medication for treating delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. When administrated orally or intravenously, systemic hypotension is an undesirable side effect. Intracranial subarachnoid delivery of nimodipine during aneurysm clipping may be more efficient way of preventing vasospasm and DCI due to higher concentration of nimodipine in cerebrospinal fluid (CSF). The risk of systemic hypotension may also be decreased with intracranial delivery. We used animal models to evaluate the feasibility of surgically implanting a silica-based nimodipine releasing implant into the subarachnoid space through a frontotemporal craniotomy. Concentrations of released nimodipine were measured from plasma samples and CSF samples. Implant degradation was followed using CT imaging. After completing the recovery period, full histological examination was performed on the brain and meninges. The in vitro characteristics of the implant were determined. Our results show that the biodegradable silica-based implant can be used for an intracranial drug delivery system and no major histopathological foreign body reactions were observed. CT imaging is a feasible method for determining the degradation of silica implants in vivo. The sustained release profiles of nimodipine in CSF were achieved. Compared to a traditional treatment, higher nimodipine CSF/plasma ratios can be obtained with the implant.

Nimodipine is an L-type calcium channel blocker and is used to treat vasospasm in patients with subarachnoid hemorrhage. Its putative mechanism of action is relaxation of smooth muscle cells in cerebral arteries. In addition, nimodipine may have pleiotropic effects against vasospasm. Systemic hypotension is an adverse effect when patients are treated with oral or intravenous nimodipine. Intracranial administration of nimodipine formulations may produce higher concentration of nimodipine in the cerebrospinal fluid (CSF) than is possible to achieve orally or intravenously, while resulting in lower incidence of systemic hypotension. The aim of this study was to provide information on plasma and CSF levels of nimodipine in beagle dogs as a comparative data for development of experimental intracranial treatment modalities. Plasma levels of nimodipine were measured after current 30 and 60 mg single oral dose of nimodipine (Nimotop(®) 30 mg tablets), a single intravenous bolus 0.72 mg/dog of nimodipine (Nimotop(®) 0.2 mg/ml infusion solution) and CSF levels after 60 mg single oral dose of nimodipine. CSF/Plasma concentration ratio of nimodipine after oral administration of 60 mg at 1 h was 0.013 ± 0.0005. The mean terminal elimination half-life of nimodipine after i.v. bolus dose 0.72 mg was 1.8 h and mean plasma clearance was 40.3 and 3.4 l/h/kg. Absolute bioavailability was 22 %. Maximum plasma concentration and area under the plasma concentration-time curve from time of administration until the last measurable plasma concentration increased in a dose-proportional manner comparing the exposure parameters at oral doses of 30 and 60 mg. Individual variation in the kinetic profile of nimodipine was measured.