Biomedical subjects

K D Wilner

Publications and source records attributed to K D Wilner.

At least 19 recordsLinked to original sources

PubMed2000

Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteers.

AIMS: To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels. METHODS: Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day(-1), and using titrated regimens of 40-80 and 40-120 mg day(-1), for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated. RESULTS: Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day(-1) doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered first-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. CONCLUSIONS: Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action.

Adolescent↗

PubMed2000

Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers.

AIMS: To compare the pharmacokinetics of ziprasidone in healthy young (18-45 years) men and women, and healthy elderly (> or = 65 years) men and women. METHODS: Eight young men, 11 young women, 8 elderly men and 8 elderly women were given oral ziprasidone 40 mg day(-1), in two evenly divided daily doses, for 7 days, followed by a single 20 mg dose on day 8. Serum samples were collected immediately before the morning dose on days 1-8, for up to 12 h after dosing on day 1 and for up to 96 h after dosing on day 8. The resulting data were used to derive pharmacokinetic parameters of ziprasidone in each age and gender group. RESULTS: Steady-state serum concentrations of ziprasidone were achieved within 2-3 days. The steady-state pharmacokinetics of ziprasidone, determined 8 days after the initiation of treatment, were similar in the young men, elderly men and young women. Assessment of gender effects by analysis of variance revealed statistically significant differences in Cmax (85 vs. 69 ng ml(-1) and tmax (3.19 vs. 4.81 h) but no differences in AUC(0,12 h) or lambda(z). Assessment of age effects by analysis of variance revealed statistically significant differences in AUC(0,12 h) (560 vs. 465 ng ml(-1) h), Cmax (85 vs. 69 ng ml(-1) and lambda(z) (0.126 vs. 0.197 l h(-1) but no difference in tmax. Assessment of age and gender effects by analysis of covariance, with body weight as the covariate, did not reveal any significant differences. The mean t(1/2), z in the young men, young women, elderly men and elderly women were 3.1, 4.1, 5.7 and 5.3 h, respectively. Standard deviations of the means for the pharmacokinetic parameters for the elderly women tended to be large. CONCLUSIONS: The influence of age and gender on the pharmacokinetics of ziprasidone is not clinically significant.

Adolescent↗

PubMed2000

The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function.

AIMS: To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone. METHODS: Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled into an open-label, multicentre, multiple-dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine. RESULTS: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml(-1) h vs. 467 ng ml(-1) h, P = 0. 042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone lambda(z) in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P<0.001). There was no correlation between antipyrine lambda(z) and ziprasidone lambda(z) in the subjects with normal hepatic function or in those with hepatic impairment. CONCLUSIONS: The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.

Adolescent↗

PubMed2000

The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function.

AIMS: To assess whether renal impairment influences the pharmacokinetics of ziprasidone, and to determine whether ziprasidone is cleared via haemodialysis. METHODS: Thirty-nine subjects with varying degrees of renal impairment were enrolled into an open-label, multicentre, multiple-dose study and assigned to four groups according to their renal function: normal (group 1, creatinine clearance > 70 ml min(-1); mildly impaired (group 2, creatinine clearance 30-60 ml min(-1); moderately impaired (group 3, creatinine clearance 10-29 ml min(-1), and severely impaired (group 4, requiring haemodialysis three times-a-week). Subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 7 days and a single 20 mg dose on the morning of day 8. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 8 (haemodialysis day for subjects with severe renal impairment). Additional samples were collected from subjects with severe renal impairment on day 7 (nonhaemodialysis day). RESULTS: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0, 12 h), Cmax, tmax) of ziprasidone among subjects with normal renal function and those with mild, moderate and severe renal impairment. The AUC(0,12 h) and Cmax in subjects with mildly impaired renal function were statistically significantly greater than in those with moderately impaired renal function (P = 0.0163-0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml(-1) h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 47, 61, 41 and 50 ng ml(-1) and corresponding mean tmax values were 5, 6, 5 and 5 h. On day 8 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax, lambda(z), Fb) of ziprasidone among subjects with normal renal function and those with moderate or severe renal impairment. The AUC(0,12 h) in subjects with mild renal impairment was statistically significantly greater than those in the other three groups (P = 0.0025-0.0221), but this was not considered clinically significant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml(-1) h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 68, 93, 54 and 70 ng ml(-1), corresponding mean tmax values were 4, 5, 4 and 5 h and corresponding mean lambda(z) were 0.14, 0.11, 0.14 and 0.17 h(-1). The mean percentage Fb was 99.84-99.88% across all groups and the mean t(1/2),z ranged from 4.2 to 6.4 h. Comparison of the mean AUC(0,12 h) and Cmax values in subjects with severe renal impairment on day 7 with those on day 8 suggested that haemodialysis does not have a clinically significant effect on the pharmacokinetics of ziprasidone. CONCLUSIONS: The findings of this study indicate that mild-to-moderate impairment of renal function does not result in clinically significant alteration of ziprasidone pharmacokinetics and therefore does not necessitate dose adjustment.

