厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型

目的研究厄贝沙坦在健康志愿者体内的药代动力学-药效学结合模型,探讨其临床药效学特征。方法18例健康志愿者厄贝沙坦片口服给药,测定血药浓度,同时测量收缩压(SBP)、舒张压(DBP)及心率(HR)等药效指标。计算厄贝沙坦的药动学参数,并根据sheiner效应室模型理论,计算药效学参数。结果厄贝沙坦的血药浓度时间曲线呈二室模型;厄贝沙坦抑制SBP和DBP的效应滞后于血药浓度,药效与血药浓度之间存在逆时针滞后环,药效和效应室浓度的关系符合SigmoidEmax模型。厄贝沙坦抑制SBP和DBP的药效学参数Emax分别为(14.8±1.5)和(9.8±2.1)mmHg,EC50分别为(0.29±0.11)和(0.18±0.07)mg·L-1,Keo分别为(0.62±0.09)和(0.68±0.07)h-1。结论建立了厄贝沙坦在健康者体内的药代动力学-药效学结合模型,有利于临床合理用药。     

Pharmacokinetic and pharmacodynamic of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions.

The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of irbesartan in renal hypertensive dogs under non-steady-state and steady-state conditions using pharmacokinetic-pharmacodynamic (PK/PD) modeling. Drugs were administered intragastrically to renal hypertensive dogs, plasma drug concentration was determined by HPLC method and Pharmacologic effects, including SBP, DBP, dp/dtmax and LVSP, were measured simultaneously. AT II, Aldosterone (ALD) and Endothelin (ET) were also used as measurement of effect. The PK and PD data were quantitatively analyzed according to the PK/PD model theory. The pharmacokinetic profiles of irbesartan conformed to a two-compartment open model. There was hysteresis loops between effects and plasma concentrations under non-steady-state condition. The relationship between effects and effect compartment concentrations (Ce) could be represented by the Sigmoid-Emax model. The Hysteresis loops disappeared under steady-state condition with more rapidly attainment of maximum concentration and effect. There were certain difference of pharmacokinetic and pharmacodynamic properties between non-steady-state and steady-state condition.     

Pharmacokinetic and pharmacodynamic population modeling of orally administered rabeprazole in healthy Chinese volunteers by the NONMEM method.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the proton pump inhibitor rabeprazole in healthy Chinese volunteers was characterized via a population approach. Healthy Chinese male volunteers were enrolled in the clinical trial. Subjects were divided into three groups by their CYP2C19 genotype. Serum concentrations of rabeprazole were determined using high performance liquid chromatography (HPLC). The intragastric pH values were monitored simultaneously. Data analysis was performed using nonlinear mixed-effects modeling as implemented in the NONMEM software package. The final PK-PD model incorporated a one-compartment PK model with one-order absorption from the gastroenteric trace, first-order elimination pathway with one fixed-effect genotype modeling, and a full sigmoidal Emax PD model (X +/- SE: E0 = 2.30 +/- 0.189; Emax = 7.32 +/- 0.662; EC50 = 51.3 +/- 2.142 ng/ml; Hill coefficient = 5.00 +/- 0.556). The time profiles for concentration and pH value, as well as the concentration-pH value relationship of rabeprazole in healthy Chinese volunteers were well described by the developed population PK-PD model.     

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 interaction between irbesartan and hydrochlorothiazide in renal hypertensive dogs

Combined irbesartan/hydrochlorothiazide (HCTZ) formulations are often used clinically. Pharmacokinetic-pharmacodynamic (PK/PD) modeling was applied to investigate the pharmacokinetic and pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs at non-steady-state and steady-state. The renal hypertensive dogs were treated with oral irbesartan alone, or HCTZ alone, or the combination of irbesartan and HCTZ for 8 days. Blood pressure and plasma concentrations were measured and pharmacokinetic-pharmacodynamic parameters were analyzed. Irbesartan showed a two-compartment model pharmacokinetic profile. The concentration-time course of irbesartan was not changed by HCTZ, but irbesartan increased the peak plasma concentration and area under the curve of HCTZ at steady-state. HCTZ had no blood pressure lowering effect at non-steady-state. Irbesartan plus HCTZ had greater blood pressure lowering action than irbesartan alone. HCTZ increased actions of irbesartan. Hysteresis loops were found between effect and plasma concentrations of irbesartan after a single dose. However, hysteresis loops disappeared at steady state with more rapid realization of maximum concentration and effects. The relationship between effects and effect-compartment concentrations of the drugs was represented by a sigmoid Emax model. The results suggest synergistic pharmacodynamic interaction between irbesartan and HCTZ in renal hypertensive dogs and some differences of pharmacokinetic-pharmacodynamic properties between irbesartan and irbesartan/HCTZ combinations at non-steady-state and steady state.     

