Pharmacokinetics of sarizotan after oral administration of single and repeat doses in healthy subjects

OBJECTIVE: Sarizotan is a 5-HTIA receptor agonist with high affinity for D3 and D4 receptors. Here we report the pharmacokinetic and tolerability results from four Phase 1 studies. MATERIALS: Two single-dose (5 -25 mg, n = 25, 0.5 - 5 mg, n = 16) and two multiple-dose (10 and 20 mg b.i.d., n = 30, 5 mg b.i.d., n = 12) studies with orally administered sarizotan HCl were carried out in healthy subjects. METHODS: Plasma sarizotan HCl concentrations were measured using a validated HPLC method and fluorescence or MS/MS detection. Pharmacokinetic parameters were obtained using standard non-compartmental methods. RESULTS: Sarizotan was rapidly absorbed, group-median times to reach maximum concentration (tmax) ranged from 0.5 -2.25 h after single doses and during steady state. Maximum plasma concentration (Cmax) and tmax were slightly dependent on formulation and food intake, whereas area under the curve (AUC) was unaffected by these factors. AUC and Cmax increased dose-proportionally over the tested dose range. Independently of dose and time, sarizotan HCl plasma concentrations declined polyexponentially with a terminal elimination half-life (t1/2) of 5 - 7 h. Accumulation factors corresponded to t1/2 values, and steady state was reached within 24 h. Plasma metabolite concentrations were considerably lower than those of the parent drug. The ratio metabolite AUC : parent drug AUC was time- and dose-independent for all three metabolites suggesting that the metabolism of sarizotan is non-saturable in the tested dose range. CONCLUSIONS: The pharmacokinetics of sarizotan were dose-proportional and time-independent for the dose range 0.5 -25 mg). The drug was well-tolerated by healthy subjects up to a single dose of 20 mg.     

Pharmacokinetics of fluvoxamine maleate after increasing single oral doses in healthy subjects

The pharmacokinetics of fluvoxamine after single oral administration of 25, 50, and 100 mg fluvoxamine maleate was studied in a three-way cross-over study in 12 healthy male subjects. Fluvoxamine was administered orally in a solution. For doseproportionality, AUC, and C_max-dose relationships were evaluated by linear regression. Plasma concentrations increased in a linear dose-dependent manner in the dose range between 25 and 100 mg; t_1/2 and T_max showed no significant differences among treatments. Fluvoxamine was well tolerated.     

Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

OBJECTIVE: To study the pharmacokinetics of esomeprazole, one of the optical isomers of omeprazole, after 20 mg or 40 mg single and repeated oral and intravenous administration to healthy subjects. The main metabolites of esomeprazole were also assessed after the 40-mg oral dose. METHODS: In two separate studies, 16 healthy male subjects and 16 healthy male and female subjects received intravenous doses of 20 mg and 40 mg esomeprazole, respectively, on the first investigation day. After a washout period of 5-14 days, the same doses (20 mg as a solution and 40 mg as a capsule) were given orally for 5 days and then again intravenously on day 6. Blood samples for determination of esomeprazole and its metabolites were collected 12 h or 24 h post-dose and were analysed using normal-phase liquid chromatography with ultraviolet (UV) detection. Pharmacokinetic parameters of esomeprazole and its metabolites were estimated using non-compartmental analysis. Geometric means and ratios of the geometric means together with 95% confidence intervals (CI) of the pharmacokinetic parameters were calculated using analysis of variance (ANOVA). RESULTS: Plasma clearance (CL) of esomeprazole decreased from 22 l/h to 16 l/h and from 17 l/h to 9 l/h following repeated dosing of 20 mg and 40 mg, respectively. Total area under the plasma concentration-time curve (AUC) increased (from 1.34 micromol x h/l to 2.55 micromol x h/l) with absolute bioavailability (F) being 50% on day 1 and 68% on day 5 after the 20-mg oral dose. AUC increased (from 4.32 micromol x h/l to 11.21 micromol x h/l) with F being 64% on day 1 and 89% on day 5 after the 40-mg oral dose. The plasma levels for esomeprazole sulphone were substantially higher on day 5 than on day 1, while those for 5-hydroxy esomeprazole were marginally higher on day 5 than on day 1 following repeated oral dosing of 40 mg esomeprazole. No side effects attributable to esomeprazole were noticed. CONCLUSION: The increased AUC of esomeprazole with repeated dosing is probably due to a combination of a decreased first-pass elimination and a decreased systemic clearance.     