Adolescent↗

PubMed2000

Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers.

AIMS: To determine whether ziprasidone alters the metabolizing activity of the 2D6 isoenzyme of cytochrome P450 (CYP2D6). METHODS: Twenty-four healthy young subjects aged 18-45 years were screened for CYP2D6 metabolizing activity and shown to be extensive metabolizers of dextromethorphan. These subjects were then randomized to receive a single dose of ziprasidone 80 mg, paroxetine 20 mg or placebo, 2 h before receiving a dose of dextromethorphan. Urine samples for the determination of dextromethorphan concentrations were collected over the 8 h period following dextromethorphan dosing, and used for the determination of dextromethorphan/dextrorphan ratios. Blood samples were collected immediately before and up to 10 h after the administration of ziprasidone or paroxetine, and used to derive pharmacokinetic parameters of ziprasidone and paroxetine. RESULTS: There were no statistically significant changes in the urinary dextromethorphan/dextrorphan ratio in the ziprasidone group or the placebo group. By contrast, there was a 10-fold increase in the urinary dextromethorphan/dextrorphan ratio in the paroxetine group and this differed significantly from those in the ziprasidone and placebo groups (P = 0.0001). CONCLUSIONS: The findings of this study suggest that ziprasidone does not inhibit the clearance of drugs metabolized by CYP2D6.

Adolescent↗

PubMed2000

The pharmacokinetics of ziprasidone in healthy volunteers treated with cimetidine or antacid.

AIMS: To evaluate the effects of cimetidine and Maalox(R) (aluminium hydroxide 1.35 g and magnesium hydroxide 1.2 g) on the pharmacokinetics of ziprasidone. METHODS: Eleven healthy young subjects aged 18-45 years were given single oral doses of ziprasidone 40 mg on three occasions at least 7 days apart. On one occasion ziprasidone was administered alone, on another occasion ziprasidone was co-administered with oral cimetidine 800 mg and on a third occasion ziprasidone was co-administered with oral Maalox(R). RESULTS: The administration of cimetidine increased the ziprasidone AUC(0,infinity) by 6% but there were no statistically significant differences in Cmax, tmax or lambda(z) between the ziprasidone+cimetidine group and the ziprasidone group. The administration of Maalox did not produce any statistically significant differences in AUC(0,infinity), Cmax, tmax or lambda(z) between the ziprasidone+Maalox group and the ziprasidone group. CONCLUSIONS: The pharmacokinetics of ziprasidone are not affected by concurrent administration of cimetidine or Maalox. This suggests that other nonspecific inhibitors of cytochrome P450 and antacids are unlikely to alter the pharmacokinetics of ziprasidone.

Adult↗

PubMed2000

The effects of ziprasidone on steady-state lithium levels and renal clearance of lithium.

AIMS: To assess the potential of ziprasidone to alter the renal clearance and steady-state serum levels of lithium. METHODS: Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day(-1), given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day(-1), given as two divided daily doses, on days 9-11 followed by 80 mg day(-1), given as two divided daily doses on days 12-15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium. RESULTS: Ziprasidone administration was associated with a 0.07 mmol l(-1) (13%) mean increase in steady-state serum lithium levels compared with a mean increase of 0.06 mmol l(-1) (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h(-1) (5%) in the ziprasidone group and by 0.14 l h(-1) (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant. CONCLUSIONS: Ziprasidone does not alter steady-state serum lithium concentrations or renal clearance of lithium.

