Allometric relationships between the pharmacokinetics of propofol in rats, children and adults

AIMS: Allometric equations have proven useful for the extrapolation of animal data to determine pharmacokinetic parameters in man. It has been proposed that these equations are also applicable over the human size range including the paediatric population. The aim of this work was to study the relationship between various pharmacokinetic parameters for propofol and body weight using data from rats, children and adults. Furthermore, the utility of allometric scaling is evaluated by the prediction of propofol concentrations in humans based on data obtained in the rat. METHODS: The relationship between the pharmacokinetic parameters of propofol obtained in rats, children and adults was analyzed by plotting the logarithmically transformed parameters against the corresponding logarithmically transformed body weights. In addition, based on allometric equations, pharmacokinetic parameters obtained in rats were scaled to humans. These parameters were used to simulate propofol concentrations in long-term sedated critically ill patients using NONMEM. Simulated concentrations were then compared with actually observed concentrations in humans. RESULTS: The relationship between pharmacokinetic parameters of propofol from rats, children and adults was in good agreement with those from the literature on allometric modelling. For clearance, intercompartmental clearance, central volume of distribution and peripheral volume of distribution, the power parameters were 0.78, 0.73, 0.98 and 1.1, respectively, and r2 values for the linear correlations were 0.990, 0.983, 0.977 and 0.994, respectively. On the basis of data obtained after a single bolus injection in the rat, adequate predictions of propofol concentrations in critically ill patients can be made using allometric equations, despite the long-term nature of the use of the drug, the large number of infusion changes per day and/or differences in state of health and age. CONCLUSIONS: For propofol, allometric scaling has proved to be valuable for cross species extrapolation. Furthermore, the use of the allometric equation between adults and children seems to be an adequate tool for the development of rational dosing schemes for children of varying body weights, and requires further study.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

3岁以下儿童丙泊酚药动学研究

目的研究3岁以下儿童丙泊酚(异丙酚)药物动力学特征。方法选择3岁以下无心、肺、肝、肾和中枢神经疾病的手术儿童12例。单次静脉注射异丙酚3mg.kg-1。应用高效液相色谱法测定给药后不同时间点的血清中异丙酚浓度。用3P87实用药代动力学程序计算各项药动学参数。结果3岁以下儿童异丙酚诱导静脉麻醉主要药动学参数t1/2α=(2.372±0.565)m in,t1/2β=(16.364±4.442)m in,t1/2γ=(416.591±97.184)m in,Vd=(7.980±1.863)L.kg-1,CL=(0.015±0.007)L.kg-1.m in-1,AUC=(267.353±100.247)μg.m in.mL-1。结论3岁以下儿童异丙酚诱导静脉麻醉符合开放性三室模型特征,具有分布快、分布广等特点。     

The pharmacokinetics of propofol in laboratory animals.

1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.     

NONMEM法分析静滴异丙酚在中国人体的群体药代动力学

目的　考察中国人静脉匀速滴注异丙酚的群体药代动力学。方法　51例腰麻-硬膜外联合麻醉病人匀速输注异丙酚直至暴发脑电抑制,以HPLC法测定异丙酚血浆浓度,用NONMEM程序分析中国人异丙酚群体药代动力学。结果　异丙酚药代动力学符合三室线性开放模型,群体参数CL(L.min-1)、Vc(L)、Q2(L.min-1)、V2(L)、Q3(L.min-1)和V3(L)的标准值分别为1.10,7.63,1.54,15.0,0.76和175;体重对CL的校正为体重除以60的0.70次方,CL和Q2年龄≥60的病人较年龄<60的分别低18.1%和32.1%;年龄对V2和Q3的校正分别为年龄除以50的-0.66次方和-0.71次方。结论　NONMEM法对以三室模型群体参数估算的血药浓度值与实测值有良好相关性,体重、年龄对参数影响较大。     

Diphenhydramine: pharmacokinetics and pharmacodynamics in elderly adults, young adults, and children

