Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine.

1. We studied the effects of pre-treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double-blind four-way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration-response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side-effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.     

The pharmacokinetics of oral nifedipine--a population study.

1. The pharmacokinetics and metabolism of nifedipine have been studied in a population of 59 young male volunteers following administration of a 10 mg capsule. 2. The area under the plasma concentration-time curves (AUC) for nifedipine demonstrated a skewed but not a bimodal distribution (mean 154 ng ml-1 h; range 54-306 ng ml-1h). 3. Calculation of the ratio of the AUC of nifedipine to the AUC of its nitropyridine metabolite did not separate those individuals with high AUC values of nifedipine from the remainder of the population. 4. Similarly there was no evidence for bimodality in the excretion of the major urinary metabolite. Those subjects with high plasma AUC values for nifedipine excreted similar amounts to the remainder of the population. 5. In contrast to a previous study using a 20 mg oral dose, there was no evidence of polymorphism in the pharmacokinetics or metabolism of nifedipine following a single 10 mg oral dose.     

人血浆中非洛地平的LC-MS测定法及其在药动学研究中的应用

目的建立人血浆中非洛地平浓度的液相色谱-质谱联用的测定方法。方法以尼莫地平为内标,血浆样品经100μL1.0mol·L-1NaOH溶液碱化,采用乙醚-正己烷(4∶1)萃取后进行LC-MS分析。色谱柱为C18柱(150mm×4.6mm,5μm),流动相为甲醇-0.1%甲酸(84∶16),流速为0.8mL·min-1;离子源为电喷雾离子化源(ESI源),正离子方式检测;扫描方式为选择离子监测(SIM),用于定量分析的离子分别为m/z406(非洛地平)和m/z441(尼莫地平)。结果非洛地平在0.2～20.0μg·L-1浓度范围内线性关系良好(r=0.9948),定量下限为0.2μg·L-1,低、中、高浓度的提取回收率均大于81.9%,日内、日间精密度(RSD)均小于14.9%。结论该方法准确可靠,灵敏度高,适用于血浆中非洛地平浓度的测定及其药动学研究。     

Stereoselective pharmacokinetics of oral felodipine and nitrendipine in healthy subjects: correlation with nifedipine pharmacokinetics

Summary The pharmacokinetics of racemic (rac) felodipine, rac-nitrendipine and nifedipine (all given as an oral dose of 20 mg in solution) have been investigated in a randomised cross-over study in 12 healthy male subjects using stereoselective assays. Both felodipine and nitrendipine exhibited stereoselective pharmacokinetics. On average, the AUCs of the active (S)-enantiomers of felodipine and nitrendipine were 139% and 104% higher than those of their optical antipodes, but the elimination half-lives of the enantiomers of each racemate were not different. The AUCs of nifedipine, rac-felodipine, rac-nitrendipine and of their enantiomers were highly correlated (all r>0.83), suggesting closely related rate limiting steps in the in vivo first-pass metabolism of these high-clearance drugs. Stereoselectivity was only a minor contributor to inter-individual variability in the oral pharmacokinetics of these compounds in healthy subjects.Haemodynamic data and pharmacokinetic-pharmacodynamic relationships obtained in this study are reported in the accompanying paper     

A study of the acute pharmacodynamic interaction of ramipril and felodipine in normotensive subjects.

1. The possibility of an acute pharmacokinetic or pharmacodynamic interaction between the ACE inhibitor ramipril and the calcium antagonist felodipine was examined in 12 normotensive male volunteers. 2. Ramipril (5 mg) and felodipine ER (10 mg) were administered orally in a double-blind, randomised, placebo-controlled, Latin square design to fasting subjects. 3. There was no evidence of a pharmacokinetic interaction between agents. The concentration-time profiles remained unaltered by coadministration of both agents. 4. Plasma ACE inhibition by ramiprilat was unaffected by concurrent felodipine. The trend towards increased fractional sodium excretion after felodipine was not influenced by ramipril. Plasma renin activity, aldosterone and catecholamines remained unaltered. 5. Combination therapy produced a statistically significant fall in blood pressure supine and erect which was not evident with monotherapy. The reflex tachycardia associated with felodipine monotherapy was significantly attenuated by the coadministration of ramipril. 6. This study presents further evidence for the effective combination of ACE inhibitors and calcium antagonists to lower blood pressure. The reflex tachycardia associated with calcium antagonist therapy can be significantly reduced by coadministration with sustained antihypertensive effect.     

Effect of menthol on the pharmacokinetics and pharmacodynamics of felodipine in healthy subjects

Objectives The present study was undertaken to determine whether menthol affects the metabolism of and pharmacological responses to the calcium channel antagonist felodipine in people.Methods Eleven healthy subjects (ten female, one male) participated in a randomized, double-blind, two-way crossover study, comparing the kinetics and effects of a single oral dose of felodipine ER tablet (Plendil, 10 mg) with menthol (test) or placebo (reference) capsules. Ten subjects completed the study. At the beginning of the study, a 10-mg felodipine ER tablet and a 100-mg menthol or placebo capsule were given. During the 2^nd, 5^th and 7^th hours of the study, 50, 25 and 25 mg menthol or placebo capsules were given, respectively. Blood samples and cardiovascular measurements were obtained at frequent intervals. Serum felodipine and dehydrofelodipine concentrations were determined by means of gas chromatography/mass spectrometry.Results Pharmacokinetic parameters of felodipine and dehydrofelodipine (AUC_0–24, C _max, t _max, dehydrofelodipine/felodipine AUC_0–24 ratio) were not markedly changed with menthol coadministration. Only eight female subjects cardiovascular data were included in the analysis because of technical problems during the measurements. There were no statistically significant differences in blood pressures and heart rates between the two treatments.Conclusions We conclude that the pharmacokinetics and pharmacodynamics of felodipine were essentially unaltered by menthol.     

A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat.

The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (means s and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC50. Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.     

非洛地平与美托洛尔复方透皮贴剂的药代动力学和生物利用度评价

目的研究非洛地平(Fel)与美托洛尔(Met)复方透皮贴剂(Fel+Met-P)在兔体内的药代动力学和生物利用度。方法6只健康新西兰白兔分2次实验,先后分别随机交叉单次给予Fel+Met-P(1+10),(3+30)和(9+90)mg.kg-1,和随机交叉单次给予Fel+Met静脉注射液〔Fel+Met-I,(0.2+2)mg.kg-1〕、口服混悬液〔Fel+Met-S,(1+10)mg.kg-1〕及2药市售缓释片〔Fel+Met-T,(1+10)mg.kg-1〕,气相色谱-电子捕获法分别测定血浆中Fel和Met浓度,DAS软件计算药代动力学参数并进行生物利用度评价。结果Fel+Met-P血药浓度可平稳维持2～3d。在Fel+Met-P不同剂量组,Fel和Met的血药峰浓度(cmax)、血药-时曲线下面积(AUC)(0→60)和AUC(0→∞)分别随Fel+Met-P剂量增加而增大,且均与剂量(D)呈良好线性关系,Fel的回归方程为cmax=6.6342D+4.355(r=0.9969)和AUC(0→∞)=295.08D+92.322(r=0.9963),Met为cmax=8.4628D+51.528(r=0.9957)和AUC(0→∞)=315.14D+1474.8(r=0.9993);不同剂量组之间Fel和Met的达峰时间(tmax)、平均吸收时间(MAT)、平均驻留时间〔MRT(0→60)和MRT(0→∞)〕及各自绝对生物利用度均无显著性差异。与Fel+Met-S和Fel+Met-T比较,Fel+Met-P3个剂量组Fel和Met的tmax和MRT(0→∞)均延长,tmax分别为(21.5±8.1)～(27.0±12.3)和(25.3±14.4)～(37.5±10.0)h,MRT(0→∞)分别为(28.5±2.7)～(31.8±0.8)和(28.1±4.4)～(31.8±1.3)h;与Fel+Met-S比较,Fel的绝对生物利用度分别为Fel+Met-S的2.25,2.75和2.28倍,Met分别为Fel+Met-S的2.10,1.90和1.64倍;与Fel+Met-T比较,Fel的绝对生物利用度无明显变化,Met分别为Fel+Met-T的2.13,1.93和1.67倍。结论Fel+Met-P在兔体内具有缓释长效药代动力学特征,达到了提高药物生物利用度、延长药物体内驻留时间、维持平稳血药浓度和方便用药新剂型的设计目的。     

高脂饮食对非洛地平在中国健康受试者体内药动学的影响

目的研究高脂饮食对非洛地平在健康中国人体内的药动学影响。方法 10名健康男性受试者随机分成2组,分别于空腹或进食高脂餐后口服非洛地平缓释片1片(10 mg/片),采用液相色谱-串联质谱(LC-MS/MS)法测定血浆中非洛地平的浓度,用DAS 2.1.1软件计算主要药动学参数,用SPSS 19.0软件对主要药动学参数进行统计学分析。结果受试者于空腹和进食高脂餐后口服非洛地平缓释片的主要药动学参数ρmax、tmax、AUC0-36 h分别为(5.78±3.22)μg·L-1和(9.29±3.47)μg·L-1、(3.11±1.27)h和(5.33±1.80)h、(46.6±24.2)μg·h·L-1和(58.7±18.6)μg·h·L-1;对空腹与进食高脂餐后给药的主要药动学参数采用配对t检验进行统计分析,ρmax和tmax具有显著性差异(P<0.05)。结论高脂饮食可显著降低非洛地平的吸收速度,并显著提高峰浓度。     

Bayesian parameter estimation and population pharmacokinetics.

