Steven M. Troy

Comparison of the effects of zaleplon, zolpidem, and triazolam on memory, learning, and psychomotor performance

Twenty-four healthy male and female subjects, who participated in this randomized, double-blind, crossover study, received single nighttime doses of zaleplon 10 mg (therapeutic dose), zaleplon 20 mg, zolpidem 10 mg (therapeutic dose), zolpidem 20 mg, triazolam 0.25 mg (positive control), and placebo. Subjective behavioral ratings and psychomotor tests were completed before and 1.25 and 8.25 hours after administration of the study drug. The Immediate and Delayed Word Recall tests and the Digit Span Test were used to assess memory. The Digit-Symbol Substitution Test, Paired Associates Learning Test, and Divided Attention Test were used to assess other cognitive skills. Zaleplon 10 mg did not produce any significant changes in memory or learning compared with placebo. All other active treatments, including zolpidem 10 mg, caused psychomotor impairment at the 1.25-hour test battery. Zolpidem 20 mg (twice the therapeutic dose) produced more psychomotor impairment at the 1.25-hour assessment than did any of the other active treatments, including zaleplon 20 mg. At the 8.25-hour time point, test scores for subjects who received zaleplon 10 mg and 20 mg did not differ from the test scores for those who received placebo. However, cognitive impairment persisted up to the 8.25-hour observation for subjects who were administered triazolam 0.25 mg and zolpidem 20 mg. Adverse events associated with the use of zaleplon were transient and mild-to-moderate in severity. Overall, this study shows that zaleplon is a safe hypnotic that does not affect memory, learning, or psychomotor skills associated with vigilance.

Multiple‐Dose, Linear, Dose‐Proportional Pharmacokinetics of Retigabine in Healthy Volunteers

Retigabine, a first‐in‐class selective M‐current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo‐controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half‐life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabines pharmacokinetics was linearly dose proportional. Steady‐state pharmacokinetics was in agreement with single‐dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21‐360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed‐dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.

Zaleplon pharmacokinetics and absolute bioavailability

The pharmacokinetics and absolute oral bioavailability of zaleplon were assessed to evaluate the extent of presystemic metabolism of this new nonbenzodiazepine hypnotic agent. A partially randomized, single-dose, four-period crossover study was conducted in 23 healthy subjects. Subjects received 1 and 2.5 mg intravenous (i.v.) infusions of zaleplon during the first and second periods, respectively, and then were randomly assigned to receive a 5 mg oral dose or 5 mg i.v. infusion of zaleplon in a crossover design during the final two periods. Zaleplon pharmacokinetics were determined in 20 subjects (ten men and ten women) after the two 5 mg treatments. The oral and i.v. doses of zaleplon administered in this study were safe and well-tolerated. Following i.v. administration, zaleplon had a moderate to high systemic clearance (mean +/- S.D., 0.94 +/- 0.20 L/h/kg), rapid elimination (half-life, t1/2 = 1.05 +/- 0.13 h), and a steady-state volume of distribution of 1.27 +/- 0.25 L/kg, indicating substantial distribution into extravascular tissues. Zaleplon was rapidly absorbed after oral administration, and the mean apparent elimination t1/2 was similar to that obtained after i.v. infusion. The absolute bioavailability was 30.6 +/- 10.2%.

The Pharmacokinetics of Venlafaxine When Given in a Twice-Daily Regimen

The comparative bioavailability of the novel antidepressant venlafaxine and its pharmacologically active metabolite O‐desmethylvenlafaxine was assessed when venlafaxine was given orally twice daily (75 mg bid) or 3 times daily (50 mg tid). Eighteen healthy subjects participated in an open‐label, randomized, two‐period, crossover study lasting 12 days. Each subject was randomly assigned to take venlafaxine according to a bid or a tid regimen through day 8 and was crossed over to the other regimen on days 9 to 12. The daily dose was titrated up to 150 mg/d and was held constant on days 5 to 12. Plasma samples for quantitation of venlafaxine and O‐desmethylvenlafaxine were obtained during a 24‐hour steady‐state interval on days 8 and 12. Analysis of variance showed no significant differences between the two venlafaxine regimens for peak concentration (Cmax), area under the curve during 24 hours (AUC0–24), trough concentration, or fluctuation ratio for venlafaxine or O‐desmethylvenlafaxine in plasma. The bioequivalence ratios for Cmax and AUC0–24 of both compounds were calculated to compare the bid regimen and the tid regimen. The mean value for each of the 4 ratios was between 96 and 100%, and the 90% confidence limits around each ratio were within 90 to 110%. These results indicate that dividing a daily 150‐mg venlafaxine dose into 2 or 3 doses provides equivalent total exposure and peak plasma concentrations of venlafaxine and O‐desmethylvenlafaxine, its active metabolite. Therefore, based on pharmacokinetic considerations, it appears that the same daily dose of venlafaxine can be given in either two or three divided doses without compromising efficacy.

