For nested models, the justification for each additional effect (additional parameter) was for it to improve the goodness-of-fit statistic (−2 log likelihood) by more than 3.84 (evaluated against the chi-square distribution, this is equivalent to significance at the 0.05 concentration). The appropriateness of the base model and the requirement for interindividual variability parameters (ETAs) were assessed using the likelihood ratio test (where appropriate, i.e. , for nested models) and by consideration of the Akaike Information Criterion (nonnested models) and the precision of the final parameter estimates (all models). 17Intraindividual variability was described using a log error model. Allometric scaling was applied to all structural model parameters, standardized to a 70-kg person. The drug concentration versus time data were applied to one-, two-, and three-compartment mamillary models. Assessment of dose proportionality (Power Test) was performed using AUC 0-tbecause the parameter AUC 0-∞could not be calculated adequately for every subject. Renal clearance was calculated as Ae/AUC 48. Pharmacokinetic analysis of urinary data of JM-1232(–) and its metabolite JM-Metabo-3 included the following parameters Ae, the amount excreted fe the fraction of the administered dose excreted unchanged in urine, CLr (renal clearance). Where appropriate, terminal rate constants (λ z) were estimated by fitting a linear regression of log mean concentration against time using data points randomly distributed approximately a single straight line. The areas under the plasma concentration–time curves to the last quantifiable sample point (AUC 0-t) and up to 48 h postdose (AUC 48) were estimated by the linear trapezoidal rule, and the areas under the plasma concentration–time curves to infinite time (AUC 0-∞) were calculated as AUC 0-t+ C last/λ z. The maximum plasma concentrations (C max) of JM-1232(–) and its metabolite JM-Metabo-3 were the observed values during a 48-h sampling period. JM-1232(–) and JM-Metabo-3 were shown to be stable in human plasma for up to 3 months at −20☌, after three freeze/thaw cycles. Relative error at this concentration ranged from −2.8 to 14.3% following the analysis of the QC sample on three separate occasions. The precision at the lower limit of quantification (0.4 ng/ml) ranged from 3.5% to 9.5%. Intrabatch relative error ranged from −10.8% to 5.3% for QC samples analyzed at 1.2, 7.5, and 75 ng/ml on three separate occasions. The intrabatch coefficient of variation ranged from 1.9% to 7.7% for QC samples analyzed at 1.2, 7.5, and 75 ng/ml on three separate occasions. The accuracy (expressed in terms of the relative error) of the back-calculated concentrations of all acceptable standards (parent and metabolite) was between −6.6% and 3.0%. Dilution factors of 1–10 and 1–50 were validated, allowing samples to be measured up to a concentration of 5,000 ng/ml. The assay demonstrated linearity of response in the range 0.4–100 ng/ml. Recovery of the analyte after extraction from plasma ranged from 70% to 77% for JM-1232(–) and from 60% to 70% for JM-Metabo-3 over the assay calibration range. Reformulation of propofol in nonlipid vehicles remains the subject of intense development activity. 9, 10Propofol is widely used as an anesthetic and sedative however, it causes pain on injection and is typically presented in lipid formulations which may support bacterial growth. 4, –, 8Attempts to develop new water-soluble benzodiazepines with properties superior to midazolam have been unsuccessful.
1, 3However, comparative clinical studies suggest that differences between the two agents are modest and inconsistent. 2Blood-brain equilibration of midazolam is slower than that of diazepam with t 1/2 k e0for midazolam being 2.5–3 times greater for midazolam than for diazepam. 1Midazolam has an active metabolite α-hydroxy-midazolam and is prone to accumulation when infused over prolonged periods with subsequent slow recovery. Although the solubility of midazolam avoids the use of a lipid or Cremofor vehicle, its onset is slower than diazepam. Diazepam was used widely for intravenous sedation until the introduction of the water-soluble midazolam. Diazepam is presented in a lipid emulsion and has an active metabolite des-methyldiazepam. BENZODIAZEPINES are used extensively for human sedation with indications ranging from brief procedures to prolonged periods of critical care.