Bioavailability and Pharmacokinetics of Lorazepam after Intranasal, Intravenous, and Intramuscular Administration

Abstract

The purpose of this study was to evaluate the pharmacokinetic profile of intranasal lorazepam in comparison to currently established administration routes. Eleven healthy volunteers completed this randomized crossover study. On three occasions, each separated by a 1-week washout, subjects received a 2 mg dose of lorazepam via the intranasal, intravenous, or intramuscular route. Blood samples were collected serially from 0 to 36 hours. Noncompartmental methods were used to determine pharmacokinetic parameters. Lorazepam was well absorbed following intranasal administration with a mean (%CV) bioavailability of 77.7(11.1). Intranasal administration resulted in a faster absorption rate than intramuscular administration. Elimination profiles were comparable between all three routes. The concentration-time profile for intranasal delivery demonstrated evidence of a double peak in several subjects, suggesting partial oral absorption. Females were found to have significantly higher AUC values than males for all three delivery routes. Overall, this study demonstrated favorable pharmacokinetics of intranasal lorazepam in relation to standard administration methods. Intranasal delivery could provide an alternative, noninvasive delivery route for lorazepam.

A Workflow Example of PBPK Modeling to Support Pediatric Research and Development: Case Study with Lorazepam

“…Concentration-time data from four separate adult PK studies (15,(20)(21)(22) were dose-normalized and compared with the output of the initial adult PBPK model. Outputs were generated using the average observed clearance in conjunction with the mean age and weight of participants in the studies to define anatomical and physiological values (23).…”

“…3) logP logarithm of the octanol-water partition coefficient (lipophilicity), pKa negative logarithm of the acid dissociation constant, fu p plasma fraction unbound, CL int(hep-UGT2B7) intrinsic clearance of hepatic isozyme UGT2B7, CL GFR renal (plasma) clearance due to glomerular filtration, B/P blood/plasma partition coefficient, ADME absorption, distribution, metabolism, and excretion of individuals with associated variability consistent with real life observations. Demographic constraints (sex, age, weight) of the simulated population were reflective of the adult subjects included among the lorazepam PK studies (15,(20)(21)(22). All subjects received a 2 mg intravenous dose, representing a commonly prescribed adult dosage.…”

“…Proposed workflow for scaling adult PBPK models toward children concentration (C last ) by the elimination rate constant (λz), where λz was calculated based on a linear regression of the final 10% of predicted time points transformed on the natural log scale. To evaluate the range of PK variability among the virtual population, 5% and 95% prediction intervals for concentration-time values were generated and compared with dose-normalized observed values (assuming linear PK) from each of the four lorazepam PK studies (15,(20)(21)(22).…”

New Non-Intravenous Routes for Benzodiazepines in Epilepsy: A Clinician Perspective

“…Due to the rich vascularization, the olfactory and in particular the respiratory zone, with a total surface of approximately 145 cm2, may serve as an efficient absorption surface for topically applied drugs [9]. The intranasal administration of BDZs became rapidly attractive because the nasal cavity is easily accessible and the nasal absorption is not subjected to the hepatic first-pass effect [10] [11]. In addition, the absorption through the cribriform plate can lead to a rapid increase in drug concentrations in the CSF as compared to other delivery methods and this is obviously crucial for a brain disorder like epilepsy [12].…”

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

“…[25][26][27][28][29][30][31][32][33][34] The main considerations from these data might be whether maximum plasma concentrations represented by C max are within ranges known to produce pharmacologic effects, and the second consideration is whether the concentrations are achieved rapidly enough to be appropriate for treating a seizure. Well-designed nasal preparations may demonstrate a pharmacokinetic profile in which the rate and extent of drug exposure is superior to intramuscular injection and approximates IV infusion (FIG.…”