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Thomas Roth - One of the best experts on this subject based on the ideXlab platform.
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gender differences in pharmacokinetics and pharmacodynamics of Zolpidem following sublingual administration
The Journal of Clinical Pharmacology, 2014Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Frank Steinberg, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of Zolpidem after administration of a buffered Zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects Zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma Zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of Zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that Zolpidem clearance is lower in females than in males. PD effects of Zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.
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comparison of pharmacokinetic profiles of Zolpidem buffered sublingual tablet and Zolpidem oral immediate release tablet results from a single center single dose randomized open label crossover study in healthy adults
Clinical Therapeutics, 2013Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:Abstract Background A Zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. Objective The aim of this study was to compare the Zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral Zolpidem in healthy female and male adults. Methods This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral Zolpidem in healthy adults. Results The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean Zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both Zolpidem formulations were generally well tolerated by both genders. Conclusions Systemic exposure of Zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both Zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.
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efficacy and safety of Zolpidem extended release in elderly primary insomnia patients
American Journal of Geriatric Psychiatry, 2008Co-Authors: James K Walsh, Christina Soubrane, Thomas RothAbstract:Objectives To evaluate the clinical efficacy and safety of Zolpidem extended release for the treatment of primary insomnia in elderly patients. Methods A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 ± 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–defined primary insomnia patients were randomized to 3 weeks of nightly treatment with either Zolpidem extended release 6.25 mg or placebo; 198 patients completed the study. Results Relative to placebo, Zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with Zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of Zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups. Conclusions Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly primary insomnia patients during three weeks of administration.
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efficacy and safety of Zolpidem mr a double blind placebo controlled study in adults with primary insomnia
Sleep Medicine, 2006Co-Authors: Thomas Roth, Christina Soubrane, Laurence Titeux, James K WalshAbstract:Abstract Background and purpose To evaluate the clinical efficacy and safety of modified-release Zolpidem (Zolpidem-MR 12.5 mg) for the treatment of primary insomnia in adults. Patients and methods Two hundred and twelve (123 women, 89 men; mean age 44.3±SD 3.0 years), Diagnostic and Statistical Manual of Mental Disorders—4th Edition (DSM-IV)-defined primary insomnia patients were randomized in a double-blind, placebo-controlled, parallel-group study. The study was completed by 192 patients. Patients received 3 weeks of nightly treatment with either Zolpidem-MR 12.5 mg or placebo, preceded and followed by two nights of single-blind placebo. The main outcome measures were mean polysomnographic (PSG) sleep parameters of nights 1/2 and nights 15/16 of double-blind treatment and daily subjective sleep estimates from sleep questionnaires to assess efficacy, and PSG parameters of nights 22 and 23 of single-blind placebo substitution to assess the effect of drug discontinuation. Results Relative to placebo, Zolpidem-MR 12.5 mg improved sleep maintenance by significantly reducing PSG wake time after sleep onset (WASO) during the first 6 h of sleep as well as the number of awakenings. Consistent with the effects of standard Zolpidem, Zolpidem-MR also significantly reduced latency to persistent sleep, and significantly increased sleep efficiency, both at the beginning and after 2 weeks of double-blind treatment. There was no evidence of next-day residual effects as measured objectively by psychometric tests. Rebound insomnia on the first night after abrupt discontinuation resolved the following night. Overall, Zolpidem-MR was well tolerated. Conclusions Zolpidem-MR 12.5 mg is effective and safe in treating primary insomnia in adults and improves sleep maintenance, induction and duration of sleep.
Jerold S Harmatz - One of the best experts on this subject based on the ideXlab platform.
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gender differences in pharmacokinetics and pharmacodynamics of Zolpidem following sublingual administration
The Journal of Clinical Pharmacology, 2014Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Frank Steinberg, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of Zolpidem after administration of a buffered Zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects Zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma Zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of Zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that Zolpidem clearance is lower in females than in males. PD effects of Zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.
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comparison of pharmacokinetic profiles of Zolpidem buffered sublingual tablet and Zolpidem oral immediate release tablet results from a single center single dose randomized open label crossover study in healthy adults
Clinical Therapeutics, 2013Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:Abstract Background A Zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. Objective The aim of this study was to compare the Zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral Zolpidem in healthy female and male adults. Methods This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral Zolpidem in healthy adults. Results The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean Zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both Zolpidem formulations were generally well tolerated by both genders. Conclusions Systemic exposure of Zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both Zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.
