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Selective serotonin reuptake inhibitors (SSRIs) may be associated with electrocardiographic effects. The electrocardiographic pharmacodynamics of dapoxetine, a short-acting SSRI being developed for the treatment of premature ejaculation, are compared with those of placebo and moxifloxacin (positive control) in 2 single-center, randomized, crossover studies in healthy men. In study 1, subjects receive 2 doses of dapoxetine 120 mg, given 3 hours apart; a single dose of moxifloxacin 400 mg; and 2 doses of placebo, given 3 hours apart. In study 2, subjects receive single doses of dapoxetine 60 mg, dapoxetine 120 mg, moxifloxacin 400 mg, and placebo. Moxifloxacin significantly increases QT and corrects QT intervals (QTc) compared with placebo in both studies (eg, Bazett-corrected QTc of 11.90 milliseconds [95% confidence interval, 2.68 to 21.11] and 5.06 [95% confidence interval, -2.26 to 12.38]). Dapoxetine 60,120, and 240 mg do not prolong the QT/QTc interval and have no clinically significant electrocardiographic effects. Dapoxetine and moxifloxacin pharmacokinetics are similar to previous reports. Adverse events are generally mild in severity; nausea is the most common. The results demonstrate that dapoxetine does not have electrocardiographic effects at doses of 60, 120, and 240 mg. [ABSTRACT FROM AUTHOR]

The effect of food on the pharmacokinetics of 15 mg oxybutynin XL was evaluated in a single dose, randomized, crossover, open label study in healthy volunteers. A validated, stereospecific, high performance liquid chromatography assay was used to simultaneously determine the plasma concentrations of R-and S-oxybutynin and active metabolite R-and S-desethyloxybutynin. The mean AUC and Cmax values for each of the four analytes in the fed treatment were within ±20% of the fasting treatment values. The 90% confidence intervals for the treatment ratios (fed/fasted) for log-transformed Cmax and AUCinf values for the drug isomers and AUCinf values for the metabolite isomers were all within the 80% to 125% range. Only the ranges for the Cmax values for R-and S-desethyloxybutynin were slightly wider but were well within the 70% to 143% criteria recommended for Cmax when comparing effect of food. Lack of effect of food on oxybutynin XL is consistent with the previous observation that the osmotically controlled formulations are nearly insensitive to the gastrointestinal environment, including food. Oxybutynin XL was well tolerated, and the safety results were comparable whether administered alone or with food. In conclusion, oxybutynin XL administration does not require any caution to be exercised regarding food. [ABSTRACT FROM PUBLISHER]

Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS®). Plasma concentrations of l-methylphenidate were 40-fold lower than those ofd-methylphenidate, whereas plasma concentrations ofd- -phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng•h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values forl-methylphenidate were only ˜1% of d-methylphenidate (0.43, 0.96, and 1.82 ng•h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d-andl-PPA were comparable. The dose-normalized d-andl-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d-and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS® (methylphenidate HCl) exhibits doseproportional and linear pharmacokinetics. [ABSTRACT FROM PUBLISHER]

The testosterone circadian rhythm has been reported extensively in the literature and has been described by a cosine function. Typically, these data are measured at frequent and regular (e.g., hourly) intervals. However, modeling circadian rhythm with data collected sparsely at irregular intervals and/or data that are not collected at the same time in all individuals has not been reported. The population nonlinear mixed-effects approach can handle such data and also allows covariates to be incorporated into the model. Frequent hourly testosterone concentration data available in the literature for young and elderly healthy volunteers were analyzed first. In the elderly, blunted or completely absent circadian rhythm has been reported, but a full circadian model was significantly better than a model containing one or no circadian component. Therefore, data from both the elderly and young were modeled together, and age was included as a categorical variable (young or elderly). Consistent with literature, the rhythm-adjusted mean testosterone concentrations was lower, and the deviation from the mean, especially to the maximum daily value, was less than half in the elderly (7%) compared to young subjects (16%). The testosterone concentration data measured infrequently and at varying intervals in young normal men and hypogonadal men were evaluated next. Although not measured at regular frequency in each individual, the data were obtained at different clock times for different subjects. Since for population mixed-effects analysis, data from all subjects are pooled, there was enough information to profile the 24-hour circadian cycle. In healthy young subjects, the mean Cnadir,Cpeak,Tnadir, and Tpeak values estimated from the model were 420 ng/dL, 577 ng/dL, 21:42 hours, and 0600 hours, respectively, and were similar to the parameters obtained for the frequently sampled young subjects. In hypogonadal men (testosterone concentrations < 300 ng/dL), the mean testosterone concentrations were much lower than the healthy young or elderly men, and a straight-line model was the best descriptor (i.e., no circadian rhythm was detected). It was also shown that with the application of a transdermal testosterone system, the mean testosterone concentrations in the treated men were within the 95% confidence interval for healthy young men. The results presented here suggest that the advantages of the analysis approach— namely, handling of covariates and handling of sparse, infrequently collected data—can be used in characterizing testosterone circadian rhythm or the lack of it. [ABSTRACT FROM PUBLISHER]

