Pharmacokinetic and pharmacodynamic responses to caffeine in poor and normal sleepers

Pharmacokinetic and pharmacodynamic responses to caffeine (2.5 mg/kg) were compared between ten healthy self-rated poor sleepers and ten normal sleepers. Sleep pattern assessed by the Pittsburgh Sleep Quality Index (PSQI). There was no significant difference in mean estimated daily caffeine consumption between the groups. The poor sleepers had significantly higher scores for neuroticism on the Eysenck Personality Questionnaire (EPQ) and anxiety on the Hospital Anxiety Depression (HAD) scale, compared with normal sleepers. Caffeine pharmacokinetics were assessed by measurement of saliva caffeine concentrations. Poor sleepers showed significantly greater variability in caffeine C_max, clearance and half-life, compared to normal sleepers. Pharmacodynamic measures included heart rate, blood pressure, visual analogue scales for concentration, vigilance and relaxation, psychomotor performance [Digit Symbol Substitution Test (DSST) and tapping rate (TR)] and EEG activity [Contingent negative variation (CNV), auditory evoked potential and power spectral analysis]. Prior to caffeine administration, poor sleepers compared to normal sleepers had faster heart rates, lower ratings for concentration and relaxation, poorer performance on the DSST, greater CNV magnitude, faster peak alpha frequency and lower delta, theta and beta power. These differences persisted after caffeine ingestion and overall differences between the groups on these measures were significant (P<0.01–0.001). Post-dose, but not pre-dose, scores for vigilance and TR were significantly lower overall in poor compared with normal sleepers. Despite the baseline differences between poor and normal sleepers, the changes following caffeine administration were similar in direction and magnitude in both groups.     

Pharmacokinetic and pharmacodynamic characterization of gliclazide in healthy volunteers

Pharmacokinetic and pharmacodynamic properties of gliclazide were studied after an oral administration of gliclazide tablets in healthy volunteers. After an overnight fasting, gliclazide tablet was orally administered to 11 volunteers. Additional 10 volunteers were used as a control group (i.e., no gliclazide administration). Blood samples were collected, and the concentration determined for gliclazide and glucose up to 24 after the administration. Standard pharmacokinetic analysis was carried out for gliclazide. Pharmacodynamic activity of the drug was expressed by increase of glucose concentration (deltaPG), by area under the increase of glucose concentration-time curve (AUC(deltaPG)) or by the difference in increase of glucose concentration (D(deltaPG)) at each time between groups with and without gliclazide administration. Pharmacokinetic analysis revealed that Cmax, Tmax, CL/F (apparent clearance), V/F (apparent volume of distribution) and half-life of gliclazide were 4.69+/-1.38 mg/L, 3.45+/-1.11 h, 1.26+/-0.35 L/h, 17.78+/-5.27 L, and 9.99+/-2.15 h, respectively. When compared with the no drug administration group, gliclazide decreased significantly the AUC(deltaPG) s at 1, 1.5, 2, 2.5, 3 and 4 h (p<0.05). The deltaPGs were positively correlated with AUC(gliclazide) at 1 and 1.5 h (p<0.05), and the correlation coefficient was maximum at 1 h (r = 0.642) and gradually decreased at 4 h after the administration. The AUC(deltaPG)s were positively correlated with AUC(gliclazide) at 1, 2, 3 and 4 h (p<0.05), and the maximum correlation coefficient was obtained at 2 h (r=0.642) after the administration. The D(deltaPG) reached the maximum at 1 h, remained constant from 1 h to 3 h, and decreased afterwards. Therefore, these observations indicated that maximum hypoglycemic effect of gliclazide was reached at approximately at 1.5 h after the administration and the effect decreased, probably because of the homeostasis mechanism, in health volunteers.     