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter "Keo" in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.     

Prediction of valproate serum concentrations in adult psychiatric patients using Bayesian model estimations with NPEM2 population pharmacokinetic parameters.

Valproate serum concentrations between 45 and 125 microg/mL are associated with the drug's efficacy in acute mania. Adaptive control dosing of valproate has not been fully studied in psychiatry. The objective of this study was to derive population pharmacokinetic (PK) parameters for valproate in healthy volunteers and to test the ability of these PK parameters to estimate concentrations in adult psychiatric patients using a Bayesian program. Population PK parameters for oral valproate were estimated from 18 PK studies in six healthy volunteers (1) using NPEM2. A Bayesian PK program using these population parameters was used to predict valproate concentration-time points in a second cohort of 21 adult psychiatry patients using 0, 1, or 2 prior concentrations. Estimated population parameters (mean +/- SD) were: Ka, 1.15+/-1.75/h; V, 0.14+/-0.042 L/Kg; and CL, 0.902+/-0.133 L/h. Bayesian valproate estimations using these parameters were negatively biased (underestimations) using zero prior concentration and unbiased using 1 or 2 prior concentrations. Mean error values (95% CI) in microg/mL for predictions using 0, 1, or 2 prior concentration-time points were -12.0 (-22.5, -1.5), -9.5 (-19.1, 0.1), and -2.5 (-11.1, 6.1), respectively, and mean absolute error values in microg/mL (95% CI) were 19.8 (12.6, 27.1), 16.3 (9.4, 23.3), and 10.1 (4.9, 15.2), respectively. Population parameters derived from healthy adult volunteers provided biased predictions of valproate concentrations in adult psychiatric patients. However, estimates using 1 or 2 valproate concentration time points predicted future concentrations that were precise and unbiased, given the wide therapeutic target range.     

健康受试者口服氟罗沙星的药动学/药效学研究

目的:研究健康受试者口服氟罗沙星的药动学(PK)和药效学(PD),从而优化氟罗沙星的临床给药方案。方法:采用三周期自身交叉对照的方式对15名健康受试者分别口服200,300,400 mg氟罗沙星片后,以高效液相色谱法(HPLC)测定血药浓度,进而求出药动学(PK)参数。体外药效学(PD)研究是测定氟罗沙星对临床分离的15种494株常见致病菌的最低抑菌浓度(MIC)。以AUC_0-24/MIC作为氟罗沙星的PK/PD参数(靶值为100和125),采用蒙特卡洛(Monte Carlo)模拟评价氟罗沙星的3种治疗方案对不同分离菌株AUC_0-24/MIC值的药效学累积反应分数(CFR)。结果:以CFR> 90%作为抗感染经验治疗的合理选择,对于大肠杆菌和淋球菌引起的感染,或口服200 mg(qd)即可;对硝酸盐阴性杆菌、肠杆菌属和哈夫尼亚菌属引起的感染,或口服300 mg(qd)即可;对于表葡球菌、铜绿假单胞菌、志贺菌属、肺炎克雷伯杆菌、柠檬酸杆菌属、普通变形杆菌、肺炎链球菌、沙门菌属和金葡球菌(MSSA)引起的感染,或口服400 mg(qd)可获得预期满意的临床疗效并能有效预防细菌耐药性产生,而对于耐甲氧西林金葡菌(MRSA),PK/PD参数显示疗效不佳。结论:应用Monte Carlo模拟评价氟罗沙星的PK/PD参数,可以为氟罗沙星的临床最佳给药方案的制定提供参考依据。     

A population pharmacokinetic-pharmacodynamic model for simvastatin that predicts low-density lipoprotein-cholesterol reduction in patients with primary hyperlipidaemia