The widespread application of Bayesian parameter estimation in the area of therapeutic drug monitoring (TDM) has prompted the need for well conducted population studies to obtain relevant prior pharmacokinetic parameter estimates. In many cases the population has consisted of a relatively small number of subjects. This may be unavoidable for drugs used in cancer chemotherapy or in small, specific populations of patients. In contrast, information about drugs which are used extensively, such as the aminoglycosides, can be obtained by population studies which involve a large number of individuals. Indeed, this technique has proved particularly useful for determining parameter estimates which can be employed in neonatal TDM. Bayesian parameter estimation has been most frequently used for drugs with narrow therapeutic ranges such as the aminoglycosides, cyclosporin, digoxin, anticonvulsants (especially phenytoin), lithium and theophylline. However, the technique has now been extended to cytotoxic drugs, Factor VIII and warfarin. Bayesian methods have also been used to limit the number of samples required in more conventional pharmacokinetic studies with new drugs. Further advances in the use of these methods are likely to include measures of drug response and toxicity requiring population studies which also include relevant pharmacodynamic information.     

Software for population pharmacokinetics and pharmacodynamics.

Pharmacokinetic-pharmacodynamic modelling is being used increasingly as a tool in drug development because often in phase III clinical trials only sparse data are available for analysis and so a nonlinear mixed effects modelling approach has to be adopted. Specialist data analytical techniques and software are required to analyse such data. This article reviews some of the software currently available for performing nonlinear mixed effects modelling. A questionnaire was devised and sent to a number of software producers and the findings are presented and discussed in this paper. The programs could be grouped into 3 main categories: parametric and nonparametric maximum likelihood and Bayesian. It was apparent from the questionnaire that software development for population data analysis is a very active area of investigation. The implementation of methodologies varied widely between the packages: some were self-contained programs, whereas others were written within another application, usually a statistical package. They also varied with respect to their ease of use and level of support offered by the software producers. Although robustness and reliability are important concerns, they were not addressed in the present review. Most of the programs surveyed are in continual development.     

A comparison of computational approaches to the population pharmacokinetics. An example of toxicological data

Four different approaches to population pharmacokinetic analysis were applied to routine clinical data on carbamazepine intoxications in epileptic and alcoholic patients. The computational issues were noticed for maximum likelihood based methods, while Markov Chain Monte Carlo approach revealed that the estimates of absorption and lag parameters might be unreliable. Non-identifiability of these parameters may be the source of computational problems with other methods. Simultaneous use of different approaches to population pharmacokinetics is therefore advised, since it allows for verification of the obtained results.     

非洛地平对依那普利及依那普利拉在中国受试者体内药动学的影响

目的探讨非洛地平对依那普利及其代谢物依那普利拉在中国健康受试者体内药动学的影响。方法 12例健康受试者(男女各半)采用随机开放二重3×3拉丁方试验设计,受试者在空腹状态下分别口服依那普利片5 mg、非洛地平片5 mg或依那普利片5 mg+非洛地平片5 mg。以高效液相色谱-串联质谱(HPLC-MS/MS)法测定血浆中依那普利及其代谢物依那普利拉的浓度,采用非房室模型法计算药动学参数,用SPSS 18.0软件对主要药动学进行统计学分析。结果单服依那普利片和同服依那普利片+非洛地平片血浆中依那普利的t_(1/2)分别为(1.08±0.59)和(1.17±0.72)h;ρ_(max)分别为(44.27±13.30)和(43.15±8.38)μg·L~(-1);AUC_(0-72h)分别为(84.90±19.50)和(82.70±16.50)μg·h·L~(-1);AUC_(0-∞)分别为(85.80±19.80)和(83.30±16.50)μg·h·L~(-1)。依那普利拉的t_(1/2)分别为(14.73±3.29)和(17.35±5.56)h;ρ_(max)分别为(37.61±15.01)和(34.07±11.78)μg·L~(-1);AUC_(0-72) h分别为(372.60±84.60)和(361.00±90.70)μg·h·L~(-1);AUC_(0-∞)分别为(400.60±84.60)和(361.00±90.70)μg·h·L~(-1)。依那普利及依那普利拉的所有参数均无显著差异(P>0.05)。结论本研究建立的HPLC-MS/MS法快速,灵敏度高,专属性强,测定结果准确,适用于临床试验中依那普利及依那普利拉血药浓度测定;非洛地平对依那普利及其代谢物依那普利拉的药动学无明显影响。     

