Pharmacokinetics Of Zolpidem Research Articles

Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects.

Zolpidem is extensively metabolized by CYP3A4, CYP2C9 and CYP1A2. Previous studies demonstrated that pharmacokinetics of zolpidem was affected by CYP inhibitors, but not by short-term treatment of clarithromycin. The objective of this study was to investigate the effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. In the control phase, 33 subjects received a single dose of zolpidem (5mg). One week later, in the clarithromycin phase, the subjects received clarithromycin (500mg) twice daily for 5days to reach steady state concentrations, followed by zolpidem (5mg) and clarithromycin (500mg). In each phase, plasma concentrations of zolpidem were evaluated up to 12h after drug administration by using liquid chromatography-tandem mass spectrometry method. In the clarithromycin phase, mean total area under the curve of zolpidem (AUCinf) was 1.62-fold higher and the time to reach peak plasma concentration of zolpidem (tmax) was prolonged by 1.95-fold compared to the control phase. In addition, elimination half-life (t1/2) of zolpidem was 1.40-fold longer during co-administration with clarithromycin and its apparent oral clearance (CL/F) was 36.2% lower with clarithromycin administration. The experimental data demonstrate the significant pharmacokinetic interaction between zolpidem and clarithromycin at steady-state.

Zolpidem and zolpidem phenyl-4-carboxylic acid pharmacokinetics in oral fluid after a single dose.

Oral fluid zolpidem detection in the settings of drug-facilitated crime and roadside drug testing indicates recent zolpidem intake. Zolpidem pharmacokinetics in classical biological matrices such as blood and urine have been described; however, reports of such data based on oral fluids are limited. The aim of this study is to describe the pharmacokinetics of zolpidem and its major metabolite zolpidem phenyl-4-carboxylic acid (ZPCA) in oral fluids after intake. Ten milligrams of zolpidem tartrate tablets were orally administered to 14 volunteers, and oral fluid samples were collected at various times up to 72 hours and analyzed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) with post-column reagent addition. Both zolpidem and ZPCA could be detected in oral fluid after 1 hour and were rapidly eliminated, with half-lives of 2.77±0.71hours and 5.11±0.67hours, respectively. Maximum zolpidem concentrations (36.73±10.89ng/mL) occurred at 2±0.52hours, and maximum ZPCA concentrations (0.28±0.16ng/mL) occurred at 2±0.37hours. Zolpidem/ZPCA ratios decreased after zolpidem intake, an observation that might be helpful for determining the time of drug use. The results showed that the measurement of zolpidem in oral fluid can be used for the non-invasive monitoring of zolpidem consumption and misuse in drug-facilitated crime and roadside drug testing settings.

Zolpidem and Gender: Are Women Really At Risk?

In 2013 the Food and Drug Administration (FDA) claimed the existence of new data showing women to be at risk for excessive daytime sedation and impaired driving proficiency following bedtime doses of zolpidem. The putative explanation was the reduced metabolic clearance of zolpidem and higher morning blood concentrations in women compared to men. The FDA acted to reduce the recommended dosage for women down to 50% of the dose for men. No other regulatory agency worldwide has taken similar action. Gender effects on zolpidem pharmacokinetics, pharmacodynamics, adverse effects, clinical efficacy, and driving performance were evaluated through a further analysis of data from a previous study, together with a literature review. Women had on average 35% lower apparent clearance of zolpidem than men (236 vs 364 mL/min, P < 0.001). This difference was not explained by body weight. In some laboratory studies, women had greater functional impairment than men taking the same dose, but in all studies active drug was not distinguishable from placebo at 8 hours after oral dosage. On-the-road driving studies likewise showed no evidence of driving impairment in men or women at 8 hours after 10 mg of oral immediate-release zolpidem. No clinical trial demonstrated a gender-related difference in clinical efficacy or adverse reactions, and there was no evidence of a particular risk to women. Dosage reduction in women is not supported by available scientific evidence, and may in fact lead to underdosing and the consequent hazard of inadequately treated insomnia.

The influences of CYP2C9*1/*3 genotype on the pharmacokinetics of zolpidem.

