Comparative bioavailability of two zolpidem hemitartrate formulations in healthy human Brazilian volunteers using high‐performance liquid chromatography coupled to tandem mass spectrometry

Abstract

To assess the bioequivalence of two zolpidem hemitartrate formulations in 30 healthy volunteers. Plasma samples were obtained over a 24 h period. Plasma concentrations of zolpidem were analyzed by liquid chromatography coupled to tandem mass spectrometry with positive ion electrospray ionization using multiple reaction monitoring. Values of peak concentration (Cmax), area under curve (AUC), half‐life, elimination constant, volume of distribution and clearance showed statistically significant differences when comparing women (604.34 ng h/ml, 127.36 ng/ml, 4.4 h, 0.18 1/h, 50.56 L and 8.55 L/h, respectively) and men (276.1 ng h/ml, 70.9 ng/ml, 3.3 h, 0.26 1/h, 91.42 L and 24.34 L/h, respectively), receiving the same dose (5 mg), respectively. The geometric means with corresponding 90% confidence interval for Test/Reference percentage ratios were 99.73% (CI 93.69–106.16) for Cmax, 97.44% (90% CI = 91.85–103.37%) for area under curve of plasma concentration until the last concentration observed (AUClast) and 98.30% (90% CI = 92.48–104.49) for the area under curve between the first sample (pre‐dosage) and infinity (AUC0–inf). Since the 90% CI for AUClast, AUC0–inf and Cmax ratios were within the 80–125% interval proposed by the US Food and Drug Administration, it was concluded that zolpidem hemitartrate formulation (5 mg orodispersible tablet) is bioequivalent to the zolpidem hemitartrate formulation (Patz SL 5 mg sublingual tablet) with regard to both the rate and the extent of absorption. A new formulation of zolpidem 2.5 mg may be useful in women for the same clinical benefits as the 5 mg formulation in men.

Bioequivalence of zolpidem hemitartrate: new formulations of 5 mg SL, 10 mg and 12.5 mg XR and comparison of their bioavailabilities

“…Both reference and test products for 5 mg sublingual formulations showed a maximum plasma concentration Cmax of 98.753 ng/mL and 105.737 ng/mL, respectively, consistent with the values found by other authors [29,34].…”

“…Forty study subjects were to participate in this study in order to meet the requirements of nominal significance level of 50 %, 2x2 crossover design, 80-125% equivalence range, 28% maximum CVintra for pharmacokinetic parameters, population ratio between 95-105% for treatment average plus an additional number of 8 volunteers to compensate possible losses due to dropout/exclusions. The planned number of subjects for the study is consistent with studies reported buy some authors [29][30][31] and higher than the number estimated by other [10,32]. The study was completed with 38 subjects, an amount higher than the 32 estimated volunteers in case of loss of the 8 subjects considered in the sample size determination, fact which contributed to maintain the obtained test power for pharmacokinetic parameters near 100%.…”

“…As in other published works, the analytical selected technique of the study to quantify zolpidem in human plasma was LC-MS/MS [29,37,38].…”

Evaluation of Physiologically Based Pharmacokinetic Models to Predict the Absorption of BCS Class I Drugs in Different Pediatric Age Groups

“…Thereafter, the fitted parameter values were transferred to PK‐Sim, and the specific intestinal permeability was fitted to pharmacokinetic data in the fasted state from multiple clinical studies 27,28,31–33 . Another independent set of clinical data not used during parameter optimization was thereafter used to evaluate the adult PBPK model 34–45 …”

Development and Validation of a Sonication-Assisted Dispersive Liquid–Liquid Microextraction Procedure and an HPLC-PDA Method for Quantitative Determination of Zolpidem in Human Plasma and Its Application to Forensic Samples

“…Several analytical methods have been reported for the quantification of zolpidem in blood, including HPLC with fluorescence detection [ 2 , 10 ], HPLC-DAD [ 11 ], GC/MS [ 12 ], GC/MS/MS [ 13 ], LC/MS [ 8 , 14 ], UPLC/MS [ 15 ], LC/MS/MS [ 16 , 17 , 18 , 19 , 20 , 21 ], and UHPLC-MS/MS [ 5 , 22 , 23 ]. The most commonly used techniques for zolpidem extraction from biological matrices are liquid–liquid extraction (LLE) [ 2 , 5 , 14 , 16 , 19 , 20 , 21 ] and solid-phase extraction (SPE) [ 8 , 12 , 15 ].…”