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS′ (methylphenidate HCI) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS′ (methylphenidate HCI) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd, and the immediate-release (IR) for mu la tion given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single and multiple-dose pharmacokinetics of the OROS′ formulation were studied. Following OROS® (methylphenidate HCl), there was a grad ual in crease in the mean methylpheni date plasma con cen tra tions with peakcon centrationsnoted at6 to 8 hours. With the SR formulation, peak plasma concentrations were notedat∼4 hours. Following the IR regimen, methylpheni date plasma con centra tionsfluctu atedin tan dem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of methyl pheni date was similar for the three formulations. The dose-normalized methylphenidate Cmaxfor OROS® (methylpheni date HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS® (methylpheni date HC) rela tive to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half-life were similar after single (32.9 ng•h/mL and 3.9 hours) and multiple doses (35.2 n•h/mL and 3.9 hours) of OROS (methylphenidate HCI). [ABSTRACT FROM PUBLISHER]

OROS ® (melatonin), an oral osmotic system for controlled drug delivery, was evaluated in an open-label, two-way crossover study to test the feasibility of continuous overnight melatonin delivery. Twelve healthy subjects with no sleep disorders, ranging from 60 to 73 years of age, were enrolled in the study. Two doses of melatonin (1 ´110 mg and 4´110 mg) were administered on two separate occasions. Endogenous baseline nighttime serum melatonin concentrations were measured the night before each treatment. Following treatment at 2100 hours, the lights were extinguished at 2200 hours and remained so, except during blood sample collection, which was performed under dim light (< 50 lux) at specified times. Serum samples were analyzed for melatonin by an LC/MS/MS method. In addition, safety measurements such as vitals and serum samples for endocrine functions were measured both prior to and after melatonin dosing. The serum melatonin concentration profile following OROS® (melatonin) dosing mimicked the normal endogenous serum melatonin concentration-time profile. The mean maximal melatonin concentration occurred at 3 a.m. The mean AUCs of endogenous melatonin before the two treatment days were 248 and 234 pg•h/mL, respectively. Serum concentrations of melatonin corrected for endogenous production increased proportionally with dose, with AUCs of 288 and 1069 pg•h/mL, respectively. Deconvolution of the serum concentration data showed good correlation between the in vitro amount released and the in vivo amount absorbed, suggesting continuous absorption throughout the gastrointestinal tract. Less than 5% residual content was observed in the recovered OROS® system. Minimal changes in serum hormone concentrations (luteinizing hormone, follicular stimulating hormone, and prolactin) and no serious adverse events were observed following OROS® treatment in these subjects. Delivery of melatonin with OROS® formulation may result in a physiologic nocturnal profile in elderly subjects. [ABSTRACT FROM PUBLISHER]

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS® oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan®). Thirteen healthy female volunteers received three 5 mg OROS® oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS® oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS® oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS® oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS®systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS® oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect). [ABSTRACT FROM PUBLISHER]

This open-label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E-TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E-TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 μA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 μA for 26 hours plus 4 additional doses at 1,200 μA over 2.5 minutes during hour 1 (group E); or 500 μA for 0.5 hours and 100 μA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1-3 ng/mL) were attained in treatments using the E-TRANS (fentanyl) system with basal current of 100 μA for 26 hours. There were no safety issues after treatment with E-TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E-TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant-current fentanyl delivery. [ABSTRACT FROM AUTHOR]

In this study of 13 hypogonadal men (25-69 years of age), three open-label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration-time curve from 0 to 27 hours (AUC0-27) values for testosterone after one-day applications to the upper buttocks, upper arm, and back were 9,560 ng · hr/dL, 8,651 ng · hr/dL, and 8,988 ng · hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days. [ABSTRACT FROM AUTHOR]

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate-release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled-release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration-time curve (AUC0-24) for the OROS and IR formulations were 1,265 and 1,393 ng·hr/mL, respectively. The drug-to-metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline-corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency. [ABSTRACT FROM AUTHOR]

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters. [ABSTRACT FROM AUTHOR]

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37°C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high-performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen-induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0-10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect. [ABSTRACT FROM AUTHOR]

In this study of the relationship between dose and plasma concentration of verapamil, controlled-release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5-day dosing segments. Blood samples were collected frequently to obtain first-dose and steady-state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R-and S-verapamil and R- and S-norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration-time curve (AUC) values for R- and S-verapamil at both the 120-mg and 180-mg doses were about 1.5 times higher than the corresponding first-dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120-mg and 180-mg doses. A dose-proportional relationship also was found between the 360-mg and 540-mg dose levels. However, nonlinearity was found between the 180-mg dose and higher doses, suggesting saturable metabolic pathways. The dose-proportional relationship between the 360-mg and 540-mg doses suggests that other first-order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose-proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first-order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates. [ABSTRACT FROM AUTHOR]