Zolpidem is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C9, CYP1A2, CYP2D6 and CYP2C19. The aim of this study was to identify the effects of CYP2C9*3 allele on the pharmacokinetics of zolpidem. Healthy male subjects were divided into two genotype groups, CYP2C9*1/*1 and CYP2C9*1/*3. They received a single oral dose of 5mg zolpidem, and the plasma concentrations of zolpidem were determined up to 12h after drug administration. In addition, since zolpidem is metabolized at a high rate by CYP3A4, the effect of CYP2C9*3 allele on the pharmacokinetics of zolpidem was also observed in the condition where CYP3A4 was sufficiently inhibited by the steady-state concentration of clarithromycin, a potent CYP3A4 inhibitor. For this, clarithromycin 500mg was administered twice daily for 5days. Plasma concentrations of zolpidem were determined using liquid chromatography-tandem mass spectrometry method. The overall pharmacokinetic parameters of zolpidem were not significantly different between two CYP2C9 genotypes. Even with the potent CYP3A4 inhibitor clarithromycin present at steady-state concentrations, there were no significant differences in the exposure of zolpidem, except for elimination half-life (t1/2). In conclusion, our study suggests that CYP2C9*1/*3 genotype does not affect the plasma exposure of zolpidem.

Effects of genetic polymorphisms of CYP2C19 on the pharmacokinetics of zolpidem.

Zolpidem is indicated for the short-term treatment of insomnia and it is predominantly metabolized by CYP3A4, and to a lesser extent by CYP2C19, CYP1A2, and CYP2C9. Therefore, we evaluated the effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of zolpidem in healthy male subjects. Thirty-two male subjects were recruited and all subjects were classified into three groups according to their genotypes: CYP2C19EM (CYP2C19*1/*1, n = 12), CYP2C19IM (CYP2C19*1/*2 or *1/*3, n = 10), and CYP2C19PM (CYP2C19*2/*2, *2/*3 or *3/*3, n = 10). The pharmacokinetic parameters of zolpidem were compared in three CYP2C19 genotype groups after zolpidem administration with or without a CYP3A4 inhibitor at steady-state concentration. Plasma concentrations of zolpidem were determined up to 12h after drug administration by liquid chromatography-tandem mass spectrometry method. The maximum plasma concentration (Cmax) differed, but mean total area under the plasma concentration-time curve (AUCinf), half-life (t1/2), and apparent oral clearance (CL/F) of zolpidem administered alone did not significantly differ among the three different CYP2C19 genotype groups. Furthermore, when zolpidem was administered with a CYP3A4 inhibitor at steady-state concentration, there were no significant differences in any of the pharmacokinetic parameters of zolpidem in relation to CYP2C19 genotypes. In conclusion, we did not find any evidence for the impact of CYP2C19 genetic polymorphisms on the pharmacokinetic parameters of zolpidem.

P1.7 - Effects of Genetic Polymorphism of Cyp2c19 on the Pharmacokinetics of Zolpidem

P1.7 - Effects of Genetic Polymorphism of Cyp2c19 on the Pharmacokinetics of Zolpidem

Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats.

Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression.Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain.Key findings: Sex differences in PK were evident: females had a higher CMAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h∗ug/L) than uncastrated males. Castration induced an earlier TMAX (0.25 vs. 1 h), greater CMAX (109.1 vs. 68.1 ug/L), and a corresponding AUC increase (339.7 vs. 231.8 h∗ug/L). Administration of disulfiram caused more drastic CMAX and TMAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations.Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens.

Effect of CYP3A4*18 genotype on the pharmacokinetics of zolpidem in healthy Chinese Hui subjects

Effect of CYP3A4*18 genotype on the pharmacokinetics of zolpidem in healthy Chinese Hui subjects

Preliminary Assessment of Zolpidem Pharmacokinetics in Pediatric Burn Patients

Severely burned patients frequently experience sleep fragmentation and insomnia. This study evaluated the population pharmacokinetics of the sleep-enhancing agent zolpidem among burned children. Zolpidem was administered according to the following age-based dosing schedule: 2.5 mg per dose for 2-4 year olds, 5.0 mg per dose for 5-10 year olds, and 10 mg per dose for older than 10 years. Serum samples were collected before and 1, 2, 4, 5, 6, and 8 hours after dosing. The population pharmacokinetic analysis modeled zolpidem concentrations using nonlinear mixed effects models. Eleven patients with a mean (±SD) age of 8.3 ± 4.0 years and a mean total burn surface area of 56% ± 22% were recruited. Seventy-three zolpidem concentrations were measured with a mean Cmax of 291 ± 140 ng/mL. A 2-compartment model with first-order absorption best described the data. Zolpidem clearance was estimated at 0.03 L·h(-1)·kg(-1) (relative standard error, 55%) and increased with body weight (P < 0.05). The central compartment volume of distribution was estimated at 0.05 L/kg (relative standard error, 25%), which was inversely related to the proportion of the body surface with third-degree burns (P < 0.001). A population pharmacokinetic model has been developed that reliably characterized the pharmacokinetic parameters of zolpidem when used as a sleep-enhancing agent among pediatric burn patients. Additional studies are needed to link this pharmacokinetic model with pharmacodynamic data, which may include an assessment of the effects of higher zolpidem doses and/or more frequent administration upon sleep architecture.