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pharmacokinetic properties of Zolpidem in elderly and young adults possible modulation by testosterone in men
British Journal of Clinical Pharmacology, 2003Co-Authors: Joel O Olubodun, Jerold S Harmatz, Richard I Shader, Lisa L Von Moltke, Hermann R Ochs, Ronenn Roubenoff, Leah M Hesse, David J GreenblattAbstract:Aims The influence of ageing on the pharmacokinetics of Zolpidem, an extensively prescribed hypnotic medication, was evaluated in healthy human volunteers. Methods A series of 16 elderly (age: 61–85 years) and 24 young (age: 22–42 years) volunteers received single 5 mg oral doses of Zolpidem tartrate. Serum Zolpidem concentrations were determined by HPLC with fluorescence detection in samples drawn during 8 h after dosage. The effect of testosterone on Zolpidem biotransformation was evaluated in vitro using human liver microsomes. Possible induction of CYP3A protein expression and function was studied in cultured human hepatocytes. Results Among men, apparent oral clearance of Zolpidem was decreased in elderly compared to young subjects (3.8 vs 11.0 ml min−1 kg−1, P < 0.01), Cmax was increased (93 vs 40 ng ml−1, P < 0.01), and half-life increased (2.7 vs 1.5 h, P < 0.03). Among women, Zolpidem oral clearance was decreased in the elderly (3.0 vs 5.8 ml min−1 kg−1, P < 0.02), Cmax increased (108 vs 60 ng ml−1, P < 0.001), with no difference in t1/2 (2.3 vs 2.4 h). Among male subjects, free serum testosterone concentrations were lower in the elderly (10.5 vs 19.0 pg ml−1, P < 0.01), and were significantly correlated with Zolpidem clearance (r2 = 0.46, P < 0.001). Multiple regression analysis indicated a greater relative contribution of serum testosterone than age to the oral clearance of Zolpidem among men. In human liver microsomes, co-incubation of Zolpidem (10 µm) with varying concentrations of testosterone produced activation of biotransformation of Zolpidem to its principal hydroxylated metabolite. Maximum activation was achieved at equimolar concentrations of testosterone (10 µm). However, testosterone did not induce immunoactive CYP3A4 expression or catalytic function in cultured human hepatocytes. Conclusions The increased Cmax and lower oral clearance of Zolpidem in the elderly are consistent with recommendations of lower clinical doses of Zolpidem in the elderly. Our clinical and in vitro data both suggest that reduced free serum testosterone may have a modulatory role in age-dependent changes in Zolpidem pharmacokinetics in men.
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differential impairment of triazolam and Zolpidem clearance by ritonavir
Journal of Acquired Immune Deficiency Syndromes, 2000Co-Authors: Von Moltke Ll, Jerold S Harmatz, Anna Liza B Durol, Johanna P Daily, Jennifer A Graf, Polyxane Mertzanis, J L Hoffman, Richard I ShaderAbstract:BACKGROUND: The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. METHODS: The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and Zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg Zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo. RESULTS: Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of Zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to < 4% of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced Zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of Zolpidem were not altered by ritonavir. CONCLUSION: Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in Zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of Zolpidem clearance on CYP3A.
