构建沙格列汀PK/PD模型——模拟其在健康人群和肝损伤患者的药动学和药效学

在本次研究中,我们旨在开发和评价沙格列汀的全身生理药代动力学(WB-PBPK)/药效学(PD)模型,模拟其在健康成人及肝功能损害患者中的药代动力学和药效学特性,为特殊患者的临床药学研究提供新方法.基于文献中获取的如logD和血浆蛋白结合率等药物特征参数,建立WB-PBPK模型和PD模型.将模拟所得的血药浓度-时间曲线及...     

Prediction of human pharmacokinetics of panipenem, a new carbapenem antibiotic, from animal data.

The prediction of human pharmacokinetics of Panipenem (PAPM), which is a new carbapenem antibiotic, was investigated using animal data. The plasma concentration-time curve after intravenous administration of PAPM in each animal showed biexponential elimination. There were good allometric correlations between pharmacokinetic parameters (CLtotal and Vd,ss) calculated from the plasma concentration in animal species and body weight of experimental animals. Predicted human pharmacokinetic parameters calculated by these allometric equations agreed with the values observed in humans.     

Human variability in glucuronidation in relation to uncertainty factors for risk assessment

The appropriateness of the default uncertainty factor for human variability in kinetics has been investigated for glucuronidation using an extensive database of substrates metabolised primarily by this pathway. Inter-individual variability was quantified for 15 compounds from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time–curve (AUC)) and acute exposure (C_max). Low inter-individual variability (about 30–35%) was found for all parameters (clearance corrected or not corrected for body weight, metabolic clearance, oral AUC and C_max) after either iv or oral administration to healthy adults. The overall variability of 31% for glucuronidation in healthy adults supported the validity of the default kinetic uncertainty factor of 3.16 for this group, because it would cover more than 99% of individuals. Comparisons between potentially sensitive subgroups and healthy adults using differences in means and variability indicated that neonates showed the greatest impairment of glucuronidation, and that the 3.16 kinetic default factor applied to the mean data for adults would be inadequate for this subpopulation. The in vivo data have been used to derive pathway-related default factors for compounds eliminated largely via glucuronidation.     

TNF‐α level affects etanercept clearance: TNF‐α concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis

Etanercept (ETN) is a widely used anti‐tumour necrosis factor‐α (TNF‐α) agent, which relieves the symptoms of ankylosing spondylitis (AS) by binding to TNF‐α to inhibit its inflammation effects. In this study, the effect of TNF‐α level on ETN clearance (CL) was investigated, and the TNF‐α concentration was initially set as a correction factor for allometric scaling to improve the predictions of individual ETN CLs. Individual ETN CLs and TNF‐α concentrations in healthy volunteers and patients with AS were determined by performing ETN pharmacokinetic studies in the two cohorts. Accordingly, individual ETN CLs in both healthy volunteers and patients with AS were predicted from data of two animal species using different methods, including simple allometric scaling, scaling with a correction factor of maximum life span potential or brain weight, and scaling with a correction factor of the TNF‐α concentration. The accuracies of such predictions were evaluated by the percentage errors. Consequently, increased TNF‐α concentration was shown to improve ETN CL, by comparing both ETN CLs and TNF‐α concentrations between healthy volunteers and patients with AS. More importantly, better predictions of individual ETN CLs were achieved in patients with AS using allometric scaling with TNF‐α concentration as the correction factor. In conclusion, in vivo levels of TNF‐α can affect ETN CL, and allometric scaling corrected with the TNF‐α concentration can be used to estimate the individual CLs of anti‐TNF‐α monoclonal antibodies based on preclinical data.     