Adult↗

PubMed1999

A double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of CP-101,606 in patients with a mild or moderate traumatic brain injury.

CP-101,606 is a postsynaptic antagonist of the glutamate-mediated NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. When administered intravenously (i.v.) at the time of injury, CP-101,606 is neuroprotective in animal models of traumatic brain injury (TBI) and ischemia. Minimal adverse effects have been observed in normal human volunteers given i.v. doses of up to 3 mg/kg/hr for 72 hours. The objective of the present clinical trial was to assess the safety, pharmacokinetics, and tolerability of CP-101,606 infused for various times in patients who had suffered either an acute moderate or mild TBI (Glasgow Coma Score 9-14) or hemorrhagic stroke. Patients began receiving treatment within 12 hours of brain injury. A total of 53 subjects (45 with TBI and 8 with stroke) were randomized in a double-blind fashion to receive CP-101,606 or placebo (4 drug: 1 placebo). Drug/placebo was administered by i.v. infusion (0.75 mg/kg/hr) for 2 hours and then stopped (n = 25) or continued for 22 hours (n = 4) or 70 hours (n = 24) at a rate of 0.37 mg/kg/hr. Mean plasma drug concentrations were well above the predicted therapeutic concentration of 200 ng/ml within two hours of initiating treatment and were sustained as long as drug was infused. All the patients tolerated their drug/placebo treatment, and there were no clinically significant cardiovascular or hematological abnormalities in either group. A Neurobehavioral Rating Scale, used to detect personality changes and behavioral disturbances, indicated that all subjects showed an improvement from their postinjury, predosing baseline but did not significantly differ from each other with respect to type of head injury and/or treatment with drug or placebo. Modified Kurtzke Scoring also showed a similar pattern of improvement irrespective of type of head injury or drug/placebo treatment. This study suggests that CP-101,606, infused for up to 72 hours has no psychotropic effects and is well-tolerated in patients who have sustained a mild or moderate TBI or hemorrhagic stroke.

Adolescent↗

PubMed1999

An open-label study of CP-101,606 in subjects with a severe traumatic head injury or spontaneous intracerebral hemorrhage.

CP-101,606 is a postsynaptic antagonist of N-methyl-D-aspartate (NMDA) receptors bearing the NR2B subunit. When administered intravenously (i.v.), it decreases the effects of traumatic brain injury (TBI) and focal ischemia in animal models. Therapeutic plasma concentrations (200 ng/ml) in animals, have been well tolerated in healthy human volunteers. The purpose of the present dose escalation study was to assess the safety, tolerability, and pharmacokinetics of CP-101,606 in subjects who had suffered either an acute severe TBI (Glasgow Coma Scale 3-8) or spontaneous intracerebral hemorrhage. Thirty patients, 20 with a TBI and 10 with a stroke, were enrolled in the trial and began receiving an i.v. infusion of CP-101,606 for 2 hours, 24 hours, or 72 hours within 12 hours of brain injury. For the first two hours, the drug was given a rate of 0.75 mg/kg/hr and then stopped (n = 17) or continued for 22 (n = 2) or 70 hours (n = 11) at 0.37 mg/kg/hr. Plasma and cerebrospinal fluid (CSF) were collected at serial times during and after treatment. There were no consistent changes in blood pressure or pulse nor any clinically significant hematological or electrocardiogram (ECG) abnormalities attributable to CP-101,606. No adverse events or behavioral changes were considered to be related to the drug. Plasma concentrations of CP-101,606 over 200 ng/ml were rapidly achieved in the blood and CSF within two hours and were sustained there as long as the drug was infused. CSF concentrations were slightly higher than that in plasma by the end of infusion suggesting good penetration of CP-101,606 into the CSF. Outcome in the severe TBI patients, as measured by the Glasgow Outcome Score at six months, suggested that a two-hour infusion yielded a range of scores similar to contemporary patients with a severe TBI treated at our hospital while the outcomes of the patients treated with either a 24- or 72-hour infusion were better on average. Thus, these results indicate that CP-101,606 infused for up to 72 hours is well tolerated, penetrates the CSF and brain, and may improve outcome in the brain-injured patient.