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comparative kinetics and dynamics of zaleplon Zolpidem and placebo
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Jerold S Harmatz, Lisa L Von Moltke, Bruce L Ehrenberg, L HarrelAbstract:Purpose This study evaluated the relationship of dose, plasma concentration, and time to the pharmaco-dynamics of zaleplon and Zolpidem, 2 structurally distinct benzodiazepine receptor agonists. Method Ten healthy male volunteers received single oral doses of placebo, 10 mg zaleplon, 20 mg zaleplon, 10 mg Zolpidem, and 20 mg Zolpidem in a double-blind, 5-condition crossover study, with 48 hours elapsing between trials. Plasma drug concentrations and pharmacodynamic effects were measured during the 8 to 24 hours after administration. Results Kinetics of zaleplon and Zolpidem were not significantly related to dose. However, zaleplon had more rapid elimination (apparent elimination half-life [t½] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than Zolpidem (t½, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min). Active treatments produced pharmacodynamic effects consistent with benzodiazepine agonist activity: self- and observer-rated sedation, impairment of digit symbol substitution test (DSST) performance, impaired memory, and increased electroencephalographic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 10 mg Zolpidem < 20 mg Zolpidem; on a number of measures, 20 mg zaleplon was comparable to 10 mg Zolpidem. Quantitative effects of Zolpidem 20 mg far exceeded those of other treatments. Dynamic effects of both drugs were significantly related to plasma concentration. Conclusions Benzodiazepine agonist effects of zaleplon and Zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of Zolpidem exceeded those of zaleplon. Clinical Pharmacology & Therapeutics (1998) 64, 553–561; doi:
James K Walsh - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Zolpidem extended release in elderly primary insomnia patients
American Journal of Geriatric Psychiatry, 2008Co-Authors: James K Walsh, Christina Soubrane, Thomas RothAbstract:Objectives To evaluate the clinical efficacy and safety of Zolpidem extended release for the treatment of primary insomnia in elderly patients. Methods A randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 205 (117 women, 88 men; mean age 70.2 ± 4.5 years) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–defined primary insomnia patients were randomized to 3 weeks of nightly treatment with either Zolpidem extended release 6.25 mg or placebo; 198 patients completed the study. Results Relative to placebo, Zolpidem extended release 6.25 mg significantly decreased wake time after sleep onset during the first six hours of the night, as measured by polysomnogram (PSG). PSG latency to persistent sleep was reduced and PSG total sleep time was increased, both at nights 1/2 and 15/16. Patient self-report measures were significantly better with Zolpidem extended-release 6.25 mg than with placebo throughout treatment. Some PSG measures indicated a worsening of sleep for a single night after abrupt discontinuation of Zolpidem extended release. No next-morning residual effects were observed. The overall incidence and nature of adverse events was comparable between the two groups. Conclusions Zolpidem extended release 6.25 mg improved both sleep maintenance and sleep induction in elderly primary insomnia patients during three weeks of administration.
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efficacy and safety of Zolpidem mr a double blind placebo controlled study in adults with primary insomnia
Sleep Medicine, 2006Co-Authors: Thomas Roth, Christina Soubrane, Laurence Titeux, James K WalshAbstract:Abstract Background and purpose To evaluate the clinical efficacy and safety of modified-release Zolpidem (Zolpidem-MR 12.5 mg) for the treatment of primary insomnia in adults. Patients and methods Two hundred and twelve (123 women, 89 men; mean age 44.3±SD 3.0 years), Diagnostic and Statistical Manual of Mental Disorders—4th Edition (DSM-IV)-defined primary insomnia patients were randomized in a double-blind, placebo-controlled, parallel-group study. The study was completed by 192 patients. Patients received 3 weeks of nightly treatment with either Zolpidem-MR 12.5 mg or placebo, preceded and followed by two nights of single-blind placebo. The main outcome measures were mean polysomnographic (PSG) sleep parameters of nights 1/2 and nights 15/16 of double-blind treatment and daily subjective sleep estimates from sleep questionnaires to assess efficacy, and PSG parameters of nights 22 and 23 of single-blind placebo substitution to assess the effect of drug discontinuation. Results Relative to placebo, Zolpidem-MR 12.5 mg improved sleep maintenance by significantly reducing PSG wake time after sleep onset (WASO) during the first 6 h of sleep as well as the number of awakenings. Consistent with the effects of standard Zolpidem, Zolpidem-MR also significantly reduced latency to persistent sleep, and significantly increased sleep efficiency, both at the beginning and after 2 weeks of double-blind treatment. There was no evidence of next-day residual effects as measured objectively by psychometric tests. Rebound insomnia on the first night after abrupt discontinuation resolved the following night. Overall, Zolpidem-MR was well tolerated. Conclusions Zolpidem-MR 12.5 mg is effective and safe in treating primary insomnia in adults and improves sleep maintenance, induction and duration of sleep.