Physiologically based pharmacokinetic model for cefazolin in rabbits and its preliminary extrapolation to man

In the present study, the physiologically based pharmacokinetic model, which succeeded previously in predicting the pharmacokinetics of beta-lactam antibiotics in rats [A. Tsuji, T. Yoshikawa, K. Nishide, H. Minami, M. Kimura, E. Nakashima, T. Terasaki, E. Miyamoto, C.H. Nightingale, and T. Yamana: Physiologically based pharmacokinetic model for beta-lactam antibiotics. I: tissue distribution and elimination in rats. J. Pharm. Sci. 72, 1239-1252 (1983)], was applied to cefazolin pharmacokinetics in rabbits and man. After iv bolus dosing in normal rabbits, the time courses of cefazolin concentration in plasma and various tissues (lung, heart, muscle, skin, bone, gut, liver, and kidney) were found to be very similar to those in rats. The values of physiological parameters (tissue plasma flows, tissue volumes, tissue/plasma albumin ratio) and biochemical parameters determined in this study (for nonlinear plasma protein binding, intrinsic renal clearance of active secretion and reabsorption) were incorporated into mass balance equations derived from the model. There was reasonable agreement between the model predictions and the observed data for cefazolin and inulin in rabbits. The model was also successful in the prediction of cefazolin disposition in rabbits with renal failure. Using available information reported for cefazolin in man, a preliminary extrapolation from the present model was attempted, and the overall predicted results after iv administration of 1 g cefazolin in man were compared with the serum and bone tissue data. The length of the effective antibacterial period for the drug is also discussed in terms of its predicted concentration unbound with proteins in various tissue interstitial fluids in man.     

Pharmacokinetics of intravenous amodiaquine.

Amodiaquine hydrochloride (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg-1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml-1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6-95.0) h-1, lambda 2 = 0.33 (0.12-0.79) h-1, V1:1.1 (0.3-3.6) 1 kg-1, Vss: 17.4 (2.3-95.9) 1 kg-1 and systemic clearance 13.0 (4.7-56.6) 1 kg-1 h-1. After intravenous infusion there was also considerable variability between patients with post-infusion plasma concentrations ranging between 82 and 836 ng ml-1. The plasma concentration-time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60-8.52) h-1, beta = 0.069 (0.021-0.265) h-1, V1: 4.6 (0.5-29.3) 1 kg-1, Vss: 38.3 (3.7-127.9) 1 kg-1 and systemic clearance CL (1.6-17.3) 1 kg-1 h-1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

迭代二步法估算阿米卡星的群体药动学参数

目的：用迭代二步法估算阿米卡星的群体药动学参数。方法：收集58例呼吸系统感染病人静脉滴注阿米卡星的临床血药浓度监测数据,用荧光偏振免疫法测定阿米卡星血药浓度。用迭代二步法估算阿米卡星的群体及个体药动学参数。比较性别、年龄、体重、肌酐清除率等因素对药动学参数的影响。结果：性别对药动学参数无影响,CL与CLcr呈正相关,Vd与体重呈正相关。结论：迭代二步法能较好地估算出阿米卡星的群体及个体药动学参数,用于优化给药方案及预测血药浓度可满足临床需要。     

Prediction of plasma concentration-time curve of orally administered theophylline based on a scintigraphic monitoring of gastrointestinal transit in human volunteers

The plasma concentration-time profile of theophylline after oral administration in human volunteers was predicted using the individual gastrointestinal (GI) transit data monitored by a gamma scintigraphic technique. Theophylline was administered as aminophylline under fasted and fed condition, along with 99mTc-labeled diethylenetriamine-pentaacetic acid (DTPA), an unabsorbable marker to evaluate the GI transit by a gamma scintigraphic technique. Two healthy male volunteers participated under fasted and fed conditions in a crossover study. The GI transit was evaluated by dividing the GI tract to four segments, stomach, jejunum, ileum and cecum/colon. Under the fed condition, the GI transit pattern for each segment was confirmed to alter considerably, causing a delay in the gastric emptying mainly. Further, the plasma concentration curves of theophylline after oral administration were predicted using the GI-Transit-Absorption Model on the basis of individual GI transit parameters calculated by the fitting of the observed data to the GI-Transit Kinetic Model. The absorption rate constant in each segment and the pharmacokinetic parameters after intravenous administration used for the prediction were the values extrapolated from the data in rats and the ones normalized from the values in literatures, respectively. The plasma concentration-time curves for theophylline were well predicted using obtained individual GI transit parameters. The analysis using this method could estimate the variable absorption behavior governed by the GI transit in detail.     

Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study.

Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.     

A pharmacokinetic dosing method for oral theophylline in pediatric patients

Requirements for regular-release oral theophylline were determined in 34 pediatric patients aged 0.25-14.8 years using orally derived pharmacokinetic data and the first-order absorption equation. Large ranges were found in the half-life (2.3-21.3 h) and calculated apparent volume of distribution (Vd) (0.300-1.54 L/kg). Mean serum theophylline concentration was more closely correlated with actual mean concentration (r = 0.61, p less than 0.0002) when calculated with the individual patients' Vd values than with the standard Vd of 0.5 L/kg (r = 0.31, NS), and predictions obtained with the individuals' Vd values were more precise (p less than 0.05) and less biased than those obtained with the standard Vd. The precision of prediction based on individual Vd values was quantitatively similar (root mean squared error = 3.38 mg/L) to reported predictions based on pharmacokinetic values derived from an initial intravenous course of aminophylline therapy. We conclude that theophylline dosage requirements can be accurately estimated from orally derived pharmacokinetic data and that the method described may be useful for patients in whom intravenous therapy is not required or contraindicated.     

Uncertainty factors for chemical risk assessment. human variability in the pharmacokinetics of CYP1A2 probe substrates.

A 100-fold uncertainty factor is used to derive acceptable daily intakes for compounds causing thresholded toxicity. The 10-fold factor for human variability can be further subdivided into two factors of 10(0.5) (3.16) to allow for toxicokinetics and toxicodynamics. The validity of the human kinetic subfactor has been analysed in relation to CYP1A2 metabolism using published in vivo pharmacokinetic parameters selected to reflect chronic exposure (metabolic and total clearances and area under the plasma concentration-time curve: CLm, CL and AUC) and acute exposure (the peak plasma concentration, C(max)). The variability in CYP1A2 activity in healthy adults, based on data after oral and intravenous dosage (CLm, CL and AUC), ranged from 34 to 42%. The variability in C(max) was 21%. The default kinetic factor of 3.16 would cover at least 99% of the healthy adult population, assuming that the data were log-normally distributed, but would give lower protection for some subgroups (pregnant women at term, healthy elderly, patients with liver disease), and was inadequate for neonates. This analysis of in vivo kinetic data for CYP1A2 substrates illustrates the importance of quantifying human variability in specific metabolic pathways, and of identifying potentially susceptible subgroups of the human population, in order to determine the scientific validity of uncertainty factors.     

Physiologically based pharmacokinetic modelling of methotrexate and 6-mercaptopurine in adults and children. Part 2: 6-mercaptopurine and its interaction with methotrexate

6-mercaptopurine (6-MP) is a purine antimetabolite and prodrug that undergoes extensive intracellular metabolism to produce thionucleotides, active metabolites which have cytotoxic and immunosuppressive properties. Combination therapies involving 6-MP and methotrexate have shown remarkable results in the cure of childhood acute lymphoblastic leukaemia (ALL) in the last 30 years. 6-MP undergoes very extensive intestinal and hepatic metabolism following oral dosing due to the activity of xanthine oxidase leading to very low and highly variable bioavailability and methotrexate has been demonstrated as an inhibitor of xanthine oxidase. Despite the success recorded in the use of 6-MP in ALL, there is still lack of effect and life threatening toxicity in some patients due to variability in the pharmacokinetics of 6-MP. Also, dose adjustment during treatment is still based on toxicity. The aim of the current work was to develop a mechanistic model that can be used to simulate trial outcomes and help to improve dose individualisation and dosage regimen optimisation. A physiological based pharmacokinetic model was proposed for 6-MP, this model has compartments for stomach, gut lumen, enterocyte, gut tissue, spleen, liver vascular, liver tissue, kidney vascular, kidney tissue, skin, bone marrow, thymus, muscle, rest of body and red blood cells. The model was based on the assumption of the same elimination pathways in adults and children. Parameters of the model include physiological parameters and drug-specific parameter which were obtained from the literature or estimated using plasma and red blood cell concentration data. Age-dependent changes in parameters were implemented for scaling and variability was also introduced on the parameters for prediction. Inhibition of 6-MP first-pass effect by methotrexate was implemented to predict observed clinical interaction between the two drugs. The model was developed successfully and plasma and red blood cell concentrations were adequately predicted both in terms of mean prediction and variability. The predicted interaction between 6-MP and methotrexate was slightly lower than the reported clinical interaction between the two drugs. The model can be used to predict plasma and tissue concentration in adults and children following oral and intravenous dosing and may ultimately help to improve treatment outcome in childhood ALL patients.     

Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model

Limited pharmacokinetic (PK) and pharmacodynamic (PD) data are available to use in methadone dosing recommendations in pediatric patients for either opioid abstinence or analgesia. Considering the extreme inter-individual variability of absorption and metabolism of methadone, population-based PK would be useful to provide insight into the relationship between dose, blood concentrations, and clinical effects of methadone. To address this need, an age-dependent physiologically based pharmacokinetic (PBPK) model has been constructed to systematically study methadone metabolism and PK. The model will facilitate the design of cost-effective studies that will evaluate methadone PK and PD relationships, and may be useful to guide methadone dosing in children. The PBPK model, which includes whole-body multi-organ distribution, plasma protein binding, metabolism, and clearance, is parameterized based on a database of pediatric PK parameters and data collected from clinical experiments. The model is further tailored and verified based on PK data from individual adults, then scaled appropriately to apply to children aged 0–24 months. Based on measured variability in CYP3A enzyme expression levels and plasma orosomucoid (ORM2) concentrations, a Monte–Carlo-based simulation of methadone kinetics in a pediatric population was performed. The simulation predicts extreme variability in plasma concentrations and clearance kinetics for methadone in the pediatric population, based on standard dosing protocols. In addition, it is shown that when doses are designed for individuals based on prior protein expression information, inter-individual variability in methadone kinetics may be greatly reduced.     

Assessment of acyclovir intraindividual pharmacokinetic variability during continuous hemofiltration, continuous hemodiafiltration, and continuous hemodialysis.

The use of intravenous acyclovir can be particularly complicated in pediatric patients with evolving renal impairment, because of intraindividual pharmacokinetic variability linked to the patient's clinical condition. The objective of this study was to use therapeutic drug monitoring data to assess acyclovir intraindividual pharmacokinetic variability during several types of renal replacement therapy. Bayesian adaptive control of acyclovir dosage regimen was performed in a pediatric patient with bone marrow transplant who developed severe renal impairment. Acyclovir pharmacokinetic parameter values corresponding to the different techniques and periods of renal replacement therapy were estimated using USCPACK PC Clinical Programs and therapeutic drug monitoring data. Results showed a wide intraindividual pharmacokinetic variability during CAVH, CAVHDF, and CVVHD, reflecting not only the performance of each dialysis technique but also the difficulty in making use of each one. The acyclovir elimination rate constant was higher during CVVHD compared to CAVH or CAVHDF. Bayesian method appears to be valuable in assessing intraindividual pharmacokinetic variability, as it allows the clinician to deal with sparse routine patient data.     

A limited sampling strategy for estimating individual pharmacokinetic parameters of coagulation factor VIII in patients with hemophilia A