Adolescent↗

PubMed1998

Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP-105,696 in man following single oral administration.

AIMS: CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP-105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg. METHODS: Forty-eight subjects participated in a randomized, double-blind, parallel group study. Plasma and urine concentrations of CP-105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP-105,696, the inhibiton of LTB4-induced upregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration using an ex vivo whole blood flow cytometry assay. RESULTS: Cmax and AUC(0, infinity) increased in a dose-related manner. Respective mean Cmax values were 0.54 to 30.41 microg ml(-1) following doses of 5 to 640 mg. Respective mean AUC(0, infinity) values were 1337 to 16819 microg ml(-1) h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half-lives ranging from 289 to 495 h. Group mean terminal elimination half-lives were dose-independent. Urinary excretion of unchanged drug accounted for < 1% of the administered dose. A linear relationship was observed between CP-105,696 plasma concentrations and inhibition of LTB4-mediated CD11b upregulation on human neutrophils in whole blood. CP-105,696 plasma concentrations of 5-6 microg ml(-1) were necessary to elicit a two-fold shift to the right of the LTB4 concentration response curve for CD11b upregulation. CONCLUSIONS: These studies demonstrate pharmacologically significant LTB4-receptor antagonism following a single dose of CP-105,696 and pharmacokinetics consistent with once-daily dosing.

Administration, Oral↗

PubMed1998

An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder.

Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind, exploratory, dose-ranging trial. After a single-blind washout period of 4 to 7 days, patients were randomly assigned to receive one of four fixed doses of the new antipsychotic, ziprasidone 4 (N = 19), 10 (N = 17), 40 (N = 17), or 160 (N = 20) mg/day or haloperidol 15 mg/day (N = 17) for 4 weeks. A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity (CGI-S) score (p = 0.002) but not in Brief Psychiatric Rating Scale (BPRS) total score (p = 0.08). The intent-to-treat analysis of mean changes from baseline in the BPRS total, BPRS Psychosis core, and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day. Despite the small sample size and short duration of the trial, the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day (p = 0.001 andp = 0.005, respectively). The percentage of patients classified as responders on both the BPRS total (> or = 30% improvement) and CGI-Improvement (score of 1 or 2) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group. On all assessments of clinical efficacy, the improvements associated with ziprasidone 4 mg/day, 10 mg/day, and 40 mg/day were similar. Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day (15%) than with haloperidol (53%). Haloperidol was associated with a sustained hyperprolactinemia, unlike ziprasidone, where only transient elevations in prolactin that returned to normal within the dosing interval were observed. Ziprasidone was well tolerated, and the incidence of adverse events was similar in all groups. The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms.

Adult↗

PubMed1997

Pharmacokinetics of sertraline and its N-demethyl metabolite in elderly and young male and female volunteers.

A nonblinded study was conducted to compare the pharmacokinetic properties of the selective serotonin reuptake inhibitor sertraline in 22 young (aged 18 to 45 years) and 22 elderly (> 65 years) volunteers, of whom half were male and half were female. In this study, sertraline was administered at a dosage of 200mg once daily (the maximum recommended daily dosage) for 21 days after upward dosage titration from 50 mg/day over a 9-day period. Thus, this study was designed to measure the effect of age and gender on the pharmacokinetic properties of sertraline at the maximum dosage recommended for clinical use. The terminal elimination half-life (t1/2 beta ) of sertraline was similar in young females, elderly males and elderly females (mean t1/2 beta ranged from 32.1 to 36.7 hours in these groups) but shorter (22.4 hours) in the young males. The mean maximum plasma sertraline concentration (Cmax) and the mean steady-state area under the plasma concentration-time curve from time zero to 24 hours postdose (AUC24) were also similar between the young females, elderly males and elderly females, but were approximately 25% lower in the young males. The time to Cmax was unaffected by age or gender and ranged from 6.4 to 6.9 hours. N-Demethylsertraline is the principal metabolite of sertraline and does not contribute significantly to its serotonergic actions. The mean values for N-demethylsertraline trough plasma concentrations, AUC24 and Cmax were comparable in elderly males and females and young females but lower in young males. The ratios of mean AUC24 and Cmax for N-demethylsertraline to the AUC24 and Cmax for sertraline were similar between the 4 groups.