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subjective hypnotic efficacy of trazodone and Zolpidem in dsmiii r primary insomnia
Human Psychopharmacology-clinical and Experimental, 1998Co-Authors: James K Walsh, Milton K Erman, C W Erwin, Andrew O Jamieson, Mark W Mahowald, Quentin R Regestein, Martin B Scharf, P Tigel, Gerald W Vogel, Catesby J WareAbstract:Trazodone is an antidepressant which is used at low doses as a hypnotic. The hypnotic efficacy of trazodone in non-depressed insomniacs is unknown, especially in comparison to hypnotic medications such as Zolpidem. Following a placebo screening week, DSM-IIIR defined primary insomniacs were randomized into a parallel-group, double-blind, 14-day comparison of trazodone 50 mg, Zolpidem 10 mg and placebo. Patients completed daily morning questionnaires and weekly office visits. Self-reported sleep latencies were compared by the Cox proportional hazards regression technique; self-reported sleep duration by ANOVA. During treatment Week 1, both drugs produced significantly shorter self-reported sleep latencies and longer self-reported sleep durations than placebo. Self-reported sleep latency was significantly shorter with Zolpidem than with trazodone. During Week 2, only the Zolpidem group maintained a significantly shorter sleep latency than the placebo group, and self-reported sleep duration did not vary significantly among groups. The incidence of adverse events was low in all groups. Both trazodone and Zolpidem improved self-reported sleep latency and duration of non-depressed, primary insomniacs; Zolpidem was somewhat more efficacious at the doses studied. © 1998 John Wiley & Sons, Ltd.
Ram P Kapil - One of the best experts on this subject based on the ideXlab platform.
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gender differences in pharmacokinetics and pharmacodynamics of Zolpidem following sublingual administration
The Journal of Clinical Pharmacology, 2014Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Frank Steinberg, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of Zolpidem after administration of a buffered Zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four-way crossover study. In male and female subjects Zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half-life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5-mg dose. For several PD variables, PD effects were significantly related to plasma Zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of Zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that Zolpidem clearance is lower in females than in males. PD effects of Zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.
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comparison of pharmacokinetic profiles of Zolpidem buffered sublingual tablet and Zolpidem oral immediate release tablet results from a single center single dose randomized open label crossover study in healthy adults
Clinical Therapeutics, 2013Co-Authors: David J Greenblatt, Jerold S Harmatz, Nikhilesh N Singh, Thomas Roth, M Moline, Stephen C Harris, Ram P KapilAbstract:Abstract Background A Zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. Objective The aim of this study was to compare the Zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral Zolpidem in healthy female and male adults. Methods This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral Zolpidem in healthy adults. Results The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean Zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both Zolpidem formulations were generally well tolerated by both genders. Conclusions Systemic exposure of Zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both Zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.
L Harrel - One of the best experts on this subject based on the ideXlab platform.
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comparative kinetics and dynamics of zaleplon Zolpidem and placebo
Clinical Pharmacology & Therapeutics, 1998Co-Authors: Jerold S Harmatz, Lisa L Von Moltke, Bruce L Ehrenberg, L HarrelAbstract:Purpose This study evaluated the relationship of dose, plasma concentration, and time to the pharmaco-dynamics of zaleplon and Zolpidem, 2 structurally distinct benzodiazepine receptor agonists. Method Ten healthy male volunteers received single oral doses of placebo, 10 mg zaleplon, 20 mg zaleplon, 10 mg Zolpidem, and 20 mg Zolpidem in a double-blind, 5-condition crossover study, with 48 hours elapsing between trials. Plasma drug concentrations and pharmacodynamic effects were measured during the 8 to 24 hours after administration. Results Kinetics of zaleplon and Zolpidem were not significantly related to dose. However, zaleplon had more rapid elimination (apparent elimination half-life [t½] of 1 hour) and higher apparent oral clearance (approximately 4300 mL/min) than Zolpidem (t½, 2.0 to 2.2 hours; apparent oral clearance, 340 to 380 mL/min). Active treatments produced pharmacodynamic effects consistent with benzodiazepine agonist activity: self- and observer-rated sedation, impairment of digit symbol substitution test (DSST) performance, impaired memory, and increased electroencephalographic activity in the beta frequency range. The overall order of agonist potency was as follows: placebo < 10 mg zaleplon < 20 mg zaleplon < 10 mg Zolpidem < 20 mg Zolpidem; on a number of measures, 20 mg zaleplon was comparable to 10 mg Zolpidem. Quantitative effects of Zolpidem 20 mg far exceeded those of other treatments. Dynamic effects of both drugs were significantly related to plasma concentration. Conclusions Benzodiazepine agonist effects of zaleplon and Zolpidem were dose and concentration dependent. At the usual clinically effective hypnotic dose (10 mg of either drug), agonist effects of Zolpidem exceeded those of zaleplon. Clinical Pharmacology & Therapeutics (1998) 64, 553–561; doi:
