Multiple-Dose Pharmacokinetics of Clozapine in Patients

After a 2-day buildup, patients were dosed continuously with clozapine solution at three ascending dose levels (37.5, 75, and 150 mg bid for 7 days at each dose level). Following the morning administration on the twenty-third day of dosing a drug holiday was instituted which lasted for a minimum of 48 hr. Serial plasma samples were obtained during each of the periods and during the drug holiday for the calculation of the steady-state parameters AUC^SS, C^SS _max, and C^SS _min at each dose level as well as for the assessment of the terminal elimination rate. Mean parameter values for AUG^SS, C^SS _max, and C^SS _min showed a linearly increasing response with the dose, well described by a straight line passing through the origin. The terminal elimination appeared to follow linear kinetics and had a mean half-life of 15.8 hr (range, 5.8–33 hr).     

Pharmacokinetics and tolerability of cinitapride in healthy Chinese volunteers: a randomized,open-label,single- and multiple-dose study

1. Cinitapride (CIN) is a drug for functional dyspepsia. The purpose of the study was to investigate the pharmacokinetics and tolerability of CIN in healthy Chinese volunteers.

2. A randomized, open-label, single- and multiple-dose study was conducted in 12 healthy volunteers. Three different doses of CIN (1, 2, 4 tablets) were given to six groups in the single-dose study, and one tablet (1?mg) of CIN was administered three times a day in the multiple-dose study. Blood samples were collected at predetermined time intervals after CIN dosing and analyzed by LC-MS/MS.

3. Eleven volunteers completed the study. After single dose, the C_max and AUC of plasma increased approximately linearly with dosage; no statistically significant differences were found in pharmacokinetic parameters between three dose groups. After multiple doses, there was no significant change in T_max and t_1/2 compared with the results from the single dose. After repeated doses, AUC_0-t and AUC_0-∞ were increased, while CLz/F slightly decreased. And no differences between male and female.

4. The pharmacokinetic parameters of this study were consistent with study results of non-Chinese subjects. Good tolerability was demonstrated in both single- and multiple-dose studies with dosage range from 1 to 4?mg in healthy Chinese subjects.

     

氯氮平在18例精神分裂症患者中的血药浓度及其疗效

系统检测18例服氯氮平的精神分裂症患者血浆药物浓度。结果表明,血药浓度和服药剂量呈正相关;而不同患者血药浓度的个体差异很大。血药浓度和临床疗效以及脑、心电图异常改变均无明显联系。初步讨论了血药浓度检测的临床意义,认为对于某些疗效较差或药物副反应较重的患者,血药浓度测定具有临床参考价值。     

注射用硫酸阿司米星多剂量给药在健康人体的药代动力学

目的 研究注射用硫酸阿司米星(氨基糖苷类抗生素)多剂量给药在健康人体的药代动力学.方法 10名受试者恒速静脉滴注硫酸阿司米星200 mg,30 min,每日2次,间隔12 h,连续7 d.在第1 d和第7 d分别在不同时间取静脉血,收集尿样,给药第4～6 d采取谷浓度.用柱前衍生化-荧光HPLC法测定血药、尿药浓度.结...     

Pharmacokinetics of a Mouse/Human Chimeric Monoclonal Antibody (C-17-1 A) in Metastatic Adenocarcinoma Patients

The pharmacokinetic characteristics of a mouse/human chimeric monoclonal antibody (C-17-1A) were determined in 10 patients with metastatic adenocarcinoma following the administration of either 10-mg or 40-mg infusions as a single or multiple dose. The administration of single 10-mg (n = 5) and 40-mg (n = 5) doses infused over 1 hr resulted in mean apparent steady-state distribution volumes of 4.13 ± 0.97 and 5.16 ± 1.92 liters, respectively, indicating that C-17-1A appears to distribute throughout the vascular compartment and into limited extracellular fluid volume. The disposition of C-17-1A was adequately characterized using a two-compartment open model with mean distribution half-lives of 15.8 and 18.5 hr and mean elimination half-lives of 90.0 and 97.6 hr for the 10- and 40-mg groups, respectively. A linear relationship was observed between AUC and dose (µLg/kg). The clearance of C-17-1A was correlated linearly with total Ig, IgG, and tumor size. Multiple administration of either 10-mg (n = 3) or 40-mg (n = 3) doses of C-17-1A infused over 1 hr every 14 days for a total of three doses resulted in superimposable mean serum concentration versus time data and consistent mean pharmacokinetic characteristics. These data indicate that C-17-1A exhibits linear, nonsaturable distribution and elimination characteristics in man over the dose range studied (i.e., 130 to 880 µg/kg). The multiple-dose pharmacokinetics of C-17-1A were predictable, indicating a lack of an antibody response to C-17-1A over a period of 42 days. The clearance of C-17-1A exhibited large interindividual variability with significant correlations to circulating IgG levels and tumor size.     

