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.     

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.     

The pharmacokinetics of single oral doses of feprazone in healthy volunteers and elderly patients

1. The pharmacokinetics of feprazone were studied in nine healthy volunteers and 10 elderly patients.

2. The mean elimination half-life of feprazone after a single oral dose in the healthy volunteers was 22.3?h, the mean apparent clearance 0.00511/h per kg and the mean volume of distribution 0.1681/kg. Corresponding values for the elderly patients were 22.6?h, 0.00561/h per kg and 0.1651/kg, which are not different from those for the volunteers. Thus, we were unable to detect any changes in feprazone pharmacokinetics which are related to age, or to the concurrent use of chronic medications, such as digoxin, diuretics, or hormones.     

Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food

Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics.     

The pharmacokinetics of single oral doses of feprazone in healthy volunteers and elderly patients.

1. The pharmacokinetics of feprazone were studied in nine healthy volunteers and 10 elderly patients. 2. The mean elimination half-life of feprazone after a single oral dose in the healthy volunteers was 22.3 h, the mean apparent clearance 0.0051 1/h per kg and the mean volume of distribution 0.1681/kg. Corresponding values for the elderly patients were 22.6 h, 0.00561/h per kg and 0.1651/kg, which are not different from those for the volunteers. Thus, we were unable to detect any changes in feprazone pharmacokinetics which are related to age, or to the concurrent use of chronic medications, such as digoxin, diuretics, or hormones.     

Pharmacokinetics of a sustained release formulation of pyridoxal phosphate of buflomedil after single or repeated oral doses in healthy volunteers.

The pharmacokinetics of a sustained release (SR) formulation of pyridoxal phosphate of buflomedil (Pirxane retard) has been studied after oral administration to healthy volunteers using among else a gaschromatographic dosage method. After oral administration of 400 mg of the SR formulation, pyridoxal phosphate of buflomedil has a much slower kinetics compared to the normal formulation (tmax:approx. 1.5 h) reaching the maximum plasma concentration, which was about 467 ng/ml, in about 3 h. After 24 h the concentrations were still about 1/10 (48 ng/ml) the maximum value. 24-h urinary excretion was about 21% of the administered dose. Repeated administration of the SR formulation for 7 days in single daily doses of 400 mg gave steady state plasma levels (ca. 250 ng/ml) 12 h after the administration without statistically significant variations. The plasma concentrations of the drug measured daily after reaching the steady state were similar one to the other. The tolerability was very good and no local or systemic side effects of any kind were reported.     

Pharmacokinetics of dipyridamole-beta-cyclodextrin complex in healthy volunteers after single and multiple doses.

Dipyridamole is a well known anti-aggregating agent characterized by poor water solubility as well as scant and variable bioavailability. Recently, the compound was complexed with beta-cyclodextrin forming a molecular encapsulation resulting in better oral absorption and stronger biological activities in animals. In the present study, a randomized double blind cross-over comparison between dipyridamole-beta-cyclodextrin complex (dip-beta-CD) and dipyridamole was performed in 12 healthy subjects after single (75mg) and multiple oral treatments (75mg TID). Dip-beta-CD showed better bioavailability and less interindividual variability than dipyridamole either after single or multiple doses. In particular, dip-beta-CD had a greater AUC and Cmax, and a smaller Tmax even at the steady state. In addition, 100% of the subjects receiving a single dose of dip-beta-CD, as compared to 66.7% of those treated with dipyridamole, had plasma levels superior to 1 microgram/ml (which is the supposed anti-aggregating threshold level). In contrast, 0 and 33.03% of the subjects showed plasma levels superior to 2.5 micrograms/ml (which might cause the appearance of side-effects) on the 7th day of the multiple treatment with dip-beta-CD and dipyridamole, respectively. In fact, the subjects presenting higher levels after uncomplexed dipyridamole also complained of headache and/or dizziness on occasion. No adverse side effects were reported for dip-beta-CD.     