Pharmacokinetic and pharmacodynamic studies in man with an antianginal agent 'Visacor'

This randomized, double-blind, crossover study in 10 healthy male volunteers compared four single oral doses of ICI 141,292 ('Visacor'), i.e. 50, 100, 200, and 300 mg, with placebo. Venous blood samples were collected pre-dose and at various times after dosing and the concentrations of ICI 141,292 in the plasma were determined by radioimmunoassay. A standardized 4-min bicycle exercise test was also performed and before this the resting haemodynamic parameters were assessed. Peak plasma concentrations of ICI 141,292 and the area under the plasma concentration-time curve increased disproportionately with dose such that after scaling to a dose of 200 mg there remained a significant linear trend with dose. The time to peak plasma concentration displayed an increasing trend with dose and, once again, the linear component of this trend was statistically significant. The mean heart rates during exercise were all significantly reduced compared to placebo for 24 h by each of the doses (range 7.8 to 17.4 beats min-1 at 24 h, p less than 0.01). The increase in heart rate during exercise was inversely related to the logarithm of the ICI 141,292 plasma concentration with higher plasma concentrations being associated with lower heart rate increases. The mean supine resting heart rates were slightly but significantly reduced at 2 and 6 h after dosing by each treatment and by the 300 mg dose at 24 h. Each of the doses of ICI 141,292 was well tolerated.     

药动学药效学结合模型对美托洛尔降压效应的研究

目的应用药动学药效学结合模型的方法研究美托洛尔效应室药物浓度与降压效应之间的关系。方法原发性高血压患者1次口服美托洛尔片剂50mg,用She iner等提出的药动学药效学结合模型,表达美托洛尔降低动脉收缩压效应与药物浓度之间的关系。结果美托洛尔体内代谢呈一室模型,降低动脉收缩压效应与血药浓度之间存在逆时针滞后现象,效应室药物浓度(Ce)与降压效应(E)的关系为E=Em axCes/[Ces Ce(50)s],Ce(50)为(122.32±75.82)μg/L,效应室消除速率常数Keo为(0.043±0.032)m in。结论药动学药效学结合模型可较好地应用于美托洛尔治疗高血压病过程中降压效应的预测。     

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

Rationale  The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known. Objectives  Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well-known neurosteroid, acting via the GABA_A receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA_A receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA_A receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans. Materials and methods  Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self-rated sedation, and mood rating scales were used during the test day. A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle. Results  Exogenously administered isoallopregnanolone produced a dose-dependent increase in the serum concentration of isoallopregnanolone. In parallel, there was also a rise in the allopregnanolone concentration. There was a decrease in saccadic eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle. Conclusions  After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.     

Pharmacokinetic and pharmacodynamic interaction between the antidepressant tianeptine and oxazepam at steady-state

To assess if any pharmacokinetic or pharmacodynamic interaction at steady-state occurs between the new antidepressant tianeptine and a benzodiazepine (oxazepam) following multiple oral dosing of both drugs, 12 healthy male volunteers entered a balanced three-way double blind cross-over study. Tianeptine (12.5 mg) and/or oxazepam (10 mg) were given three times daily for 4 days. Pharmacokinetic data within a dosing interval at steady-state showed that there were no statistically significant changes in the pharmacokinetics of either tianeptine (and its two major metabolites) or oxazepam when both drugs were co-administered. Psychometric data showed that there was no synergistic negative interaction between the two drugs and that their combination may result in beneficial effects on alertness and happiness     

Pharmacokinetic pharmacodynamic evaluation of the combined administration of alprazolam and fluoxetine

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.     

厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内药动学-药效学关系研究

目的:应用药动学-药效学结合模型研究厄贝沙坦与氢氯噻嗪联用在肾性高血压大鼠体内单剂量及多剂量用药时的药动学-药效学关系。方法:将SD大鼠制备成2肾1夹型肾性高血压模型,给大鼠单剂量或多剂量灌胃给药,分别于第1天和第8天连续的预定时间点测定血药浓度,同时测定动脉收缩压(SBP)和动脉舒张压(DBP)等药物效应,建立效应室药动学-药效学结合模型并计算相关的药动学和药效学参数。对单用、联用及单剂量、多剂量的药动学-药效学规律进行定量研究。结果:厄贝沙坦的药动学特征呈二室模型,氢氯噻嗪在非稳态和稳态条件下均未改变厄贝沙坦的药动学参数,而在稳态条件下,厄贝沙坦可增高氢氯噻嗪的血药浓度及曲线下面积。厄贝沙坦和氢氯噻嗪联用降压效应优于单用的效应。药物效应和效应室浓度之间符合Sigmoid-Emax药效学模型。单剂量下药物效应与血药浓度间存在滞后现象,多剂量下滞后现象消失。Emax、EC50、Keo等药效学参数在厄贝沙坦组和两药联用组之间的差异有统计学意义。结论:建立了PK-PD定量数学模型研究厄贝沙坦和氢氯噻嗪联用在大鼠体内单剂量和多剂量用药后药动学-药效学(暴露-反应)关系的规律,并提供了相关的药动学和药效学参数,可为临床合理用药提供参考依据。     

Pharmacokinetic and pharmacodynamic interactions between almorexant,a dual orexin receptor antagonist,and desipramine

Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200 mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50 mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.     

Pharmacokinetic/pharmacodynamic modeling of roxadustat's effect on LDL cholesterol in patients in Japan with dialysis-dependent chronic kidney disease and anemia

AimsThe objective of this analysis was to develop and evaluate a pharmacokinetic/pharmacodynamic (PK/PD) model of the effect of roxadustat on low-density lipoprotein cholesterol (LDL-C) in Japanese patients with anemia of dialysis-dependent chronic kidney disease while considering the impact of covariates on model parameters.MethodsA total of 2330 LDL-C measurements from 275 patients in 3 clinical studies were analyzed using a nonlinear-mixed effects modeling approach in NONMEM software.ResultsThe PK/PD relationship between roxadustat exposure and LDL-C was well described by a kinetic-pharmacodynamic model with a physiological indirect response model as the PD component. Co-administered statin usage, sevelamer usage, type of dialysis (hemodialysis or peritoneal dialysis), and sex were selected as covariates for LDL_baseline. Weight was selected as a covariate for ID_50. I_max and ID₅₀ were estimated as 0.661 and 1.51 mg/h, respectively.ConclusionRoxadustat can decrease LDL-C independent of statins and sevelamer. Further study of the ability of roxadustat to lower LDL-C and any potential effects on outcomes is needed.     

Pharmacokinetic and pharmacodynamic evaluation of cyclosporin A O/W-emulsion and microsphere formulations in rabbits

O/W-emulsion and microspheres containing cyclosporin A (CSA) were prepared to investigate the feasibility of developing new formulations. The pharmacokinetic and pharmacodynamic characteristics of these preparations were evaluated in rabbits and compared to two commercial products, Sandimmun Neoral^® for oral administration and CIPOL Inj.^® for intravenous administration. After oral or intravenous administration (10 mg/kg) to male rabbits, CSA concentration and lymphocyte population in whole blood were measured by TDxFLx^® and Coulter STKS^®, respectively. Total clearance (CL_t) was increased after intravenous administration of CSA O/W-emulsion compared with intravenous administration of CIPOL Inj^®. In case of oral administration, AUC and bioavailability of CSA microspheres and O/W-emulsion were not significantly different (P>0.05) from those of Sandimmun Neoral^®, however, MRT and T_max of CSA microspheres and O/W-emulsion were significantly increased (P<0.05). There were no significant differences in the area between the baseline and effect curves (ABEC) among these formulations (P>0.05), but the pharmacodynamic availability (F_PD) of CSA O/W-emulsion was 5.51-fold higher than that of CIPOL Inj.^® and was significantly greater than that of Sandimmun Neoral^® (P<0.05). These results suggest that CSA microspheres and O/W-emulsion have sustained release characteristics and may be used as such formulations for oral or intravenous administration of CSA.     