Variables influencing patient satisfaction for hypnotics: difference between zolpidem and brotizolam.

The pharmacokinetics of zolpidem and brotizolam is affected by gender and age, that is, increased clearance in males taking zolpidem and younger subjects taking brotizolam. The purpose of this study was to determine the variables including gender and age influencing patient satisfaction for hypnotics, zolpidem and brotizolam. The study included 329 patients who were treated with zolpidem (n=172) and brotizolam (n=157) for insomnia. Patients were interviewed to evaluate individual satisfaction and drug efficacy. The factors associated with dissatisfaction of zolpidem and brotizolam were identified using multiple logistic analysis. Of the participating patients, 40 (23%) and 41 (26%) complained of dissatisfaction with zolpidem and brotizolam, respectively. An insufficient amount of sleep (<6h) and the number of awakenings were common factors cited for dissatisfaction for both drugs. Males were found to report a higher rate of dissatisfaction for zolpidem, whereas patients younger than 65years and those receiving corticosteroid therapy reported a higher rate of dissatisfaction with brotizolam. These results suggested that patient satisfaction was different between zolpidem and brotizolam in terms of gender for zolpidem and age and corticosteroid co-administration for brotizolam, which could be used to help choose a better drug among the two in patients with insomnia.

Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets

Ingesting food can impact the pharmacokinetics of sedative-hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle-of-the-night awakening. In this randomized, open-label, single-site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high-fat meal (fed state). Healthy adults aged 18-64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post-dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post-dose (corresponding to "morning wake time"), higher zolpidem plasma levels were evident in the fed state. Area under the concentration-time curve (AUC) values for the 0-8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P < .001). In the fed versus fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation.

Drug interaction between St John’s wort and zolpidem in healthy subjects

St John's wort (SJW, Hypericum perforatum) is one of the most commonly used herbal antidepressants for treatment of mild to moderate depression. SJW enhances CYP3A4 activity and alters the pharmacokinetics of CYP3A4 substrates. This study investigated the effect of SJW on the pharmacokinetics of zolpidem in healthy subjects. A controlled, open-label, non-randomized, fixed-dose schedule design was used. Fourteen healthy male subjects received a single 10 mg oral dose of zolpidem followed by SJW administration (300 mg orally, three times a day) for 14 days; the last dose of SJW was coadministered with a single dose of zolpidem. Blood samples were obtained over a 24-h period after zolpidem administration. Pharmacokinetic data for zolpidem alone and in combination with SJW were analysed by high-performance liquid chromatography. After repeated administration of SJW, the mean values of AUC and C(max) for zolpidem significantly decreased (380.3 ± 181.4 vs. 265.4 ± 134.2 ng h/mL, P = 0.001; 83.1 ± 30.1 vs. 55.1 ± 24.8 ng/mL, P = 0.000 respectively) and the mean value of CL/F for zolpidem significantly increased (38.4 ± 31.5 vs. 56.9 ± 57.2 mL/min, P = 0.040). However, in three subjects, the AUC showed a small increase after SJW treatment. The effect of SJW on the pharmacokinetics of zolpidem has not previously been reported. Repeated administration of SJW decreases the plasma concentration of zolpidem, probably by enhancing CYP3A4 activity. Given the wide inter-subject variability observed, for personalized medicine, advice on the use of the combination should be individualized, based on the circumstances of the patient.

