Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.

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.

The glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide was approved in 2010 by the US Food and Drug Administration (FDA) as an adjunct treatment to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. This article provides insights into the use of pharmacometric analyses for regulatory review with a focus on the dosing recommendations. The assessment was based on the totality of exploratory and confirmatory analysis of dose-finding and pivotal clinical data and was structured around a set of key questions in accordance with current FDA review practice. For the pharmacometric review of liraglutide, the key questions focused on exposure-response relationships for effects on fasting plasma glucose, hemoglobin A(1c), and calcitonin and on variability in exposure across demographic subgroups of patients. The importance of conducting exploratory exposure-response analysis and population pharmacokinetic studies in clinical drug development to support dosing recommendations is highlighted.

The current mechanism-based pharmacokinetic-pharmacodynamic model quantified the relationship between in vitro hERG channel blockade and clinical QT prolongation for dofetilide. This model may prove valuable for assessing the risk of QT prolongation in humans for other drugs that selectively block the hERG channel on the basis of in vitro assays and pharmacokinetic properties.