Hypokalaemia in healthy volunteers after single and multiple doses of formoterol or salbutamol

A specific beta(2)-adrenoceptor-mediated effect, hypokalaemia, was studied in healthy volunteers after single as well as multiple dosages of the long-acting agonist formoterol and the short-acting agent salbutamol. The purpose of the study was to test with simple methodologies if rapidly induced tachyphylaxis for this well known systemic effect can be shown and if it will then be more pronounced for the long-acting compound. Hypokalaemia induced by inhalation of, respectively, 72microg formoterol and 1200microg of salbutamol was studied before and after 1 week of medication. Potassium-time curves were described by a biexponential equation and also analysed with a deconvolution technique. Both drugs induced a statistically significant hypokalaemia, the duration of this effect being considerably shorter for salbutamol than for formoterol (p < 0.05 with both methods of analysis). After multiple doses for 1 week, both maximal hypokalaemia and the area under the curve of the hypokalaemic effect had decreased after inhalation of formoterol (p < 0.05) but not after inhalation of salbutamol.It was concluded that plasma potassium as an effect measurement can be used to study in a simple but reproducible way differences of pharmacological interest between various beta(2)-adrenoceptor agonists.     

Ibudilast in healthy volunteers: safety,tolerability and pharmacokinetics with single and multiple doses

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibudilast is an oral drug approved in Asia for asthma.
• Tolerability of 10-mg regimens has been described previously.
• Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers.

WHAT THIS STUDY ADDS

• Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers.
• Higher-dose regimens are relevant for testing in new neurological indications.
• LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast).

AIMS

To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen.

METHODS

Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite.

RESULTS

Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median T_max was 4–6 h. Mean (SD) steady-state plasma C_max and AUC_0–24 were 60 (25) ng ml⁻¹ and 1004 (303) ng h ml⁻¹, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent.

CONCLUSIONS

Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day⁻¹) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models.     

Pharmacokinetics of piperaquine after single and multiple oral administrations in healthy volunteers

The aim of this work was to study the pharmacokinetics of piperaquine in healthy volunteers. Healthy volunteers received piperaquine and tablets of Artekin by oral administration. The plasma samples were analyzed for piperaquine by liquid-liquid extraction and determined by HPLC-UV. The results demonstrated that the plasma drug concentration-time curves of single and multiple dose of piperaquine were fitted to a two-compartment open model. The pharmacokinetics parameters of piperaquine alone in a single dose were: t(1/2(beta))=(317.2-/+126.6)h, AUC(0-->infinity)=(44293-/+12636)h x ng/ml, V(d)=(9490.9-/+2161.9)ml/kg, and Cl=(22.83-/+9.83)ml/h/kg. In Artekin in a single dose these parameters were: t(1/2(beta))=(302.8-/+180.7)h, AUC(0-->infinity)=(46419-/+13670)h x ng/ml, V(d)=(10188.6-/+3520.3)ml/kg, and Cl=(25.48-/+10.89)ml/h/kg, while in Artekin in multiple doses they were: t(1/2(beta))=(298.9-/+101.9)h, AUC(0-->infinity)=(227692-/+56294)h x ng/ml, V(d)=(5031.5-/+1097.8)ml/kg, Cl=(11.91-/+3.046)ml/h/kg, respectively. The absorption and distribution of piperaquine were quick while the elimination was quite slow. There were significant differences in the pharmacokinetics parameters of piperaquine in Artekin between a single dose and multiple doses (p<0.001), suggesting that piperaquine might accumulate in vivo and that attention should be given to its possible adverse drug reactions in clinical treatment.     

Pharmacokinetics of deramciclane and N-desmethylderamciclane after single and repeated oral doses in healthy volunteers

OBJECTIVE: To study the pharmacokinetics and accumulation of deramciclane and its metabolite N-desmethylderamciclane after 60 mg twice daily doses for 4 weeks. METHODS: Sixteen healthy male subjects, age range of 20-29 years, participated in this randomized, double-blind, parallel-group, placebo-controlled study. Ten subjects first received a single 60 mg dose of deramciclane followed by 60 mg deramciclane b.i.d. between days 4 and 31. Six subjects received matching placebo in a similar manner. Pharmacokinetics of deramciclane and N-desmethylderamciclane were determined on days 1, 10, 17, 24 and 31. Plasma prolactin concentrations were measured before drug administration and 4 hours after on the same days. Safety was monitored using repeat laboratory determinations and ECG recordings. RESULTS: The mean (SD) AUC(0-infinity) of deramciclane was 1,251 (385) ng x h/ml after the first dose. The AUC(tau) calculated for the dosing interval was significantly higher at week 1 (p = 0.048) than the AUC(0-infinity) after the first dose but thereafter there was no further accumulation of deramciclane. The mean accumulation indices at weeks 1, 2, 3 and 4 varied between 2.3 and 2.7 with no tendency to increase over time. The mean apparent elimination half-life of deramciclane was 24.9 (3.5) hours after the first dose and 29.3 (9.3) hours after 4-week repeated dosing; this difference was not statistically significant. The accumulation index of N-desmethylderamciclane increased from week 1 to week 2 but remained stable thereafter. The treatment was well tolerated. Plasma prolactin levels were not influenced by deramciclane administration. CONCLUSIONS: Deramciclane administration, 60 mg twice daily for 4 weeks to healthy male volunteers, is well tolerated, and there is no evidence of continuous accumulation of the drug during maintenance treatment. Deramciclane at a dose of 60 mg b.i.d. does not antagonize dopamine receptors to a significant degree.     

Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers

OBJECTIVE: To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method. DESIGN: Open, randomised, four-way cross-over trial. PARTICIPANTS: 24 healthy male and female volunteers, aged 18-46 years. METHODS: Lacidipine was administered as single doses of 2, 4, 6 and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic evaluations were performed on study days 1 and 8. Plasma concentrations of lacidipine were determined by a validated high-performance liquid chromatography-radioimmunoassay method. The ratios of dose-normalised peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) were calculated and then compared across dose groups by analysis of variance to assess dose linearity against a 4 mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity. RESULTS: After repeated 2, 4 and 6 mg doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46-2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57-6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the administration interval at steady state (AUC(tau)), respectively. Mean half-life ranged between 13.2 hours and 18.7 hours. Precision of these estimates was limited by the small number of sampling timepoints collected in the final part of the curve. After administration of single doses, no statistically significant deviation from linearity was found except for the 8 mg dose, but a trend of greater than proportional exposure was evident with increasing dose. Following repeated administration, dose linearity over the therapeutic range was observed. No statistically significant difference was observed between AUC to infinity (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of pharmacokinetics. CONCLUSIONS: Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2-6 mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8 mg dose, which is outside the recommended therapeutic range, resulted in greater than predicted exposure. After low doses, the analytical method still does not allow complete characterisation of kinetics. Time-invariance of lacidipine kinetics is suggested.     

Pharmacokinetics and pharmacodynamics of alprazolam following single and multiple oral doses of a sustained-release formulation

The pharmacokinetics and pharmacodynamics of alprazolam after IV and oral sustained-release (SR) tablet administration were evaluated in 42 healthy, normal, male volunteers. All 42 subjects received a single 1-mg intravenous (IV) alprazolam dose. After a 1-week washout period, the subjects received one of three SR treatments as a single dose: one 1-mg SR tablet, three 1-mg SR tablets, or six 1-mg SR tablets. Beginning 2 days after single-dose SR treatment, each subject received the above SR doses for 3 days. The daily dose for the multiple-dose study was the same as the subject received in the single-dose study. Serial blood samples were collected after each treatment (single-dose IV, single-dose SR, and after the last SR multiple dose), and plasma samples were analyzed by high performance liquid chromatography. Sedation was assessed by a blinded observer at each blood sampling time. Mean pharmacokinetic parameters for IV administration were consistent with previous results. Pharmacokinetic parameters for the SR doses were consistent with linear kinetics over the dosage range studied. The mean absolute bioavailabilities of the SR tablets were greater than 0.84 after single SR doses. Maximal sedation was related to dose after single-dose SR administration. During multiple dosing, chronic tolerance was observed. Maximal sedation scores after 3 days of alprazolam SR administration were independent of the dose administered and were lower after multiple-dose administration than scores observed after single oral SR doses, although plasma alprazolam concentrations were at least 1.5 times higher with multiple dosing. Sedation data indicate that oral SR doses were well tolerated in multiple dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