Target-mediated pharmacokinetic and pharmacodynamic model of recombinant human erythropoietin (rHuEPO)

A mechanism-based pharmacokinetic–pharmacodynamic (PK/PD) model was developed for recombinant human erythropoietin (rHuEPO) to account for receptor-mediated endocytosis via erythropoietin receptor (EPOR) as a primary mechanism for nonlinear disposition of rHuEPO as well as activation of erythropoietic stimulation. Time profiles of rHuEPO concentrations following a wide range of intravenous (i.v.) doses in rats (10, 100, 450, 1,350, 4,050 IU/kg), monkeys (500, 2,000, 4,000 IU/kg), and man (10, 100, 150, 300, 500 IU/kg) were examined. The mean data of reticulocytes, red blood cells (RBC), and hemoglobin for five different doses in rats were analyzed. The PK model components included receptor binding, subsequent internalization and degradation, EPOR turnover, non-specific tissue distribution, and linear first-order elimination from plasma. The equilibrium dissociation constant (K _D ) was similar between rats and monkeys (0.11 nM) and was 10-fold lower in humans (0.012 nM). The PD effects of rHuEPO were described by an indirect response model with lifespan cell loss and driven by the rHuEPO–EPOR complex. A generalized nonlinear PK model for rHuEPO taking into account EPOR binding of the drug in bone marrow was proposed and well described the PK profiles of rHuEPO following i.v. doses in rats, monkeys, and man. The present receptor-mediated PK/PD model for rHuEPO closely reflects underlying mechanisms of disposition and dynamics of rHuEPO.     

临床药代动力学和药效动力学研究中的采样优化方法

采样优化方法在临床药代动力学和药效动力学研究中受到广泛关注.本文综述了D优化法、多元线性回归法、基于最大后验贝叶斯估算法(MAPB)的有限采样法等的原理、步骤及优缺点,并总结了各方法在采样优化估算中每一步骤的特点.本文也列举了重要的应用实例,介绍了可实现其估算分析的统计软件.     

Role of baseline parameters in determining indirect pharmacodynamic responses.

Indirect Response Models account for the pharmacodynamics of numerous drugs which inhibit or stimulate the production (k(in)) or loss (k(out)) of the response variable (R). The dose and pharmacokinetics, capacity (S(max), I(max)), and potency (SC(50), IC(50)) factors of the Hill function incorporated in these models are the primary determinants of overall responsiveness. However, the initial or baseline value for the response (R(0) = k(in)/k(out)) should also be considered as an important factor for the net response. Using Indirect Response Model III (stimulation of input) as an example, the net area under the effect curve (AUEC(NET)) can be proportional to the R(0) values. Such a feature is demonstrated in this report by computer simulations, by examination of the integral of the simulated response vs time profiles, and with examples from the literature. Also shown is an adjustment of R(0) when the therapeutic agent is an endogenous substance. These analyses show that the role of R(0) and k(in) should not be overlooked as determinants of indirect responses and source of variation among subjects or patient groups.     

In vitro P-glycoprotein efflux inhibition by atypical antipsychotics is in vivo nicely reflected by pharmacodynamic but less by pharmacokinetic changes

Background

P-glycoprotein (P-gp), an efflux transporter of the blood-brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). Thus drug-dependent inhibition, induction or genetic variation of P-gp impacts drug therapy.

Methods

We investigated atypical antipsychotics and their interaction with P-gp. Amisulpride, clozapine, N-desmethylclozapine, olanzapine, and quetiapine were assessed in vitro on their inhibitory potential and in vivo on their disposition in mouse serum and brain, and behaviourally on the RotaRod test. In vivo wildtype (WT) and mdr1a/1b double knockout mice (mdr1a/1b (−/−, −/−); KO) were investigated.

Results

In rhodamine 123 efflux assay drugs inhibitory potency to P-gp could be ranked quetiapine > N-desmethylclozapine > clozapine > olanzapine. When treating WT and KO mice i.p. and assessing brain and serum levels by HPLC analysis, P-gp expression has the highest but a rather short effect on the distribution of amisulpride, whereas the others ranked N-desmethylclozapine > olanzapine > quetiapine > clozapine; contrasted by in vivo behavioral changes at various time points. Here quetiapine > clozapine > olanzapine impacts behavior most when P-gp is lacking. Present results indicate the relevance of P-gp expression for CNS-drug therapy.

