title: Pharmacokinetics and tolerability of nasal versus intravenous midazolam in healthy Dutch volunteers: a single-dose, randomized-sequence, open-label, 2-period crossover pilot study.
abstract: BACKGROUND
  Intranasal (IN) midazolam is a potential alternative to rectal diazepam for the acute treatment of epileptic seizures.
  
  
  OBJECTIVE
  The purpose of this pilot study was to investigate the pharmacokinetics and tolerability of IN midazolam (50 mg/mL) compared with intravenous (IV) midazolam (2.5 mg) in healthy adult volunteers.
  
  
  METHODS
  In this single-dose, randomized-sequence, open-label, 2-period crossover pilot study subjects were randomly assigned to receive IN or IV midazolam, with a washout period of at least 5 days between treatments. The 50-mg/mL IN midazolam formulation consisted of 5 mg midazolam base per 0.1 mL (1 spray) and was administered once in 1 nostril. The IV midazolam solution (2.5 mg) was infused over 10 seconds. Blood samples were taken before and at regular intervals up to 240 minutes after dosing. Pharmacokinetic data (ie, C(max), T(max), t(½), and AUC) were analyzed using a 2-compartment model.
  
  
  RESULTS
  Of 9 volunteers screened and enrolled, 7 completed the study (mean age 34.1 [9.0] years; mean weight, 68.6 [10.4] kg, range 53-89 kg; 6 men, 3 women; all white). The mean C(max) of 78 (40) ng/mL was reached 44 minutes after IN administration, whereas the mean C(max) was 51 (5) ng/mL after IV administration. The mean estimated C(t=5 min) was 31.4 (28.1) ng/mL after IN administration. The elimination t(½) was 1.9 (0.41) hours for IN midazolam and 2.3 (0.19) hours for IV midazolam. The bioavailability of IN midazolam was 82%. There were few adverse events, with a local burning feeling in the nose being the most reported event (6 of 7 subjects).
  
  
  CONCLUSIONS
  In this select group of healthy volunteers, concentrations of midazolam >30 ng/mL were reached within 5 minutes of IN administration at a dose of 5 mg/0.1 mL. A burning feeling in the nostril was the main adverse effect. Additional research is needed to evaluate the safety profile, convenience, satisfaction, and efficacy of nasal midazolam in the treatment of adults with seizures. This trial is registered at www.isrctn.org, No. ISRCTN79059168.
authors.affiliation: Department of Clinical Pharmacology & Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands. n.veldhorst@mumc.nl
authors.forename: Nicole M L
authors.initials: NM
authors.lastname: Veldhorst-Janssen
authors.forename: Audrey A A
authors.initials: AA
authors.lastname: Fiddelers
authors.forename: Paul-Hugo M
authors.initials: PH
authors.lastname: van der Kuy
authors.forename: H Maurice S
authors.initials: HM
authors.lastname: Theunissen
authors.forename: Marc C T F M
authors.initials: MC
authors.lastname: de Krom
authors.forename: Cees
authors.initials: C
authors.lastname: Neef
authors.forename: Marco A E
authors.initials: MA
authors.lastname: Marcus
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D008875:Middle Aged; D059085:Nasal Sprays; D009426:Netherlands; D010865:Pilot Projects
chemical_list: D000927:Anticonvulsants; D059085:Nasal Sprays; D008874:Midazolam