Pharmacokinetics and tolerance of romazarit after oral administration of ascending single doses to healthy human volunteers

Forty-four healthy male volunteers participated in an investigation of the pharmacokinetics and tolerance of single oral doses of romazarit, a potential disease-modifying antirheumatic drug. The study design involved single oral doses in ascending sequence from 40 to 1500 mg. At each dosage 9 volunteers were studied, of whom 6 received romazarit and 3 received placebo capsules in a double-blind manner. Tolerance was assessed before and after each of the 57 romazarit and 27 placebo doses. Plasma and urinary concentrations of romazarit were measured by HPLC with UV detection. Model-independent pharmacokinetic analyses showed that romazarit was rapidly and extensively absorbed in a dose-proportional manner. Urinary recovery of drug related material was about 70% of the dose and almost all in the form of labile metabolites (probably acyl glucuronides). Clearance was faster (greater than 3 l/h) at doses below 700 mg, than in the range 700-1500 mg (1.7 l/h). It is suggested that two or more clearance mechanisms are present. One of these mechanisms is saturable and may involve a reversible ester glucuronide formation coupled with saturable tubular secretion of glucuronides. Romazarit was well tolerated in these healthy volunteers. There were two reports of stomach pain, one associated with vomiting. Changes in laboratory safety test results and in measurements of vital signs were similar in frequency and magnitude after romazarit and after placebo doses.     

连续口服盐酸噻氯匹定片在健康人体的药代动力学

目的研究连续口服盐酸噻氯匹定片(抗血栓药)在健康人体的药代动力学。方法12名男性健康志愿者连续口服噻氯匹定片,每次250mg,每日2次。第11日按照预定时间点采血,用LC-MS-MS方法测定血浆稳态血药浓度,并求算其药代动力学参数。结果t1/2为(115±13.8)h,AUC0-21d为(24.48±10.02)μg.h.mL-1,tmax为(1.8±0.6)h,Cmax为(1303±428)ng.mL-1,Cmin为(235±107)ng.mL-1,Cav为(541±194)ng.mL-1,AUCss为(6.49±2.32)μg.h.mL-1,CLss为(48.1±33.7)L.h-1。结论连续口服盐酸噻氯匹定,吸收迅速,消除半衰期较单剂量大大延长;个体变异小。     

Pharmacokinetics of nilvadipine after single oral doses in healthy volunteers

Forty healthy male Caucasian volunteers were randomly assigned to five treatment groups to receive a placebo or a 4, 8, 12, 16 or 20 mg dose of nilvadipine. The drug was well tolerated by the subjects at all dose levels. Pharmacokinetic parameters for nilvadipine were determined using model-independent methods. There were no significant differences (p greater than 0.05) in the time to the maximum plasma concentration (Cmax) (tmax), the elimination half-life or the mean residence time among the five treatment groups. Up to doses of about 12 mg, there was a linear relationship between dose and Cmax or area under the plasma concentration-time curve (AUCO----infinity). At doses of 16 and 20 mg, the relationship between dose and Cmax or AUCO----infinity was no longer linear, suggesting that the pharmacokinetics of the drug after single oral doses greater than about 12 mg may be dose-dependent, probably due to concentration-dependent first-pass hepatic elimination of the drug.     