国产甲磺酸帕珠沙星注射液健康志愿者多剂连续给药药动学研究

目的:研究国产甲磺酸帕珠沙星注射液多次连续给药在健康人体内的药动学特点.方法:12例健康志愿者静滴甲磺酸帕珠沙星注射液500 mg,bid,连续5 d,并采用反相高效液相色谱法测定血药浓度数据,用DAS软件计算主要药动学参数.结果:静滴甲磺酸帕珠沙星药动学特点符合开放二室模型,第1次单次给药和最后1次给药的主要药动学参数如下:平均峰浓度分别为(10.86±2.04)和(11.72±1.82)mg·L-1,平均稳态药一时曲线下面积AUC0～∞分别为(18.29±2.36)和(19.22±2.80)mg·h·L-1,t1/2β分别为(1.64±0.27)和(1.82±0.34)h.结论:连续给药帕珠沙星5 d,受试者耐受良好,药动学过程符合二室模型,多次给药体内无蓄积.     

Pharmacokinetics of paroxetine in patients with cirrhosis

Summary In a 14-day multiple-dose study the pharmacokinetics of paroxetine was investigated in 12 patients with alcoholic cirrhosis and in 6 subjects without liver disease. The dose of 20–30 mg paroxetine daily was adjusted to the reduction in liver function, as assessed by the galactose elimination capacity. Accordingly, all but two of the cirrhotic patients received 20 mg, while all six control subjects received 30 mg.Dose-corrected, trough drug concentration at steady state (C^SS _min) and dose-corrected AUC_24h were significantly higher in the patients with liver diseases than in the control subjects [3.4 vs 1.5 ng · ml^–1 per mg paroxetine and 89 vs 43 h (ng) · ml^–1 per mg paroxetine]. The elimination t_1/2 was prolonged [83 vs 36 h], but the difference was not statistically significant, and the cirrhotic patients were still able to clear almost all the paroxetine by metabolism. All but two patients with cirrhosis experienced nausea during the first two or three days after the first dose, while none of the controls had this symptom.The study showed slower elimination of paroxetine and consequently higher plasma levels in patients with cirrhosis, suggesting that in the latter the dose of paroxetine should be in the lower end of the therapeutic range.     

Population Pharmacokinetics of an Extended-Release Formulation of Exenatide Following Single- and Multiple-Dose Administration

Exenatide is a glucagon-like peptide-1 receptor agonist with both immediate- and extended-release (ER) formulations that are approved for the treatment of type 2 diabetes mellitus. Long-term exposure from the ER formulation is achieved through slow peptide release from a degradable microsphere formulation. The goal of this analysis was to develop a pharmacokinetic model for the ER formulation following single and once-weekly multiple-dose administration. Pharmacokinetic data were collected from two clinical trials—one that evaluated single-dose administration of 2.5, 5, 7, and 10 mg of ER exenatide and a second that included weekly administration of 0.8 and 2 mg for 15 weeks. A population pharmacokinetic model, describing 1586 exenatide concentrations from 64 patients, was developed in the nonlinear mixed-effects modeling software program NONMEM. Pharmacokinetics of the ER formulation was described by a two-compartment model with linear and nonlinear elimination. The complex absorption profile was quantified using three simultaneous processes: a first-order process characterizing a rapid initial release and two series of transit compartments to describe the second (～3 weeks postinjection) and third phases of drug release (～7 weeks postinjection). Estimation of the combined single- and multiple-dose data adequately described the rise to steady-state (～8–10 weeks) and decline to undetectable concentrations that occurred about 10 weeks after treatment cessation. Thus, a population-based pharmacokinetic model was developed that provides a platform for future pharmacodynamic analyses with the ER formulation of exenatide.     

Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous plasma samples were obtained during the multiple-dose regimen, and appropriate equations were fitted to all the multiple-dose data. Diazepam absorption was satisfactorily described by a first-order process, with disposition characterized by a linear two-compartment open model. The harmonic mean absorption half-life was 32 min, and the harmonic mean terminal exponential half-life was 57hr. The mean apparent oral total drug plasma clearance was 22.7ml/hr/kg. Steady-state plasma levels of the primary metabolite, desmethyldiazepam, were reached after 5–8 days of dosing. Steady-state diazepam plasma concentration-time profiles suggested that once daily administration of the total daily dose at bedtime might be a satisfactory dosing regimen.     