Zolpidem pharmacokinetics and pharmacodynamics in metabolic interactions involving CYP3A: sex as a differentiating factor

To the editor: We read with interest the recent paper by Polasek et al. on the evaluation of zolpidem as a mechanism-based inactivator of human CYP3A in vitro that was accompanied by the assessment of its metabolic interaction potential with CYP3A drugs [1]. The article clearly points out the mechanism of inactivation of human CYP3A in vitro and describes the implications of this mechanism for the in vivo metabolic interactions involving CYP3A. Given the prescription rate of zolpidem, this issue is of vital importance in terms of the drug’s efficacy and patients’ safety. However, one issue that was not addressed in the discussion of this interesting paper is that of the association between the patient’s sex and the endocrine specificity of zolpidem—as if zolpidem pharmacokinetics is a gender-independent factor. Based on current knowledge, the pharmacokinetics of zolpidem seems to be related to endocrine factors associated with CYP3A4 metabolism. As such, low plasma concentrations of free testosterone may contribute to lower CYP3A activity, with women achieving up to 50% higher zolpidem plasma levels, while exposure to testosterone activates the biotransformation via CYP3A [2]. This effect is conspicuous in the relative higher incidence of adverse drug reactions with zolpidem in women [3]. The conclusions of the study reported in the paper are valid for the model study on male subjects. It would have been interesting, however, if the discussion were to have included the exciting element of endocrine-related differences in zolpidem action.

Response to “Zolpidem pharmacokinetics and pharmacodynamics in metabolic interactions involving CYP3A: sex as differentiating factor”

Response to “Zolpidem pharmacokinetics and pharmacodynamics in metabolic interactions involving CYP3A: sex as differentiating factor”

Potential Pharmacokinetic Basis for Zolpidem Dosing in Children With Sleep Difficulties

The pharmacokinetics of zolpidem was assessed in this open-label, dose-escalation study in children with insomnia. Twenty-one children, seven per age group (2-6, >6 to 12, >12 to 18 years), received a single dose of zolpidem at one of the three dose levels (0.125, 0.25, or 0.50 mg/kg (20 mg maximum dose)). Multiple pharmacokinetic measures were assessed at nine post-dose intervals and pharmacodynamics was assessed by polysomnography and actigraphy. Significant pharmacokinetic effects by dose were observed only as linear increases in maximum concentration (C(max), P<0.001) and area under the plasma concentration-time curve (AUC, P<0.001). Significant pharmacokinetic effects by age group included an increase in AUC (P=0.02), half-life (P=0.04), and mean residence time (P=0.01), whereas total body clearance decreased (P=0.01) and steady-state volume of distribution was variable. Pharmacodynamic measures were independent of the pharmacokinetic estimates. Overall, zolpidem was well tolerated and a pediatric dose of 0.25 mg/kg is recommended for future efficacy studies.

The Use of Pharmacotherapy in the Treatment of Pediatric Insomnia in Primary Care: Rational Approaches. A Consensus Meeting Summary

To formulate a rational approach to the pharmacologic treatment of pediatric insomnia, and to develop clinical guidelines regarding indications, target populations, and parameters for the use of these medications, especially by community-based pediatricians. A multidisciplinary task force developed under the auspices of the American Academy of Sleep Medicine, which included experts in pediatric sleep medicine, psychiatry, pharmacology, neurology, and general pediatrics. Review of existing data regarding current use of over-the-counter and prescription medications for pediatric insomnia in the primary care practice setting, and of empirical data on the pharmacology, safety, efficacy, and tolerability of medications commonly used for the treatment of pediatric insomnia. Group consensus definition of pediatric insomnia and clinical guidelines; working group recommendations regarding special populations and future directions. Use of medications for pediatric insomnia should be diagnostically driven, and should be implemented in conjunction with empirically-based behavioral treatment strategies and adequate sleep hygiene. Specific target populations include children with neurodevelopmental disorders, pervasive developmental disorders, chronic medical conditions, and psychiatric disorders. Additional research, including clinical trials, is critically needed to provide an evidence-based approach to the use of these medications in clinical practice.