A placebo-controlled dose-response study of felodipine extended release in hypertensive patients

This placebo-controlled study assessed antihypertensive effect and tolerability of two dose levels of an extended release (ER) formulation of felodipine (Plendil), given once daily to patients in primary health care. The patients had mild to moderate hypertension and were randomized to receive felodipine ER (FER) 20 mg (n = 50), FER 10 mg (n = 50), or placebo (n = 51) in a 4-week, double-blind, parallel-group multicenter study. After 4 weeks, the 24-h reduction in supine diastolic BP (DBP) was greater (p less than 0.01) in both FER groups (7 +/- 6 and 8 +/- 5 mm Hg) than in the placebo group (4 +/- 6 mm Hg). The 24-h reduction in supine systolic BP (SBP) was greater (p less than 0.01) in the FER 20-mg group (14 +/- 11 mm Hg), but not in the FER 10-mg group, than in the placebo group (8 +/- 11 mm Hg). No significant difference in blood pressure (BP) was found between FER 10 and 20 mg. Heart rate (HR) did not differ between any of the groups, nor did body weight or routine laboratory parameters. During felodipine treatment, 17 patients (12 receiving FER 20 mg) were withdrawn mostly because of vasodilatory side effects such as headache and ankle edema. We conclude that FER 10 mg and 20 mg once daily had an antihypertensive 24-h effect and that FER 10 mg may be more suitable as initial dose.     

群体药代动力学研究方法

本文着重对群体药代动力学研究方法和研究过程进行介绍,使读者进一步了解非线性混合效应模型方法的特点和具体应用。     

Population study of triazolam pharmacokinetics.

The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20-44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post-dose. The overall mean +/- s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 +/- 0.3 (1.7-9.4) ng ml-1; time of peak, 1.3 +/- 0.1 (0.5-4.0) h after dose; elimination half-life, 2.6 +/- 0.1 (1.1-4.4) h; total AUC: 19.1 +/- 1.1 (4.4-47.7) ng ml-1 h; oral clearance, 526 +/- 38 (175-1892) ml min-1. All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov-Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. Peak plasma level was highly correlated with clearance (r = -0.85, P less than 0.0001), and AUC (r = 0.85, P less than 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = -0.01). Triazolam clearance may vary widely even within a homogeneous group of healthy young men.     

A large-sample study of diazepam pharmacokinetics

Healthy male volunteers (n = 48) aged 18-44 years received a single 10-mg oral dose of diazepam. Plasma diazepam and desmethyldiazepam concentrations were measured at multiple points during the next 11 days. The distribution of peak plasma concentration (mean, 406 ng/ml) was not skewed and did not differ significantly from normal (Guassian). However, the distributions of elimination half-life (44.2 h), elimination rate constant (0.0219/h), clearance (26.6 ml/min), and volume of distribution (83 L) all were significantly skewed and deviated significantly fron normal. After logarithmic transformation, the distributions of elimination rate constant, elimination half-life, and volume of distribution were consistent with normal; however, this was not the case for time of peak plasma concentration. Thus, the pharmacokinetic characteristics of oral diazepam are highly variable even in a relatively homogeneous population. Parametric statistical testing procedures and pharmacokinetic forecasting schemes may be improved by more precise delineation of the underlying distributions for pharmacokinetic variables.     

A population analysis of the pharmacokinetics and pharmacodynamics of midazolam in the rat

The concentration-EEG effect relationship of midazolam in the rat was studied from a population perspective. Plasma concentration and EEG effect data from 27 rats were available for analysis. Effect parameters derived from aperiodic EEG analysis were used as effect parameters. The population analysis gave results that were similar to the sample theory estimates (¯xs and SDs) obtained from the fits to individual data sets. Reanalysis of the EEG data using mean population pharmacokinetic parameters as input to the pharmacodynamic model led to poorer estimation of the pharmacodynamic parameters: particularly EC₅₀.Inclusion of one observed plasma concentration per individual significantly improved the estimation of the pharmacodynamic parameters and led to results that were virtually indistinguishable from those obtained using complete pharmacokinetic data.This study was supported by Medigon grant 900-521-106.