To evaluate the influence of food, time of dosing, and body position on the steady-state pharmacokinetics of an osmotically controlled formulation of verapamil (COER-verapamil), each of 29 healthy men received one tablet a day at specified times in an open-label, multiple-dose, four-period, crossover study. The verapamil tablets were administered in a randomized, balanced, crossover design: 240 mg at 8:00 AM on an empty stomach, subjects remaining ambulatory;240 mg at 8:00 AM on an empty stomach, subjects remaining supine for 8 hours; 240 mg at 10:00 PM with a standardized meal, subjects remaining supine for 8 hours; and 240 mg at 10:00 PM on an empty stomach, subjects remaining supine for 8 hours. Plasma verapamil concentrations were measured at steady state over the dosing interval. Steady-state plasma concentrations were achieved by the fourth administration of the drug. Neither food nor posture had any effect on the pharmacokinetics of verapamil or norverapamil, or on hemodynamic measurements. Time of dosing did affect the rate of appearance and elimination of verapamil, but had no effect on the extent of verapamil absorption, norverapamil appearance, or hemodynamic measurements. [ABSTRACT FROM AUTHOR]

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking. [ABSTRACT FROM AUTHOR]

This randomized, crossover study compared the nicotine and cotinine pharmacokinetic parameters and plasma concentration profiles of two different nicotine transdermal products: Nicoderm (Alza, Palo Alto, CA; and Marion Merrell Dow, Kansas City, MO) and Habitrol (Basel Pharmaceuticals, Summit, NJ). The two treatments were randomly assigned to each of 24 male smokers and worn for 24 hours each day for 5 days, with a 6-day washout between treatments. Plasma nicotine and cotinine concentrations were measured on day 1 and day 5 of each treatment. Mean delivered dose differed significantly between products, and the two products were not bioequivalent. The Nicoderm system provided higher mean plasma nicotine concentrations, particularly during the first 8 hours after system application. The mean steady state Cmax, AUC, and degree of fluctuation (DF) values were significantly greater for the Nicoderm system than for Habitrol. The mean nicotine tmax value for the Nicoderm system was significantly shorter (P < .001) than that for Habitrol (2.7 versus 8.6 hours). Steady state cotinine AUC values and plasma concentrations were significantly lower for Habitrol than for the Nicoderm system. The incidence of adverse events was similar for both products. [ABSTRACT FROM AUTHOR]

Drug disposition kinetics are commonly assumed to be time-invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 μg/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 μg/h for 0.33 hours every 4 hours; n = 12, 150 μg/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration-time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of cyclosporine (CSA) and four metabolites were evaluated in eight hemodialysis subjects awaiting renal transplantation to compare metabolic patterns with those observed in post-transplant patients and normal volunteers. Each subject received a single 4-mg/kg intravenous and a single 10-mg/kg oral dose separated by a 1-week washout period. Blood samples were collected before and at .5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, and 24 hours after CSA dosing. Cyclosporine blood, plasma, and metabolite (M17, M1, M18, M21) levels were determined by high-pressure liquid chromatography. Mean (±standard deviation) CSA blood clearance was .47 ± .15 L/hour/kg, steady-state volume of distribution (Vss) was 1.9 ± .5 L/kg, and mean residence time (MRT) was 4.4 ± 1.8 hours after intravenous dosing. With plasma, mean clearance was .70 ± .31 L/hour/kg, Vss was 2.4 ±1.2 L/kg, and MRT was 3.7 ± 2.2 hours. Cyclosporine bioavailability (F) averaged 24 ± 11 and 24 ± 15%, using blood and plasma, respectively. Values for clearance and Vss were approximately 30 to 100% greater than comparable estimates in healthy volunteers, but F and MRT were not altered to this extent. These changes might be explained on the basis of decreased protein binding in uremic patients. The area under the curve ratio for M17 and M1 to CSA increased an average of 1.7- and 3.9-fold, respectively, after oral dosing compared with intravenous administration, indicating increased conversion during first-pass metabolism. [ABSTRACT FROM AUTHOR]

An open-label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24-hour application periods. Mean steady-state nicotine and cotinine area under the curve (AUC0-24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half-life (t 1/2), relative degree of fluctuation (DF) in steady-state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well-defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System. [ABSTRACT FROM AUTHOR]

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half-life (t 1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady-state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady-state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t 1/2 did not change compared with single application. The mean ratios of cotinine-to-nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg−1) and intravenously (4 mg kg−1) without and with high fat meals. Both blood and plasma samples (separated at 37°C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr−1 Kg−1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg−1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr−1 Kg−1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis. [ABSTRACT FROM AUTHOR]