Simvastatin (SV), a HMG-CoA reductase inhibitor, is widely used for the treatment of hyperlipidaemia. The objectives of the present study were to develop a population pharmacokinetic-pharmacodynamic (PK-PD) model for simvastatin and to evaluate its usefulness in predicting the dose-response relationship of simvastatin in patients with hyperlipidaemia. The data were obtained from a drug-drug interaction study to assess the effect of aspirin on the PK of simvastatin. Twenty-seven healthy volunteers were given simvastatin 40 mg daily for 14 days in whom aspirin 100 mg q.d. was co-administered after day 8. Full PK studies were performed on days 1, 7 and 14 in addition to trough sampling on days 5, 6, 12 and 13. Low-density lipoprotein-cholesterol (LDL-C) levels were also measured serially. Then, a population PK-PD model for simvastatin and its active metabolite, simvastatin acid (SVA), was developed using mixed effect methods (NONMEM Ver. 6.2). A simple linear PK model with parent and metabolite compartments provided the best fit for the 2647 concentrations of simvastatin and simvastatin acid, and a turnover model was used to describe the change in LDL-C levels. The dose-response curve simulated from the final model and those obtained from the literature overlapped very closely. No influence of aspirin was observed in PK or PD. A simple PK-PD model developed using only 2-week study data from fewer than 30 healthy volunteers successfully predicted the dose-response relationship of simvastatin in patients when compared with published data.     

兔体内静脉输注乙酰普鲁卡因胺的药动学—药效学结合模型分析

用药动学-约效学结合模型,对ⅳ乙酰普鲁卡因胺(NAPA)后,进行了药代动力学和药效动力学分析。兔体内NAPA ⅳ后与静脉推注后的药动学参数基本一致;但效应按QT_c延长作为指标,其药效动力学的个别参数有显著性差异。输注后,NAPA的E_max,K_eo,S和EC₅₀分别为120±13.2ms,0.0182±0.007min^-1,2.26±0.93和6.31±0.71μg/ml;推注后,分别为53.6±2.5ms,0.061±0.017min^-1,2.19±0.39和6.21±1.74μg/ml。     

Population pharmacokinetic-pharmacodynamic modeling of TF-505 using extension of indirect response model by incorporating a circadian rhythm in healthy volunteers

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the newly developed drug, (-)-(S)-4-[1-[4-[1-(4-isobutylphenyl)butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), was characterized via a population approach in early human study. Healthy volunteers were divided into six groups. The groups received four single doses (25, 50, 75 or 100 mg) and 2 multiple doses (12.5 or 25 mg) of TF-505, respectively. Dihydrotestosterone (DHT) data were collected to assess TF-505 pharmacodynamics. Population PK/PD modeling of TF-505 was performed via mixed-effects modeling using the NONMEM software package. The final PK-PD model incorporates a two-compartment PK model and an extended indirect PD model. The population PK parameters were 0.197 h(-1) for the k(a), 0.0678 h(-1) for k(e), 12.5 l for V(c), 0.0645 h(-1) for k(12), 0.0723 h(-1) for k(21). Extension of indirect response model by incorporating a time-dependent periodic function for k(in) takes into account the chronopharmacologic rhythms (I(max): 0.706+/-0.297, IC(50): 1.01+/-1.64 (microg/ml), k(out): 0.221+/-0.0486 (h(-1)), R(m): 20.4+/-8.08 (% h(-1)), R(amp): 5.06+/-3.43 (% h(-1)), T(z): 5.01+/-0.407 (h) (Population mean+/-S.E.)). R(m) is the mean DHT synthesis rate, R(amp) is the amplitude of the DHT synthesis rate, and T(z) is the acrophase time, signifying maximum synthesis rate. The present study represents a successful population PK-PD model using the full data from early human studies. The population parameters thus obtained could provide useful indicators for the determination of dosage regimens in exploratory studies in patient populations.     