Effects of zolpidem on local cerebral glucose metabolism during non-REM sleep in normal volunteers: A positron emission tomography study

Using positron emission tomography with fluorodeoxyglucose (18FDG or FDG), we compared the effects of zolpidem (10 mg), an imidazopyridine hypnotic, which is relatively selective for the BZ1 or omega receptor and placebo on cerebral glucose metabolism during the first non-REM sleep period of 12 young normal volunteers. Plasma zolpidem pharmacokinetics varied considerably among subjects, and plasma concentrations were lower than usually reported. In general, the effects of zolpidem on local cerebral glucose metabolism varied directly with plasma concentrations of zolpidem. Zolpidem induced changes in local cerebral glucose metabolism were unevenly distributed throughout the brain and were greater in subcortical areas than lateral cortical areas. Significant negative correlations were found between change in local absolute glucose metabolic rate (calculated by subtracting individual data on placebo nights from that on zolpidem nights) and plasma concentration of zolpidem for the following areas: medial frontal cortex, cingulate gyrus, putamen, thalamus, and hippocampus. The effects of zolpidem on local cerebral glucose metabolism were partially but not closely related to the reported density of BZ1 receptors.

Clinical Pharmacokinetics and Pharmacodynamics of Zolpidem

Zolpidem is an imidazopyridine which differs in structure from the benzodiazepines and zopiclone. It is a strong sedative with only minor anxiolytic, myorelaxant and anticonvulsant properties, and has been shown to be effective in inducing and maintaining sleep in adults. The available evidence suggests that zolpidem produces no rebound or withdrawal effects, and patients have experienced good daytime alertness. Zolpidem 10mg in non-elderly and a reduced dose of 5mg in elderly individuals are clinically effective. In humans, the major metabolic routes include oxidation and hydroxylation; none of the metabolites appears to be pharmacologically active. The pharmacological activity of zolpidem results from selective binding to the central benzodiazepine receptors of the omega 1 subtype. Zolpidem is approximately 92% bound to plasma proteins; absolute bio-availability of zolpidem is about 70%. After single 20mg oral doses, typical values of pharmacokinetic variables for zolpidem in humans are: a peak plasma concentration of 192 to 324 micrograms/L occurring 0.75 to 2.6 hours postdose; a terminal elimination half-line of 1.5 to 3.2 hours; and total clearance of 0.24 to 0.27 ml/min/kg. Zolpidem pharmacokinetics are unchanged during multiple-dose treatment. Zolpidem pharmacokinetics are not significantly influenced by gender. Clearance of zolpidem in children is 3 times higher than in young adults, and is lower in very elderly people. There are no significant differences in the pharmacokinetic parameters between various racial groups. Dosage reduction appears to be prudent in patients with renal disease, and caution should be exercised when prescribing zolpidem to elderly patients with hepatic impairment. Coadministration of haloperidol, cimetidine, ranitidine, chlorpromazine, warfarin, digoxin or flumazenil do not alter the pharmacokinetics of zolpidem; flumazenil predictably antagonises the hypnotic effects of zolpidem. Alertness tends to be reduced when cimetidine is combined with zolpidem. Volunteers treated with imipramine plus zolpidem developed anterograde amnesia.

EEG profile of intravenous zolpidem in healthy volunteers

Zolpidem is an imidazopyridine which binds specifically to the omega 1 receptor. Zolpidem demonstrated potent hypnotic activity at a dose of 10 mg. Pharmacodynamics and pharmacokinetics of zolpidem were studied after daytime administration in a randomised, double-blind, placebo-controlled, cross-over trial. Single doses of zolpidem (10 mg IV as a 3-min infusion and 20 mg orally) and placebo were firstly tested in 12 healthy young male volunteers. Two other doses (5 mg IV and orally) were then evaluated in 6 out of these 12 subjects. EEG (4 leads = Fp2-T4, Fp1-T3, T4-02 and T3-01), and Stanford Sleepiness Scale (SSS) were measured up to 5 h postdosing. Blood samples were also collected up to 24 h. The time course of the hypnotic activity of zolpidem, assessed by the score obtained on SSS, showed a similar profile whatever the route or the dose administered: slightly earlier onset after IV but sedative scores were reached at 30 min and the effect peaked between 1 and 1.5 h and lasted 4 h in both conditions. The EEG profile of zolpidem was characterised by a decrease of alpha activity and an increase in delta and in beta activity. The effect on beta activity was marked within the first hour and then disappeared. The time course of delta and alpha activities indicated a rapid onset (10 min after IV, 30 min after oral route) and a duration of 3-4 h. The amplitude of these relative EEG changes and their duration were independent of the route of administration and the dose administered. AUC and Cmax increased proportionally to the administered dose and elimination half life (2h), clearance and volume of distribution did not change according to the dose or the route of administration.(ABSTRACT TRUNCATED AT 250 WORDS)