The pharmacokinetics and pharmacodynamics of the H1-receptor antagonist diphenhydramine were studied in 21 fasting subjects divided into three age groups: elderly, (mean age 69.4 +/- 4.3 years), young adults, (mean age 31.5 +/- 10.4 years), and children, (mean age 8.9 +/- 1.7 years). All subjects ingested a single dose of diphenhydramine syrup 1.25 mg/kg, in mean doses of 86.0 +/- 7.3 mg, 87.9 +/- 12.4 mg, and 39.5 +/- 8.4 mg, respectively. Blood samples were collected hourly for 6 hours, every 2 hours until 12 hours, at 24 hours, and, in the adults, up to 72 hours after diphenhydramine administration. At these times, histamine skin tests were performed and wheal and flare areas were computed. The mean serum elimination half-life values for diphenhydramine differed significantly in elderly adults, young adults, and children, with values of 13.5 +/- 4.2 hours, 9.2 +/- 2.5 hours, and 5.4 +/- 1.8 hours being found respectively in each age group. Clearance rates for diphenhydramine also differed significantly with age, being 11.7 +/- 3.1 mL/min/kg in elderly adults, 23.3 +/- 9.4 mL/min/kg in young adults and 49.2 +/- 22.8 mL/min/kg in children. Diphenhydramine produced a maximum wheal suppression of 39.6 +/- 22.5% and a maximum flare suppression of 46.5 +/- 32.1% at 5 and 6 hours respectively in the elderly; a maximum wheal suppression of 45.5 +/- 25.0% and a maximum flare suppression of 53.4 +/- 16.9% at 6 and 4 hours respectively in young adults; and a maximum wheal suppression of 68.4 +/- 10.2% and a maximum flare suppression of 87.2 +/- 4.2% at 2 hours in children.     

The pharmacokinetics of propofol in laboratory animals

1. The pharmacokinetics of propofol in an emulsion formulation (‘Diprivan’) have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT.

2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood.

3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open ‘mammillary’ model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (V_ss=2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80ml/kg per min in rats, dogs and pigs to about 340ml/kg per min in rabbits.     

Population pharmacokinetics of valproate in Chinese children with epilepsy

Aim： The aim of the present study is to establish a population pharmacokinetic （PPK） model of valproate （VPA） in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. Methods： Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups： the PPK model group （n=317） and the PPK valid group （n=100）. The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight residues （WRES）, and the 95% confidence intervals （95% CI） were also calculated. Then, the values between the 2 models were compared. Results： The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was： Ka=3.09 （h^-1）, V/F=20.4 （L）, CL/F=0.296 （L/h）. The final model was： Ka=0.251＋2.24-（1-HS） （h^-l）, V/F=2.8 8＋0.157-WT （L）, CL/F=0.106^0.98.CO＋ 0.0157·AGE （L/h）. For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 （-30.36,-16.70）, 3728.96 （2872.72, 4585.20）, 39.62 （34.34, 44.90）, and-0.06 （-0.14, 0.02）, respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 （-4.85, 2.53）, 1002.83 （1050.64,1143.61）, 23.04 （21.12, 24.96）, and 0.08 （-0.04, 0.20）, respectively. The final model was more optimal than the basic model. Conclusion： The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.     

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline.

Methods:

LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models.

Results:

The final regression model for LTG was as follows: CL (L/h)=1.01^*(TBW/27.87)^0.635*e^−0.753*VPA*e^0.868*CBZ*e^0.633*PB, Vd (L)= 16.7^*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation.

Conclusion:

A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines.     

Comparative pharmacokinetics of theophylline and aminophylline in man.

1 The pharmacokinetics of theophylline and aminophylline was compared after oral administration and intravenous infusion. 2 Theophylline (250 mg) and aminophylline (390 mg) were taken orally by eight healthy volunteers in a randomized cross-over study. 3 In another cross-over study theophylline and aminophylline were administered intravenously to six healthy volunteers at a dose corresponding to 5 mg/kg pure theophylline. 4 The protein binding of the theophylline in serum collected during the intravenous study was studied by ultrafiltration. The serum concentration of theophylline was measured by high pressure liquid chromatography. 5 Almost identical concentration-time curves were found for theophylline and aminophylline in both of the studies. No significant difference was found in the pharmacokinetic parameters or protein binding with the two preparations.     