口服后莫达非尼及其代谢产物在汉族健康人体内的药物动力学

目的研究莫达非尼及其代谢产物(莫达非尼酸)在中国汉族健康人体内的药物动力学过程。方法10名健康志愿者口服莫达非尼片200 mg,采用HPLC法测定给药后不同时间点的莫达非尼及其代谢物的浓度,用DSA软件求算其药物动力学参数,并比较药物动力学参数在性别上的差异。结果莫达非尼及其代谢物莫达非尼酸的药物动力学过程符合二室模型拟合,其药物动力学参数分别为:莫达非尼tmax(1.69±0.70)h,ρmax(4.14±1.21)mg.L-1,AUC0-∞(65.96±11.69)mg.h.L-1;莫达非尼酸tmax(3.06±0.94)h,ρmax(3.19±0.95)mg.L-1,AUC0-∞(45.94±13.44)mg.h.L-1。结论口服莫达非尼在人体内其原形及代谢产物药物动力学均符合二室模型拟合,其药物动力学参数没有性别差异。     

单剂量口服奥扎格雷钠在健康人体的药代动力学

目的研究健康人体单剂口服奥扎格雷钠口服液的人体药代动力学。方法12名健康志愿者口服奥扎格雷钠口服液200mg,用反相高效液相色谱法—二极管阵列紫外法测定血浆中奥扎格雷钠浓度,并求算其药代动力学参数。结果奥扎格雷钠口服液的药代动力学参数tmax为(0.42±0.12)h、Cmax为(3.10±1.06)mg·L-1、AUC0-t为(3.50±0.91)mg·h·L-1,t1/2β为(0.72±0.26)h。结论单剂量口服奥扎格雷钠,在体内分布及消除较快,且Cmax及AUC与剂量成正比。     

铝镁匹林片单剂量和多剂量人体药动学研究

目的:研究单剂量和多剂量铝镁匹林片(每片含阿司匹林81 mg,甘羟铝11 mg,重质碳酸镁22 mg)的人体药动学特征。方法:27名健康受试者随机等分成81,162和324 mg·d~(-1)三组,每日口服规定剂量的铝镁匹林片,连续7 d。采用HPLC-MS-MS法测定血浆阿司匹林和水杨酸浓度。结果:阿司匹林的T_(max)约30 min,t_(1/2)为17．4～29．8 min;水杨酸的t_(1/2)为3～4 h,T_(max)为30～60 min;各剂量组的C_(max)AUC,T_(max),t_(1/2)和Cl/F在给药后d1和d7均无显著性差异,t_(1/2)和Cl/F在三组间无显著性差异。结论:在本研究剂量范围内,阿司匹林和水杨酸呈线性动力学,连续服药未见体内蓄积。     

Pharmacokinetics and safety of FFR-rFVIIa after single doses in healthy subjects

FFR-rFVIIa is an antithrombotic agent, which has also proven to have antirestenotic properties in animal models. FFR-rFVIIa is a modified recombinant FVIIa in which the catalytic site is irreversibly inactivated by a synthetic tripeptide covalently bound with the FVIIa molecule. The modified rFVIIa retains its tissue factor (TF) binding capacity but is otherwise enzymatically inactive. A double-blind, placebo-controlled, randomized dose escalation trial was conducted to investigate eight single i.v. doses of FFR-rFVIIa (0.01, 0.02, 0.05, 0.08, 0.12, 0.18, 0.27, or 0.40 mg/kg body weight) in healthy male volunteers (n = 62). Safety, pharmacokinetics, and pharmacodynamics of FFR-rFVIIa were assessed. Mean (SD)AUC0-infinity ranged from 0.35 (0.11) to 28.8 (3.5)microg.h/ml, and mean Cmax ranged from 0.078 (0.019) to 4.8 (0.7) microg/ml. The mean elimination half-life ranged from 3.8 to 5.8 hours. Mean AUC0-infinity increased with increasing dose levels. Cmax appeared to be proportional to the dose level, with the exception of the lowest dose level. A dose-dependent prolongation of the prothrombin time was found, demonstrating that FFR-rFVIIa inhibited coagulation via the TF-dependent pathway FFR-rFVIIa was generally well tolerated at all dose levels studied.     

Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed.     

Pharmacokinetics and bioavailability of omeprazole after single and repeated oral administration in healthy subjects.