Pharmacokinetics of lofepramine in man: Relationship to inhibition of noradrenaline uptake

Summary The pharmacokinetics of lofepramine, an imipramine analogue, have been studied by administering single oral doses to volunteers, determination of plasma levels of lofepramine and desmethylimipramine after ten days of oral administration to patients, and by relating plasma levels to the effect on uptake of noradrenaline by isolated rat irides and brain slices of plasma samples collected during treatment. The results indicate that lofepramine undergoes pronounced first pass elimination and that desmethylimipramine is a major metabolite of it. During steady-state conditions the plasma level of lofepramine fluctuates considerably between doses. A linear relation was found between inhibition of neuronal uptake of noradrenaline and the plasma concentration of desmethylimpramine. No effect was seen on the uptake of 5-hydroxytryptamine in brain slices incubated in patients' plasma which suggests that neither lofepramine nor its metabolites formedin vivo in man affect neuronal uptake of this amine. Lofepramine belongs to the group of tricyclic anti-depressants which preferentially inhibit noradrenaline uptake.Lofepramine = Leo 640 = N-methyl-N-[4-Chlorobenzoyl-methyl-3-(10.11-dihydro-5H-dibenz (b, t) azepin-5-yl]-propylamine     

Multiple-Dose Pharmacokinetics and Pharmacodynamics of Adinazolam in Elderly Subjects

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 ± 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and C _max for AD. Dose-normalized NDMAD AUC values as well as values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20-and 40-mg daily doses were 5.6 ± 2.1 and 5.5 ± 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.     

Pharmacokinetics of antofloxacin hydrochloride in healthy male subjects after multiple intravenous dose administration

1. The purpose of the study was to evaluate pharmacokinetic characteristics of antofloxacin hydrochloride, a new fluoroquinolone antibiotic, during a multiple, intravenous dosing regimen.

2. Twelve healthy, Chinese male volunteer subjects were each given 300?mg of antofloxacin by intravenous infusion once daily for 7 days. Blood and urine samples were taken at designated time points for analysis of antofloxacin concentration by high-performance liquid chromatography (HPLC). Safety and tolerability were assessed by evaluation of subject complaints, vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, haematology and urinalysis and prothrombin time.

3. The serum steady concentration of antofloxacin was obtained in 96?h after the administration of a daily intravenous dose of 300?mg of the drug. In the present study, the following pharmacokinetic parameters after 7 days of treatment with antofloxacin were determined to be: C_max 3.81?±?0.66?mg/L, C_min 0.85?±?0.19?mg/L, AUC_0–24 60.51?±?8.30?mg/L·h, C_av 2.52?±?0.35?mg/L, PTF 87.45?±?3.37%, t_1/2β 20.34?±?1.88?h. The C_max and AUC_0–24 after 7-day treatment were both higher than after the first dose (by 43% and 110%, respectively). The cumulative urinary elimination of antofloxacin within 96?h after the last dose was about 56%.

4. During the study, there were neither subject complaints nor significant adverse clinical findings.

5. Antofloxacin, administered intravenously as a single, daily 300?mg dose for 7 days, demonstrated favourable pharmacokinetic characteristics and tolerability. The results of this study indicate that antofloxacin hydrochloride is suitable for further clinical study.

     

LC-MS/MS法研究美托拉宗片在健康人体内药代动力学特征

目的:研究美托拉宗片在健康人体内单次和多次给药后的药代动力学特征。方法:10名健康受试者口服美托拉宗片1 mg,每日1次,连续6 d。给药后LC-MS/MS测定美托拉宗片血药浓度,用DAS 2.0药代动力学软件计算药代动力学参数。结果:单次和多次给药后主要药代动力学参数:Cmax分别为(20.6±4.8)和(22.4±5.0)ng.mL-1;Tmax分别为(1.60±0.6)和(2.4±1.4)h;AUC0～48分别为(122.5±36.3)和(156.8±31.6)ng.h.mL-1;AUC0～∞分别为(123.9±37.0)和(160.8±21.1)ng.h.mL-1;t1/2β分别为(7.9±1.2)和(8.9±1.4)h。结论:连续6 d口服美托拉宗片,药物在体内无蓄积,受试者耐受性良好。     

Clinical Predictors of Response to Clozapine in Patients with Treatment Resistant Schizophrenia

Objectives

Despite clozapine’s superior clinical efficacy in Treatment Resistant Schizophrenia (TRS), its adverse effects, need for periodic leukocyte monitoring, cost and variable clinical outcomes make the therapeutic decision making process difficult and mandate a clinical need to predict its treatment response. Hence, we investigated various clinical variables associated with treatment responses and adverse events of clozapine in TRS.

Experimental Design

We assessed socio-demographic and clinical profiles, premorbid adjustment, traumatic life events, cognition, disability, psychopathology and serum clozapine levels of 101 patients with TRS on stable dose of clozapine using the following instruments: Brief Psychiatric Rating Scale, Abnormal Involuntary Movements Scale, Addenbrooke’s Cognitive Examination—Revised, WHO Disability Assessment Scale-II, Childhood and Recent Traumatic Events Scale, and Premorbid Assessment Scale. We defined clozapine response a priori, adopted a case-control design framework and employed appropriate multivariate analyses.

