Pharmacokinetics of midazolam and alpha‐hydroxy‐midazolam following rectal and intravenous administration.

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Linked ArticlesThis article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685–7. doi: 10.1111/bcp.13230 AimWhen different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model‐based meta‐analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function).MethodsA systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation.ResultsNo model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), –4.1 (5), –9.2 (4), –10.8 (5) and –10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped.ConclusionNo evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.

Section: Resultsmentioning

confidence: 99%

Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?

Germovsek

Barker

Sharland

et al. 2016

113

“…Midazolam is used in a wide range of indications for conscious sedation, including sedation for the majority of outpatient diagnostic, therapeutic and endoscopic procedures, and sedation for the preparation of general anaesthesia in hospitalized patients . Administration of midazolam is generally intravenous as other administration routes such as oral, rectal, subcutaneous and buccal lead to a delayed onset of efficacy and to a large interindividual variability in efficacy onset . The nasal route therefore appears to be a very convenient route of administration for conscious sedation and for the lay treatment of acute epileptic seizures .…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation

Schrier

Zuiker

Merkus³

et al. 2016

“…The use of the water soluble benzodiazepine midazolam hydrochloride is well established as a premedicant, anxiolytic and anaesthetic induction agent [3]. Its safety and efficacy in the acute treatment of seizure exacerbations is well documented [4].…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

Knoester

Jonker

Hoeven

et al. 2002

135

113

Aims To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects. Methods Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. b-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model. Results Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (ts.d.) peak plasma concentration of midazolam of 71 (t25 ng ml x1 ) was reached after 14 (t5 min). Mean bioavailability following intranasal administration was 0.83t0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11t0.25 l kg x1 , mean systemic clearance 16.1t4.1 ml min x1 kg x1 and harmonic mean initial and terminal half lives 8.4t2.4and 79t30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration.Conclusions In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.