1. Ten healthy subjects were given 20 mg omeprazole EC (enteric coated) granules once daily for 8 days. An i.v. tracer dose of [14C]-omeprazole was given simultaneously with the first and last oral doses and blood sampling was performed thereafter. In order to study the extent of absorption at minimal acid exposure, a single dose of 20 mg omeprazole was also given as a buffered solution, before and after the treatment with EC granules. 2. Kinetic parameters of omeprazole after the i.v. tracer dose were unchanged on repeated dosing while AUC increased by approximately 40% for the solution and 60% for the EC granules. 3. The increased AUC is caused by an increased systemic availability, which may be explained by a decreased first-pass elimination during repeated treatment and/or by a reduced degradation of omeprazole in the stomach secondary to the profound decrease in intragastric acidity caused by the drug. 4. The implication of these findings is that the antisecretory effect of therapeutic doses of omeprazole must be studied during repeated administration and not judged from studies using single doses only.     

Pharmacokinetics of dexloxiglumide after administration of single and repeat oral escalating doses in healthy young males

OBJECTIVE: To assess the pharmacokinetics, safety and tolerability of dexloxiglumide, a new CCK1 receptor antagonist currently under development for the treatment of the constipation-predominant irritable bowel syndrome. SUBJECTS AND METHODS: Twelve volunteers were enrolled in the present study and received orally 100, 200 and 400 mg of dexloxiglumide as tablets as a single dose followed by repeated t.i.d. doses for 7 days according to a randomized, double-blind, double-dummy complete crossover design. Plasma and urine were collected before drug administration and up to 72 h after dosing. Dexloxiglumide plasma and urinary concentration, determined using validated HPLC methods with UV detection, were used for the pharmacokinetic analysis by standard noncompartmental methods. In addition, dexloxiglumide safety and tolerability were evaluated throughout the study period by performing standard laboratory tests, by recording vital signs and ECGs and by monitoring the occurrence and severity of adverse events. RESULTS: After a single oral administration, dexloxiglumide was rapidly bioavailable with mean t(max) ranging from 0.9 - 1.6 h at all doses. The mean peak plasma concentrations (Cmax) were 1.7+/-0.6, 5.4+/-1.7, and 11.9+/-4.7 microg/ml, and the mean area under the plasma concentration-time curves (AUC) were 4.4+/-3.3, 8.6+/-3.6, and 18.3+/-5.9 microg x h/ml at the 3 doses, respectively. Apparent plasma clearance (CL/F) was 30.8+/-13.9, 27.2+/-10.6, and 21.1+/-8.6 l/h at the 3 doses, respectively. The apparent elimination half-life from plasma (t1/2) ranged from 2.6 - 3.3 h at the 3 doses. The excretion of unchanged dexloxiglumide in 0 - 72 h urine accounted for approximately 1% of the administered dose and this was true for all doses. Dexloxiglumide renal clearance (CLR) averaged 0.4+/-0.4, 0.4+/-0.2, and 0.3+/-0.3 l/h for the 3 doses, respectively. After the last dose of the repeated dosing period dexloxiglumide Cmax occurred at 1.1 - 1.6 h after drug administration and averaged 2.4+/-1.3, 7.1+/-2.9, and 15.3+/-2.7 microg/ml for the 3 doses, respectively. The AUC values averaged 5.9+/-3.0, 16.0+/-8.8, and 50.8+/-38.1 microg x h/ml, respectively. The area under the plasma concentration-time curve calculated at steady state within a dosing interval (AUCss) averaged 4.6+/-1.6, 11.3+/-3.6, and 28.4+/-8.2 microg x h/ml, whereas CL/F averaged 20.3+/-8.3, 16.3+/-9.0, and 10.3+/-5.0 l/h at the 3 doses, respectively. Dexloxiglumide t1/2 could not be accurately calculated due to the high inter-subject variability and to sustained dexloxiglumide plasma concentrations that precluded the identification ofthe terminal phase of the plasma concentration-time profiles. However, it appeared that dexloxiglumide t1/2 was considerably prolonged at the dose of 400 mg. CLR averaged 0.4+/-0.4, 0.3+/-0.3, and 0.3+/-0.1 l/h for the 3 doses, respectively. After a single dose, the plasma pharmacokinetics of dexloxiglumide were dose-independent in the dose range 100 - 400 mg. After repeated dose the pharmacokinetics of dexloxiglumide were virtually dose-independent in the dose range 100 - 200 mg. A slight deviation from linear pharmacokinetics was found with a dose of 400 mg. Dexloxiglumide plasma pharmacokinetics were also time-independent in the dose range 100 - 200 mg with a deviation from expectation based on the superimposition principle with a dose of 400 mg. Dexloxiglumide urinary excretion and renal clearance were both dose- and time-independent in the dose range 100 - 400 mg. The safety and tolerability of dexloxiglumide administered to healthy young males was good up to the maximum investigated dose of 400 mg both after single and after repeated doses. CONCLUSIONS: The safety and pharmacokinetic profile of dexloxiglumide when the drug is administered as single and repeated doses in the dose range 100 - 400 mg provides the rationale for the choice of the treatment schedule (200 mg t.i.d.) for the efficacy trials in patients with (constipation-predominant) irritable bowel syndrome.     