Quantifying pharmacodynamic interaction between atenolol and valsartan

We used mathematical modeling in order to determine the pharmacodynamic relationship between antihypertensive drugs atenolol and valsartan, by evaluating their effects on heart rate (HR), systolic blood pressure (SP) and diastolic blood pressure (DP). A group of twelve healthy male volunteers received a single oral dose of 100 mg of atenolol and 160 mg of valsartan, both separately and in combination. Pharmacokinetic (PK), pharmacokinetic/pharmacodynamic (PK/PD) and pharmacodynamic (PD) systems were proposed and PD model of atenolol and valsartan concentration-time profiles and PK/PD model of blood pressure and heart rate effects after administration of single doses of atenolol and valsartan and their combination were constructed. Parameters of PD system, such as gain and mean effect time, were obtained by analysis of PK and PK/PD systems. Modeling of PK and PK/PD systems and their analysis to obtain the PD results could considerably change the view o treatment of individual diseases in terms of greater knowledge of pharmacokinetics and pharmacodynamics of drugs.     

CYP2C9 Ile359Leu polymorphism, plasma irbesartan concentration and acute blood pressure reductions in response to irbesartan treatment in Chinese hypertensive patients

Our previous study demonstrated that the CYP2C9*3 gene variant was significantly associated with elevated plasma irbesartan concentration and blood pressure decline, assessed by a 4-week follow-up and revisit following daily administration of irbesartan. We conducted a further analysis to examine the acute effects of the CYP2C9 polymorphism on plasma concentration and blood pressure through remeasurement 6 h after administration of irbesartan. We used an extreme-sampling approach by selecting individuals from the top and bottom deciles of blood pressure response residuals to irbesartan from the previous study population in Anhui, Taihu, and Dongzhi Counties, in China. A total of 196 subjects were available for the analysis. Pre- and posttreatment systolic and diastolic blood pressures (SBP and DBP), and venous blood samples (0.5, 2, and 6 h following the first treatment) were collected from each individual. Plasma irbesartan concentrations were determined by a standard HPLC/fluorescence method. The observed frequencies were 97.7% for CYP2C9*1 (Ile359) and 2.3% for CYP2C9*3 (Leu359). Subjects with the CYP2C9*1/CYP2C9*3 genotype had significantly higher plasma irbesartan concentrations when compared with those with the CYP2C9*1/CYP2C9*1 genotype (beta +/- SE = 81 +/- 36) and greater DBP response (beta +/- SE = 5.6 +/- 2.5 mmHg) at the 6-h time point after adjusting for important confounders. Our finding suggests that the CYP2C9*3 gene variant significantly alters the plasma concentration and acute DBP response at the 6-h point following irbesartan treatment in Chinese hypertensive patients.     

普罗帕酮在健康受试者中的药动—药效学结合模型研究

目的:采用药动-药效结合模型观察普罗帕酮血浆浓度与心电图指标PR间期延长百分率的数量关系,并求算药效学参数。方法:选择健康汉族受试者10名,其中CYP2D6表型的快代谢型(EM)和中速代谢型(IM)各5名。受试者口服普罗帕酮片剂400mg,于给药后15h内抽取静脉血,并同步测定受试者PR间期。普罗帕酮浓度采用高效液相色谱分析法测定。采用CAPP软件对普罗帕酮血药浓度及PR间期延长百分率进行药动-药效结合模型计算。结果:10例健康志愿者的普罗帕酮血浆浓度与效应之间存在着滞后现象。经采用CAPP软件拟合数据,发现效应与浓度之间符合Sigmoid E_(max)模型。IM组的AUC(μg·h·L~(-1))明显高于EM组(5126±1030 vs2948±1230,P<0.05);相对应药效参数Ce_(50)IM组也比EM组大(P<0.05)。另外,效应曲线S线程度的参数γEM组大于IM组(P<0.05)。结论:CYP2D6遗传多态性不但对普罗帕酮的药动学有影响,而且对其药效学参数可能也有明显的影响。     

Pharmacokinetic-pharmacodynamic modelling of insulin: comparison of indirect pharmacodynamic response with effect-compartment link models