Effects of age and sex on single-dose pharmacokinetics of tigecycline in healthy subjects.

ABSTRACT The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.

Effects of age and sex on the disposition of retigabine

The novel antiepileptic drug retigabine is the first selective M‐current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N‐glucuronidation, acetylation) exclusively and renal excretion.

Pharmacokinetic and Pharmacodynamic Evaluation of the Potential Drug Interaction Between Venlafaxine and Ethanol

Venlafaxine is a new antidepressant with a unique mode of action. Because many patients taking antidepressant therapy may self‐medicate with ethanol, this study was undertaken to assess the possible pharmacokinetic and pharmacodynamic interactions between venlafaxine and ethanol. This randomized, double‐blind, placebo‐controlled, two‐period crossover study was conducted with 16 healthy men. Multiple doses of venlafaxine (50 mg every 8 hours) or placebo were administered for 7 days. On days 5 and 7 a single dose of 0.5 g/kg of ethanol or a placebo solution was administered in a randomized fashion. Pharmacokinetic data indicated that ethanol administration did not affect the disposition of venlafaxine or O‐desmethylvenlafaxine. Similarly, venlafaxine administration did not affect the pharmacokinetic disposition of ethanol. Ethanol produced its expected effects on the eight psychometric tests administered. Venlafaxine produced small effects on the results of the Digit Symbol Substitution Test, the Divided Attention Reaction Time, and the Profile of Mood States. No pharmacodynamic interaction was detected between venlafaxine and ethanol.

Absolute Bioavailability and Electroencephalographic Effects of Conventional and Extended‐Release Formulations of Venlafaxine in Healthy Subjects

Venlafaxine is currently marketed for treatment of depressive disorders as a conventional tablet formulation with a twice or three times daily dosage regimen. The absolute bioavailability of the conventional (CF) and extended‐release (XR) formulations and their effects on electroencephalograms (EEG) and on a visual analog scale (VAS) for nausea were assessed in a randomized, double‐blind, four‐way crossover, placebo‐controlled study of 16 healthy young men who were given either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or an intravenous dose of 10 mg of venlafaxine, or a placebo at 1‐week intervals. The absolute bioavailability of venlafaxine was between 40% and 45% and was similar for both the CF and XR formulations. Venlafaxine produced central effects of a desipramine‐like antidepressant. Regardless of formulation tested, the main EEG changes were an increase in fast beta (20–30 Hz) energy, which was more pronounced over the frontotemporal regions and extended within the full beta range (16–40 Hz). Maximum effect was reached at 6 hours for the CF and reached a plateau from 10 to 24 hours for the XR formulation. A dose‐proportional increase in central activity, expressed as area under the effect curve (AUE) of the beta band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared with the CF tablet, the XR formulation also produced a much less intense maximum effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR formulation has the same absolute bioavailability and the same central activity as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The present findings suggest that a once‐daily dosage regimen should be sufficient. This was confirmed by several clinical trials in depressive patients.

Pharmacokinetics and Effect of Food on The Bioavailability of Orally Administered Venlafaxine

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two‐period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model‐dependent calculation of the first‐order absorption rate constant, and a model‐independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration—time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O‐demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50‐mg tablet. A standard, medium‐fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation. J Clin Pharmacol 1997;37:954–961.

Population Pharmacokinetics of Intravenous Amiodarone and Comparison with Two‐Stage Pharmacokinetic Analysis

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration—time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed‐effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight‐corrected) also were calculated using two‐stage analysis and were compared with the results obtained from the mixed‐effects analysis. The population plasma concentration—time profile of amiodarone was best described by a four‐compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two‐stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (≥65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half‐life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two‐stage analysis.