单剂口服盐酸吡格列酮片在健康人体的药代动力学

目的研究健康人体单剂量口服盐酸吡格列酮片(胰岛素增敏剂)的药代动力学。方法24名健康男性志愿者单次口服盐酸吡格列酮片30mg,用HPLC-MS/MS同时测定血浆中吡格列酮及其活性代谢产物的浓度,计算其主要药代动力学参数。结果吡格列酮:Cmax为(1504.9±447.8)ng.mL-1;tmax为(1.46±0.69)h;t1/2Ke为(7.58±3.21)h;AUC0-48为(11.22±2.60)μg.h.mL-1。吡格列酮代谢物M-Ⅲ:Cmax为(249.4±82.7)ng.mL-1;tmax为(11.94±6.14)h;t1/2Ke为(20.09±4.13)h;AUC0-120为(10.90±3.55)μg.h.mL-1。吡格列酮代谢物M-IV:Cmax为(487.2±108.6)ng.mL-1;tmax为(13.33±5.23)h;t1/2Ke为(21.07±3.99)h;AUC0-120为(22.78±5.04)μg.h.mL-1。结论健康人体单剂量口服盐酸吡格列酮片剂后,吡格列酮代谢物M-Ⅲ和M-IV的达峰时间约为12～13h,峰浓度分别约为吡格列酮的16%和32%,AUC0-120分别约为吡格列酮AUC0-48的97%和203%。     

Plasma tenoxicam concentrations after single and multiple oral doses

The pharmacokinetics of single- and multiple-dose administration of tenoxicam 20 mg were evaluated in 8 healthy males. Maximum plasma concentration (Cmax) after the first dose was 2.76 +/- 0.48 micrograms/ml (mean +/- s.d.) and the time to reach Cmax (Tmax) was 5.0 +/- 3.0 h. The area under the plasma concentration-time curve (AUC0-infinity) after a single administration of tenoxicam was 242.5 +/- 73.5 micrograms x h/ml. The elimination half-life (t1/2) was 66.3 +/- 15.8 h and the plasma concentration at 24 hours after dosing (Cmin) was 1.84 +/- 0.33 micrograms/ml. Steady-state plasma concentrations of tenoxicam were virtually reached after 10 consecutive daily doses. At steady-state, Cmax averaged 13.63 +/- 3.33 micrograms/ml and Tmax remained 5.0 +/- 3.0 hours. AUC within a dosing interval at steady-state was 262.2 +/- 67.0 micrograms x h/ml, Cminss was 9.67 +/- 3.25 micrograms/ml, and t1/2 averaged 74.2 +/- 13.3 h. The average fluctuation during multiple-dose administration was 26.8 +/- 8.0% and the accumulation ratio was 5.82 +/- 0.60. Steady-state pharmacokinetic parameters predicted from the first-dose data slightly underestimated observed values, but the results supported the assumption of linear pharmacokinetics during multiple-dose tenoxicam administration.     