1-Naphthylamine↗

PubMed1997

A study of the potential effect of sertraline on the pharmacokinetics and protein binding of tolbutamide.

The effect of the selective serotonin reuptake inhibitor (SSRI) sertraline 200 mg/day on the metabolism of intravenously administered tolbutamide was examined in a randomised nonblinded parallel-group study in 25 healthy male volunteers. There was a small but statistically significant decrease (16%) in the clearance of tolbutamide in patients receiving the maximum recommended dosage of sertraline. The terminal elimination rate constant was also significantly reduced, corresponding to the increase in the terminal elimination half-life (from 6.9 to 8.6 hours). The decrease in clearance was not associated with any significant changes in plasma protein binding or in the apparent volume of distribution of tolbutamide. This suggests that the change in tolbutamide clearance may be due to a slight inhibition of the cytochrome P450 (CYP) isoenzyme CYP2C9/10 when sertraline was administered in its maximum recommended dosage. However, the small changes in the volume of distribution and plasma binding of tolbutamide after sertraline treatment indicate that there is a minimal interaction between sertraline and tolbutamide.

1-Naphthylamine↗

PubMed1997

Effect of sertraline on protein binding of warfarin.

The effect of sertraline on the plasma protein binding of warfarin was investigated in a nonblinded randomised placebo-controlled parallel trial in 12 healthy male volunteers. The study participants received single doses of warfarin before administration of sertraline or placebo and again after sertraline or placebo had been administered for 22 days. Treatment with sertraline for 26 days increased the area under the mean prothrombin time vs time curve by 145 sec *h (7.9%), compared with a decrease of 17 sec *h (-1.0%) in the placebo group. Although statistically significant (p = 0.02), this difference was not felt to be clinically meaningful. There appeared to be a slight delay in the normalisation of the prothrombin time in the sertraline-treated group after the second dose of warfarin, which also would not be expected to be clinically significant. After 22 days, a statistically significant (p = 0.02) increase in unbound warfarin was observed in the sertraline group compared with the placebo-treated individuals. Neither the change in prothrombin time nor the change in plasma protein binding were considered to have any clinical relevance; however, good clinical practice dictates that prothrombin time should be monitored in patients treated concurrently with warfarin and sertraline to ensure that the integrity of coagulation response is maintained. The metabolism of warfarin is principally mediated by the cytochrome P450 (CYP) isoenzyme CYP2C9/10. Thus, sertraline appears to have a minimal effect on the CYP2C9/10 isoenzyme.

1-Naphthylamine↗

PubMed1997

Effect of sertraline on the pharmacokinetics and protein binding of diazepam in healthy volunteers.

A double-blind randomised placebo-controlled study was conducted in healthy male volunteers to determine the effects of sertraline on the pharmacokinetics of diazepam and its primary metabolite, N-demethyldiazepam. The effect of sertraline on the plasma protein binding of diazepam was also studied. Sertraline 50 mg/day titrated over a 10-day period to 200 mg/day or placebo was administered for 32 days. A single intravenous dose of diazepam 10 mg was given before the start, and after 21 days of sertraline or placebo treatment. The pharmacokinetic analyses were based on data from 20 individuals. The systemic clearance of diazepam decreased by 32% (-0.100 ml/min/kg) in the sertraline group compared with a 19% decrease (-0.054 ml/min/kg) in the placebo group (p = 0.0266). However, this small difference (13%) between the 2 groups was not considered meaningful. Other than a prolonged time to maximum plasma concentration for N-demethyldiazepam, no other pharmacokinetic parameters were significantly altered by sertraline. The plasma protein binding of diazepam was unchanged by concomitant administration of sertraline. These results suggest that sertraline at the maximum recommended dosage under steady-state conditions, and demethylsertraline, the principal metabolite of sertraline, are unlikely to exert significant inhibitory effects on the CYP2C19 and CYP3A3/4 hepatic isoenzymes responsible for the metabolism of diazepam. Therefore, it would be expected that sertraline would, similarly, have a minimal effect on the pharmacokinetic profile of other drugs metabolised by these hepatic isoenzymes.