注射用法罗培南钠的单剂量和多剂量药代动力学研究

目的考察单次和连续静脉滴注法罗培南钠注射液后健康人体内的药动学过程。方法12名健康受试者随机交叉单剂量静脉滴注给药100,200,300,600mg,单剂量试验结束后进人多剂量试验,8名受试者静脉滴注给药每次200mg,每日3次,连续给药7d,用高效液相色谱法测定血浆和尿中法罗培南的浓度,并采用药动学程序对试验数据进行处理,求算有关药动学参数。结果12名健康受试者单剂量静脉滴注法罗培南注射液后,主要药动学参数Cmax分别为（8．42±1．96）mg／L,（16．64±3．09）mg／L,（24．73±3．58）mg／L,（44．43±3．93）mg／L,T1/2分别为（1．72±0．72）h,（1．60±0．33）h,（1．56±0．21）h,（1．36±0．09）h,AUCOJ分别为（13．90±2．96）mg·h／L,（26．98±5．75）mg·h／L,（38．29±5．29）mg·h／L,（70．58±10．33）mg·h／L,12h累积尿药排泄率分别为31．4％,31．5％,30．5％,34．9％,多次静脉滴注后的主要药动学参数Cmax,T1/2,AUC0-4分别为（15．83±3．96）mg／L、（1．11±0．27）h、（21．93±3．59）mg·h／L,血药浓度波动系数和Gav分别为（5．34±1．30）和（2．74±0．45）mg／L,12h累积尿药排泄率为40．5％。结论单次给药在100～600mg剂量范围内法罗培南呈线性消除,性别对法罗培南的药代动力学过程无影响,肾脏是法罗培南的主要排泄器官,连续多次给药在体内无蓄积,     

Bioavailability and pharmacokinetics of a new nifedipine preparation in healthy volunteers

In the course of this trial the bioavailability and the essential pharmacokinetic parameters of a newly developed 10 mg nifedipine preparation were to be determined in comparison to a marketed reference preparation after single oral administration. For this purpose, the test and the reference preparation were examined in 16 healthy volunteers according to a randomized 2-way cross-over design (latin square), blood samples were withdrawn up to 16 h p.a. and plasma concentrations of nifedipine and NPO (primary metabolite of nifedipine) were quantified by a HPLC method. Both preparations led to mean maximum concentrations of nifedipine in plasma of 110 mg/ml about 0.5 h p.a.; the mean termial half-lives were 1.8 h (test preparation) and 1.7 h (reference preparation). The data found for the metabolite NPO largely corresponded to those of the parent substance, thus equal metabolisation and adequate pharmaceutical quality of the two galenics may be presumed. Statistical comparison (ANOVA, Pratt-Wilcoxon test) did not reveal any significant differences between the test and reference preparation and, apart from a minor deviation, confidence intervals according to Westlake were sufficiently small, such that the two formulations may be considered bioequivalent. No differences of clinical relevance were detected between the two preparations in assay. The undesired side effects/concomitant symptoms known after nifedipine administration were observed.     

A combined single and multiple dose pharmacokinetic study of oral isosorbide-5-mononitrate in healthy volunteers.

Pharmacokinetics of 20 mg isosorbide-5-mononitrate (IS-5-MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two-way crossover experimental design. Pentacard 20 mg tablets were compared with Ismo 20 mg tablets. After single-dose administration, both preparations caused a rapid increase in IS-5-MN plasma levels with the peak plasma concentration occurring between 0.5 and 1.5 h. For both formulations, the mean plasma half-life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration-time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent.     

单次和连续口服艾司西酞普兰在中国健康志愿者的药代动力学

目的 研究中国健康志愿者单次和连续口服艾司西酞普兰(抗抑郁药)的体内药代动力学特点.方法 12名健康受试者在第1、8～14天,每日1次空腹口服艾司西酞普兰20 mg;第1、14天服药后不同时间点,以及第12～14天每13服药前,取肘静脉血肝素抗凝,用高效液相色谱-荧光检测法测定血浆中的艾司两酞普兰浓度,用DAS软件计算药代动力学参数.结果 艾司西酞普兰的药代动力学特点符合二房室模型,平均t1/2为41.1 h;Cav为(76.4±26.8)μg·L-1;AUCss为(1832.4±642.4)μg·h·L-1;AUC0-∞和AUC0-∞分别为(4765.9±2171.0)和(5385.6±2851.2)μg·h·L-1;tmax为(3.2±1.3)h;t1/2为(41.1±17.7)h;CL为5.0 L·h-1;AUC的平均累积常数RAUC为(1.2±0.3).结论 艾司西酞普兰连续服药7天可以达稳态,体内无蓄积.