Pharmacokinetics and bioequivalence of two strontium ranelate formulations after single oral administration in healthy Chinese subjects

1. Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated.

2. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240-h post-dose. Serum concentrations of Sr were quantified by ICP-MS.

3. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in 6 subjects were reported. The C_max, AUC_0–72?h, AUC_0–t, and AUC_0–∞ of test and reference formulations shown as mean?±?SD were 6.97?±?1.78 and 6.78?±?1.80?µg/mL, 199?±?51 and 187?±?38?µg·h/mL, 303?±?89 and 278?±?54?µg·h/mL, and 337?±?109 and 305?±?60?µg·h/mL, respectively.

4. Two formulations were bioequivalent, and both were generally well tolerated.

     

Pharmacokinetics of rabeprazole following single intravenous and oral administration to healthy subjects

The study was designed to determine the absolute bioavailability of 20 mg rabeprazole tablets in normal, healthy subjects in comparison with intravenous administration of 20 mg rabeprazole. Twenty-eight healthy subjects were enrolled in this study. The study was a randomized, balanced, open-label, 2-period crossover study. Each subject was randomized at the beginning of the study to receive either a single 20 mg dose of rabeprazole intravenously or orally during Period 1. Following a 7-day washout period, all subjects received the alternate formulation during Period 2. Intravenous dose was given in constant infusion over five minutes. The absolute bioavailability of rabeprazole was 51.8%. The elimination half-life of rabeprazole sodium (1.47 +/- 0.82 h) after oral administration was significantly longer than the elimination half-life after intravenous administration (1.02 +/- 0.63 h), probably due to slower rate of absorption than that of elimination. The mean total body clearance was 283 +/- 98 ml/minutes following a 20 mg intravenous dose. The administration of rabeprazole sodium was safe as evidenced by the lack of serious adverse events and the rapid resolution of the mostly mild adverse events that occurred during the study. Both treatments were well-tolerated throughout the study. Rabeprazole was well-absorbed after oral administration.     

单剂量口服他达拉非在中国健康男性受试者的药代动力学和安全性

目的 研究中国健康男性受试者单剂量口服他达拉非的药代动力学和安 全性。方法 用双盲随机安慰剂对照三交叉设计。在3个周期随机单次服用 他达拉非10,20 mg或安慰剂,采集静脉血,用液相色谱-质谱法测定血药浓度 并计算药代动力学参数。结果 单次服用他达拉非10,20 mg后的主要药代动 力学参数AUC0-t分别为3750和7180 ng·h·mL-1;AUC0-∞分别为3820和 7370 ng·h·mL-1;Cmax分别为172和274 ng·mL-1;tmax分别为3．00和4．00 h;CL／F分别为2．61和2．71 L·h-1;V／F分别为67．6和73．2 L。结论 他达 拉菲在10-20 mg,中国健康男性受试者较安全,且AUC与剂量呈正相关。     

Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses.

The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg.     

Pharmacokinetics of aprepitant after single and multiple oral doses in healthy volunteers

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food. The mean (95% confidence interval [CI]) bioavailabilities of 125-mg and 80-mg final market composition (FMC) capsules, as assessed by simultaneous administration of stable isotope-labeled intravenous (i.v.) aprepitant (2 mg) and FMC capsules, were 0.59 (0.53, 0.65) and 0.67 (0.62, 0.73), respectively. The geometric mean (90% CI) area under the plasma concentration time curve (AUC) ratios (fed/fasted) were 1.2 (1.10, 1.30) and 1.09 (1.00, 1.18) for the 125-mg and 80-mg capsule, respectively, demonstrating that aprepitant can be administered independently of food. Study 2 defined the pharmacokinetics of aprepitant administered following the 3-day regimen recommended to prevent CINV (125 mg/80 mg/80 mg). Consistent daily plasma exposures of aprepitant were obtained following this regimen, which was generally well tolerated.