Clinical Pharmacokinetics of Lorazepam. III. Intravenous Injection. Preliminary Results

Abstract

Four healthy male volunteers received 5 mg lorazepam as a single intravenous injection. Concentrations of lorazepam and its glucuronide metabolite were determined in multiple venous blood samples drawn during the 48 hours after dosing and in all urine collected during 96 hours after the dose. Mean pharmacokinetic parameters for lorazepam were: apparent elimination half-life, 13.2 hours; volume of distribution, 0.84 liter/kg; total clearance, 55.3 ml/min. Lorazepam glucuronide, the major metabolic product of lorazepam, promptly appeared in blood, reached peak levels within 6 hours of the dose, then declined in parallel with the parent compound. A mean of 69 per cent of the dose was recovered in urine as lorazepam glucuronide.

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

“…Figure 2a compares the concentration-time profile derived from the optimized adult population model to dose-normalized observed data from four PK studies (15,(20)(21)(22). Observed data in the initial phase of distribution were overpredicted by the model; however, subsequent data were well described.…”

“…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).…”

Relationships Between CSF Drug Concentrations, Receptor Binding Characteristics, and Pharmacokinetic and Pharmacodynamic Properties of Selected 1,4-Substituted Benzodiazepines

“…The 1,4-substituted benzodiazepines are used extensively as anxiolytics, hypnotics and anticonvulsants, and their pharmacological, physicochemical and pharmacokinetic profiles have been previously reported (Aaltonen et al 1980;Berlin & Dahlstrom 1975;Boxenbaum et al 1977;Greenblatt et al 1977;Iisalo et al 1977;Kangas et al 1979a,b;Sjoe et al 1975). In many instances, blood or plasma concentration profiles fail to define onset and duration ofpharrnacological activity of the benzodiazepines (Bellantuono et al 1980;Garattini et al 1973;Greenblatt & Shader 1975;Mandelli et al 1978).…”