The pharmacokinetic and pharmacodynamic modelling of insulin has been reported using a combined pharmacokinetic/pharmacodynamic (PK/PD) model, in which a hypothetical effect compartment is linked to a pharmacokinetic compartment. Review of the literature, however, indicated that the recently developed PK/PD models have consisted of an indirect pharmacodynamic response component, but none of them has been applied to the modelling of insulin. To study the relative relevance of the indirect pharmacodynamic response model and the effect-compartment link model in modelling the pharmacokinetics and pharmacodynamics of insulin, regular human insulin was administered intravenously at a dose of 0.1 IU kg(-1) to healthy Yucatan minipigs (after an overnight fasting). The plasma concentrations of insulin were measured by radioimmunoassay at predetermined time intervals, while blood glucose levels were monitored continuously using a glucose monitor. Analysis of the plasma insulin and the blood glucose profiles was performed by fitting with various PK/PD models and the results indicated that all of the 12 sets of plasma insulin data (after normalizing by the basal levels) have been adequately fitted to the two-compartment open pharmacokinetic model (a mean+/-s.e. correlation coefficient of 0.996+/-0.001 was obtained). The mean+/-s.e. correlation coefficient, the weighted residuals sum of squares (WRSS), and the Akaike's information criterion (AIC) were found, respectively, to be 0.935+/-0.008, 624+/-67, and 522+/-9 for the inhibitory indirect pharmacodynamic response model and 0.941+/-0.010, 547+/-63 and 513+/-9 for the stimulatory indirect pharmacodynamic response model, as compared with 0.725+/-0.041, 2309+/-276 and 628+/-10 for the effect-compartment link model. Based on these results, one may conclude that the indirect pharmacodynamic response model is a more appropriate approach for modelling the PK/PD of insulin than the effect-compartment link model.     

Pharmacokinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat

1 Data on the relationships between plasma concentration and analgesic and anti-inflammatory effects of NSAIDs are limited because most inflammation models do not permit pharmacokinetic/pharmacodynamic (PK/PD) modelling to be readily performed. 2 In this study, a kaolin-induced inflammation model in the cat was evaluated for pre-clinical characterization of the pharmacodynamic profiles of NSAIDs (determination of efficacy, potency, sensitivity (that is the slope of the concentration-effect relationship) and duration of drug response), using meloxicam as a probe article. 3 Indirect response PK/PD models described the time course and magnitude of responses produced by 0.3 mg kg(-1) meloxicam administered subcutaneously. For endpoints for which spontaneous recovery from inflammation was superimposed on drug response, a PK/PD model with a time-dependent K(in) was used to allow for the spontaneous changes of the inflammation with time. 4 The selected endpoints were suitable for studying simultaneously the analgesic, anti-inflammatory and antipyretic effects of meloxicam, allowing comparison of relative potencies for these effects. Mean+/-s.d. IC(50) or EC(50) values (ng ml(-1)) were 777+/-124 (body temperature), 841+/-187 (locomotion variable), 883+/-215 (pain score), 911+/-189 (lameness score) and 1298+/-449 (skin temperature difference). Corresponding mean times+/-s.d. of peak responses (h) were 5.6+/-1.3, 8.6+/-3.8, 5.2+/-5.0, 5.6+/-3.7 and 4.3+/-2.4, respectively. 5 As the pharmacokinetic profiles of meloxicam in cats and humans are similar, simulations of several dosage regimens in the cat provided a pre-clinical basis, illustrating the value of the cat model for predicting a clinical dose regimen for evaluation in man. The predicted loading doses (mg kg(-1)) of meloxicam in the cat producing 70% of the maximum attainable responses were 0.29 (body temperature), 0.32 (lameness score), 0.33 (overall locomotion variable), 0.36 (pain score) and 0.50 (skin temperature difference). The values are similar to or somewhat greater than the clinically recommended doses both in cats (0.3 mg kg(-1)) and humans (7.5-15 mg, that is, between 0.1 and 0.3 mg kg(-1)). 6 These findings indicate the potential value of the cat as a laboratory model, and of a PK/PD modelling approach in assisting NSAID development programs in animals and humans.     

Pharmacokinetics and hemodynamic effects of diltiazem in healthy volunteers: comparing resting with the effect of exercise.