Comparative pharmacokinetics and pharmacodynamics of cardiac glycosides.

1 The pharmacokinetics and pharmacodynamics of ouabain, digoxinn and beta-methyl digoxin (medigoxin) have been investigated in a crossover study in four normal healthy volunteers. 2 Pharmacokinetics were studied using [3H]-labelled glycosides and the shortening of the left ventricular ejection time (LVET) was used as a measure of the effect of the drugs. A graded exercise protocol was used to correct for the effects of heart rate on LVET. 3 In three of the four subjects, both digoxin and beta-methyl digoxin produced a shortening in the LVET, but no such change could be detected with ouabain in any of the four subjects. 4 There was a good linear correlation between the shortening of the LVET and the amounts of digoxin or beta-methyl digoxin present in the body tissues. 5 One subject who showed no drug-related LVET shortening had greatly enhanced clearances of all three drugs studied.     

Population pharmacokinetics modeling of levetiracetam in Chinese children with epilepsy

Aim:

To establish a population pharmacokinetics (PPK) model of levetiracetam in Chinese children with epilepsy.

Methods:

A total of 418 samples from 361 epileptic children in Peking University First Hospital were analyzed. These patients were divided into two groups: the PPK model group (n=311) and the PPK validation group (n=50). Levetiracetam concentrations were determined by HPLC. The PPK model of levetiracetam was established using NONMEM, according to a one-compartment model with first-order absorption and elimination. To validate the model, the mean prediction error (MPE), mean squared prediction error (MSPE), root mean-squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were calculated.

Results:

A regression equation of the basic model of levetiracetam was obtained, with clearance (CL/F)=0.988 L/h, volume of distribution (V/F)=12.3 L, and K_a=1.95 h⁻¹. The final model was as follows: K_a=1.56 h⁻¹, V/F=12.1 (L), CL/F=1.04×(WEIG/25)^0.583 (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95%CI were 9.834 (−0.587–197.720), 50.919 (0.012–1286.429), 1.680 (0.021–34.184), and 0.0621 (−1.100–1.980). For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were 0.199 (−0.369–0.563), 0.002082 (0.00001–0.01054), 0.0293 (0.001−0.110), and 0.153 (−0.030–1.950).

Conclusion:

A one-compartment model with first-order absorption adequately described the levetiracetam concentrations. Body weight was identified as a significant covariate for levetiracetam clearance in this study. This model will be valuable to facilitate individualized dosage regimens.     

Stimulants and antidepressant pharmacokinetics in hyperactive children.

Psychopharmacological treatment of attention-deficit hyperactivity disorder (ADHD), is well established. The central nervous system stimulants, especially dextroamphetamine and methylphenidate, are the drugs of choice. Response is rapid, consistent and predictable. Most children respond to one or the other when a trial of both stimulants are given across wide dose ranges (Elia et al. 1991). The efficacy of pemoline is also well established, but its variable onset and duration of action in children has made it a secondary treatment. Tricyclic antidepressants also produce rapid behavioral effects in ADHD, at doses less than those used for depression. Adverse effects are a limiting factor for continued treatment as well as the fact that beneficial effects are often short-lived.     

Montelukast dose selection in 6- to 14-year-olds: comparison of single-dose pharmacokinetics in children and adults.

Montelukast, an oral leukotriene-receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once-daily 10 mg dose (film-coated tablet) was selected as the optimal adult dose based on dose-ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film-coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose-ranging studies in children. Therefore, the dose of montelukast for 6- to 14-year-old children was selected by identifying the chewable tablet dose of montelukast yielding a single-dose area under the plasma concentration-time curve (AUC) comparable to that achieved with the adult 10 mg film-coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6- to 14-year-old children with asthma.