Conclusions

Combination of in vitro, and in vivo methods highlights that inhibitory potency did not reflect P-gp related drug disposition. But, when drugs were ranked for inhibitory potency, this order is reflected in pharmacodynamic changes or vice versa. Pharmacodynamic effects otherwise were at most correlated to drug brain levels, which however, were present only to a limited extent (by positron emission tomography) accessible in humans.     

不同盐基对药物临床效果和安全性的影响分析

成盐是改善活性药物分子（API）成药性的一个重要手段,目前活性成分相同而盐基不同的药物不断出现,本文就盐基对药物药动学、药效学及药物不良反应三个方面的影响作简要综述,以对临床遴选治疗药物及新药盐基的选择提供参考。     

松果菊苷药动/药效研究进展与思考

本文综述了近年来松果菊苷（ECH）在抗衰老、提高记忆力与神经保护、抗肿瘤、保护肝脏及免疫调节等方面的药理作用研究进展,探讨了其可能的作用机制。此外,还对ECH的吸收和代谢等药代动力学最新研究进展进行总结,并将其药效学特征与药代动力学行为进行联系与比较,指出了ECH药效学和药代动力学之间存在的表面矛盾,并就如何解释这些矛盾进行了探讨。在此基础上,提出天然来源的创新药物通常具有系统前广泛代谢的特点,发挥整体药效作用的可能是其活性代谢产物;应针对中药I类新药的这些特点,加强系统前代谢转化研究;并制订科学合理的临床前药物代谢动力学技术指导原则,用以指导具有类似特点的中药I类新药的研究。     

Pharmacokinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus night-time in healthy men aged 55–70 years

Objective To investigate (1) the pharmacokinetic and pharmacodynamic profiles of desmopressin in men from an age group with a high incidence of nocturia; and (2) circadian variation in the pharmacokinetic parameters.Methods The study had an open, randomised, four-way cross-over design. Desmopressin was administered orally (0.2 mg) and intravenously (2 µg), daytime and night-time, yielding four in-hospital sessions, separated by at least 2 days. Blood samples were taken before and at predetermined time points up to 12 h after dosing. Pharmacokinetic parameters were derived using a two-compartmental model except for AUC(0t), which was derived using non-compartmental analysis. Bioavailability was estimated using AUC(0t) for the oral and the intravenous periods. Urine, for measurements of volume and osmolality, was collected in predetermined intervals before and until 12 h after dosing.Results Fifteen healthy men aged 55–70 years were included in the analysis. The concentration–time curve after 2 µg intravenous desmopressin was best described using a biexponential term. The mean (95% CI) AUC at night was 302 (272–335) pg×h/ml and in the day was 281 (253–312) pg×h/ml. No statistically significant differences were detected between night and day except for terminal half-life, which was 3.1 h at night and 2.8 h in the daytime (P=0.02). After oral desmopressin, concentrations above the limit of quantification (2.5 pg/ml) were only detected in 51% of the samples. Peak plasma concentration (C_max) was 6.2 (5.1–7.5) pg/ml at night and 6.6 (5.5–7.9) pg/ml in the daytime. Median time to reach C_max (t_max) was 1.5 (range 1.0–4.1) h at night and 1.5 (range 0.5–3.0) h in the day. The bioavailability was 0.08%. The pharmacodynamic effects of oral and intravenous desmopressin given in the daytime were similar during the first 6 h after dosing. The night-time dosing and daytime intravenous dose resulted in antidiuresis throughout the measuring period, while the effect of the daytime peroral dose receded after 6 h.Conclusion The pharmacokinetic profile of desmopressin is biexponential. Terminal half-life was longer at night than in the daytime, but the difference is considered too small to be of clinical importance. The plasma levels given by the intravenous dose resulted in a duration of action of 12 h or more. Despite low bioavailability, the pharmacodynamic effects of oral desmopressin were similar in magnitude to those after intravenous dose at night and during the first 6 h after daytime administration.