PURPOSE: To determine the steady-state plasma concentrations of diltiazem (DTZ) and hemodynamic effect in humans at rest and during exercise. METHODS: Healthy volunteers (10 F, mean age 22, and 11 M, mean age 24) were recruited. Prior to receiving DTZ, each volunteer performed two 3-minute stages of treadmill exercise according to the Bruce protocol. Intra-arterial BP and ECG recordings were obtained before, during and immediately post exercise. Each volunteer then received DTZ 60 mg qid for one week. The same exercise protocol was repeated 1 h after the last dose. Steady-state plasma concentrations of DTZ were determined by a previously reported HPLC. RESULTS: DTZ decreased resting DBP from 84 +/- 13 to 79 +/- 10 mmHg (p > 0.05), and HR from 89 +/- 11 to 82 +/- 13 bpm (p < 0.05). During exercise, an average of 32 and 10% increase in SBP and DBP, respectively, and a 47% increase of HR was found (p < 0.05). DTZ limited these increases to 21% for SBP, 5% for DBP, and 44% for HR (p < 0.05 for drug effect). Steady-state plasma DTZ concentrations were 141 +/- 56 ng/ml. CONCLUSION: DTZ significantly decreased resting HR but not BP in health volunteers. It decreased both hemodynamic variables during exercise. Thus, the hemodynamic effects of diltiazem are more profound during exercise, and may be more useful surrogate markers for calcium antagonists and other cardiovascular agents in healthy volunteer studies.     

An indirect response model of homocysteine suppression by betaine: optimising the dosage regimen of betaine in homocystinuria

AIMS: To investigate the pharmacokinetics (PK) and pharmacodynamics (PD) of betaine in the treatment of classical homocystinuria due to cystathionine beta-synthase (CbetaS) deficiency with a view to optimizing the dosage regimen. METHODS: Betaine was given as a single oral dose of 100 mg kg(-1) to six patients (age range 6-17 years) who normally received betaine but whose treatment had been suspended for 1 week prior to the study. Plasma betaine and total homocysteine concentrations were measured by high performance liquid chromatography (h.p.l.c.) at frequent intervals over 24 h. The best-fit PK model was determined using the PK-PD program Win-Nonlin and the concentration-time-effect data analysed by an indirect PD model. Using the PK and PD parameters, simulations were carried out with the aim of optimizing betaine dosage. RESULTS: Betaine PK was described by both mono- and bi-exponential disposition functions with first order absorption and a lag time. The correlation coefficient between betaine oral clearance and body weight was 0.6. Mean betaine clearance was higher in males than in females (P=0.03). PK-PD simulation indicated minimal benefit from exceeding a twice-daily dosing schedule and a 150 mg kg(-1) day(-1) dosage for betaine. CONCLUSIONS: PK-PD modelling allows recommendations for optimal dosage of betaine in the treatment of homocystinuria, that have the potential for improved patient compliance and both therapeutic and pharmacoeconomic benefit.     

Pharmacokinetic–pharmacodynamic model for the anticholinergic effect of glycopyrrolate

OBJECTIVE: The purpose of this study was to develop and test a pharmacokinetic-pharmacodynamic (PK-PD) model for the anticholinergic effect of glycopyrrolate in eight healthy male volunteers. METHODS: First, arterial drug concentration (Cp) data after a single intravenous (i.v.) bolus injection (5 micrograms/kg) were individually fitted to a three-compartment PK model. Second, the effect of a 2-h glycopyrrolate i.v. infusion (5 micrograms/kg/h) on the mean R-R interval (RRI) and the Hayano index of the high frequency variability of RRI (HF CCV) was modelled using an effect-compartment, inhibitory sigmoidal Emax model, with the individual PK parameters from the first part as constants. Third, the developed model was tested using a computer-driven infusion which aimed at two ascending steady-state effect-site concentrations (Ce) at 1-h intervals, corresponding to 20% and 80% of the maximal effect (Emax) observed in the second part. RESULTS: Modeling of the HF CCV data yielded the following mean (+/- SD) estimates: concentration at 50% of Emax (EC50), 2.46 +/- 0.58 ng/ml, equilibration half-time (t1/2 ke0), 42.5 +/- 7.7 min, and sigmoidicity factor (gamma), 7.26 +/- 2.82. The corresponding values for RRI data were 2.79 +/- 0.52 ng/ml, 58.3 +/- 17.2 min, and 4.75 +/- 1.56. During the computer-controlled two-step infusion (performed using HF CCV as the effect variable), the measured Cp approached the targeted Ce in most of the subjects, while the observed effect appeared to surpass the targeted levels. CONCLUSION: Although we were able to develop individual PK-PD models for glycopyrrolate, maintaining a stable anticholinergic effect in the computer-driven infusion appeared to be difficult. This is probably due to intra-individual variability in the PK-PD parameters and the extremely steep concentration-effect relationship of glycopyrrolate.