Principal Observations

Past history of catatonia (p = 0.005), smoking more than one pack/day (p = 0.008), hyper-somnolence (p = 0.03) and cognitive dysfunction (p = 0.007) were associated with non-response to clozapine. Outcome definitions of non-response to clozapine influenced its association with clinical predictors.

Conclusions

Clinical variables are useful to predict response to clozapine. Smoking can be a potentially modifiable risk factor. Future longitudinal studies, investigating clinical and pharmacogenetic variables together, are desired.     

Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses — A cross-over study

Summary Eight healthy volunteers received single oral doses (1 mg/kg) and 6 received multiple doses (0.4 mg/kg t.i.d. for 2 weeks) of desmethylimipramine (DMI) and nortriptyline (NT) on different occasions. Kinetic analysis of plasma levels of the drugs showed that the ratios between single-dose peak-levels, plasma half-lives and apparent mean steady-state plasma levels of the two drugs were constant in all the subjects, and averaged 0.6. Despite their closely related chemical structures the apparent plasma clearance rate of DMI was about twice that of NT, and this might be associated with their different degrees of binding to plasma proteins. — The steady-state plasma level of NT in man is known to be genetically determined, and the conformity within each individual of the plasma clearance rates of DMI and NT indicates that the plasma kinetics of both these drugs are controlled by common genetic factors. — The study also shows that the steady-state plasma level of DMI, like that of NT, can be predicted accurately from single-dose plasma-level data. Thus, if the kinetic characteristics of one of these drugs in a subject are known, it is possible to predict the plasma kinetics of the other compound.Licentiate in Medicine, Research Assistant in Clinical Pharmacology.     

Pharmacokinetics and Reversible Biotransformation of Sulfinpyrazone and Its Metabolites in Rabbits. II. Multiple-Dose Study

In crossover studies rabbits were given sulfmpyrazone (SO) and its sulfide metabolite (S) perorally once daily (10 mg/kg) for 5 days. Comparison of the pharmacokinetic parameters obtained after the first and the fifth dose indicates that repeated dosing does not alter disposition kinetics of both SO and S, except that in dosing with S the observed terminal half-life for S is significantly reduced, from 4.59 ± 0.55 to 2.86 ± 0.6 hr (SD). In other studies rabbits were given higher single doses (15, 25, and 50 mg/kg) perorally and comparison was made between these dose sizes and the first dose (10 mg/kg) of multiple administration with S. Some kinetic parameters tended to be altered in a nonlinear fashion, and greater intersubject variations were observed because of the dose increase, while oxidation to SO or p-hydroxylation to OH-S from S was not significantly altered.     

健康受试者口服Levofloxacin的药动学研究

本文报道８例健康志愿者体内单次及多次给予３００ｍｇＬｅｖｏｆｌｏｘａｃｉｎ后的药代动力学研究。血药浓度及尿药浓度采用微生物和ＨＰＬＣ测定。单次及多次给药后的数据分别采用３ｐ８７及ＳＳＤ程序处理，药－时曲线符合二室模型。单次口服３００ｍｇＬｅｖｏｆｌｏｘａｃｉｎ，其微生物和ＨＰＬＣ测定结果分别为Ｔｍａｘ１．３１和１．４３ｈ，Ｃｍａｘ３．８４和４．２０ｍｇ／Ｌ，ｔ１／２２６．１２和６．０６ｈ。０～２４ｈ尿药回收率分别为６８．７９和６６．４３％。经ｔ检验两种方法的测定结果无显著性差异（ｐ＞０．０５）。在每日３００ｍｇｑ１２ｈ连续８天的多次口服给药实验中，第１天和第８天的药代动力学参数经ｔ－检验无显著性差异（ｐ＞０．０５），说明本品每日２次重复给药无明显蓄积现象。     

Pharmacokinetics of single and multiple doses of flusoxolol (Ro 31-1411) in healthy subjects

Summary Flusoxolol (Ro 31-1411) is the pharmacologically active optical isomer of Ro 31-1118, a potent cardioselective -adrenoceptor antagonist with partial agonist activity. It was given to 6 healthy volunteers in a single dose, 40 mg, and then in multiple doses, 40 mg daily for 8 days.Plasma concentration data were best described by a linear two-compartment pharmacokinetic model with first order absorption, and the results confirmed linear kinetics.Pharmacokinetic data for flusoxolol were comparable to those for the racemate Ro 31-1118.     

Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release and Sustained-Release Adinazolam Mesylate Tablets After Single- and Multiple-Dose Administration

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on mulitiple dosing.