1-Naphthylamine↗

PubMed1997

Sertraline. Chronopharmacokinetics and the effect of coadministration with food.

Two nonblinded single-dose randomised 3-way crossover studies were conducted in healthy male volunteers to determine the effect of the time of administration (morning vs evening) and the effect of food on the pharmacokinetics of sertraline tablets. There were no significant treatment effects on the mean area under the plasma concentration-time curve (AUC), mean peak plasma sertraline concentration (Cmax), mean time to reach Cmax (tmax), mean terminal elimination half-life, or the mean elimination rate constant in either study. The results of these 2 studies show that the bioavailability and elimination of sertraline tablets are not influenced by the time of administration or administration with or without food. Thus, sertraline tablets offer the flexibility of morning or evening administration, to patients in the fasting or nonfasting state.

1-Naphthylamine↗

PubMed1996

Sertraline does not alter the beta-adrenergic blocking activity of atenolol in healthy male volunteers.

UNLABELLED: A double-blind, placebo-controlled, randomized, crossover study was conducted to determine the effect of sertraline on the beta-adrenergic blocking activity of atenolol in 10 healthy male volunteers. METHOD: To assess the existence of any possible pharmacodynamic interaction between sertraline and atenolol, the effect of sertraline and placebo on the dose of intravenous isoproterenol required to increase heart rate by 25 beats per minute (bpm; chronotropic dose25 [CD25]) and the change in heart rate during exercise in atenolol-treated subjects were determined. RESULTS: The mean CD25 of isoproterenol was 2.00 micrograms after administration of placebo plus atenolol 50 mg and 2.03 micrograms after administration of sertralnie 100 micrograms plus atenolol 50 mg. The mean heart rate during exercise testing decreased by 29 bpm after sertraline plus atenolol administration and by 31 bpm after placebo plus atenolol administration. Analysis of variance indicated no statistically significant treatment or sequence effects. Only 1 subject experienced an adverse event--a mild headache after administration of sertraline plus atenolol. No clinically significant electrocardiograph changes were observed after sertraline or placebo administration. CONCLUSION: The results of this study demonstrate that sertraline does not alter the beta-blocking activity of atenolol.

1-Naphthylamine↗

PubMed1995

Single and multiple dose pharmacokinetics of tenidap sodium in healthy subjects.

1. The absorption, protein binding, clearance and absolute bioavailability of tenidap sodium were studied after single and multiple dosing. 2. Thirteen healthy male volunteers received a single 120 mg oral dose of tenidap sodium and a 20 mg intravenous infusion of deuterated tenidap ([D3]-tenidap) on day 1. This was followed by a 6-day washout period (days 2-7) and then further daily doses of oral tenidap sodium 120 mg for 21 consecutive days (days 8-28) with an additional 20 mg intravenous infusion of [D3]-tenidap on day 28. Twelve subjects were eligible for pharmacokinetic evaluation. 3. Following multiple oral doses, the half-life of tenidap is approximately 23 h. 4. Following single and multiple dose administration, the absolute bioavailability is 85%. 5. Systemic clearance of [D3]-tenidap was 29% greater on day 28 than on day 1 indicating a significant increase in intrinsic clearance (CLint) of tenidap since protein binding of tenidap in plasma did not change during the study. Consistent with the increase in systemic clearance, the half-life of [D3]-tenidap decreased and the ratio of AUC(0,24h) day 28/AUC day 1 following oral dosing was less than one. Tenidap is subject to extensive hepatic metabolism, so the increase in CLint may indicate that tenidap induces its own metabolism. 6. Steady-state was achieved by the eleventh day of dosing. Since numerous studies in patients with rheumatoid arthritis have shown that multiple dosing with tenidap is clinically efficacious, this suggests that the pharmacokinetic differences observed between the first and twenty-first day of multiple tenidap dosing do not influence the clinical response.

Adult↗