Therapeutic drug monitoring of factor VIII is well established in the treatment of patients with hemophilia attributable to important interindividual variability. The individual initial factor VIII dosage is usually calculated according to individual pharmacokinetic parameters obtained after a dose test administered before the surgery, using at least five-concentration data. The authors proposed a limited sampling strategy to estimate individual pharmacokinetic parameters from one- or two-concentration data in patients with hemophilia A before surgery. The mean population pharmacokinetic parameters and the interindividual variability (CV) were obtained from a group of 33 patients according to a two-compartment model using NONMEM. Eighteen additional patients were used to estimate the predictive performances of the population parameters and to evaluate the limited sampling strategies. Population parameters were clearance 2.6 mL/h per kilogram (CV 45.4%), initial volume of distribution 2.8 L (CV 21.1%). From two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion), the estimation of pharmacokinetic parameters was precise and not biased. Until now, in the hemophilic center of Lyon, the factor VIII dosage before surgery was based on the determination of the clearance, estimated from five- to nine-concentration data and on the target concentration (infusion rate = clearance x target). Ruffo et al proposed a limited sampling strategy (two-stage method) to estimate pharmacokinetic parameters from two concentration measurements drawn 3 and 9 hours after the dose. No information was given on the bias and precision of the estimation. This paper reports a one-stage method for a population pharmacokinetic study of factor VIII. The Bayesian estimation of individual pharmacokinetic parameters based on only two sampling times (0.5 and 6 hours or 0.5 and 8 hours after the end of infusion) is useful to define the best factor VIII dosage in hemophilic patients before surgery.     

Prediction of human oral pharmacokinetics using nonclinical data: examples involving four proprietary compounds

The oral pharmacokinetics (concentration-time profile) of four proprietary compounds in humans were predicted using the C(vss)-MRT method. The first step was to demonstrate superposition of intravenous (i.v.) pharmacokinetic profiles of preclinical species following mathematical transformation of their respective concentration-time curves using the corresponding C(vss) (where C(vss)=dose/Vss; Vss is the volume of distribution at steady state) and mean residence time (MRT) values. The resultant profiles were then back-transformed to estimate human i.v. plasma concentration-time profiles using human C(vss) and MRT values. Human C(vss) and MRT values were estimated from projected human Vss and CL values. Projection of CL was based on scaled (in vitro) metabolic clearance, simple allometry with and without various correction factors and the unbound fraction corrected intercept method. Vss values were estimated by allometric scaling with and without correction for interspecies differences in plasma protein binding. The predicted human i.v. profiles, in combination with the estimated mean absorption rate constants and bioavailability, were then used to simulate the oral pharmacokinetics in human using one- or multi-compartment kinetic models. Overall, with this approach, key oral pharmacokinetic parameters such as AUC, C(max), C(min) and oral plasma T((1/2)) were projected to be within two-fold of the actual values in humans.     

Limiting cefotaxime pediatric dosing to adult standards: a pharmacokinetic simulation study.

OBJECTIVE: The recommended cefotaxime dose of 50 mg/kg every six to eight hours for pediatric patients with a body weight greater than 20 kg exceeds the standard 1-gram dose recommended for adult patients. This study estimated whether limiting the cefotaxime dose recommended for children with mild to moderate infections to a standard 1-gram dose would achieve serum concentrations and time above the MIC90 comparable to those in adults. METHODS: Serum concentration profiles were simulated from mean cefotaxime pharmacokinetic parameters that have been published for children and for adults using widely available spreadsheet software. The simulations employed an open, one-compartment, multiple-dose model and were calculated using a common commercial spreadsheet. The model was used to predict serum concentrations using dosage regimens of 1 g or 50 mg/kg administered every six or eight hours in pediatric patients of various weights with pediatric pharmacokinetic parameters and 1 g every six or eight hours for adult patients with adult pharmacokinetic parameters. The time that cefotaxime concentrations exceeded the MIC90 for pediatric pathogens was also calculated. RESULTS: The 50 mg/kg pediatric dosing regimens administered every 8 hours (q8h) or every 6 hours (q6h) consistently produced peak serum concentrations and area under the concentration versus time curve (AUC) values higher than those in adults. Serum concentrations and AUCs generated for the 1-gram regimens for various pediatric weight categories were also above those predicted in adults. The time above the MIC90 for pediatric patients was equivalent to or exceeded those of the adult simulations for all pathogens. CONCLUSIONS: The results support the concept of limiting cefotaxime dosage regimens to 1 g administered every 6 or 8 hours for mild to moderate infections in children weighing more than 20 kg. This dosage regimen could lead to dose standardization procedures, which could produce reductions in drug costs associated with individualized dosage preparation.     

Quantitative prediction of therapeutic antibody pharmacokinetics after intravenous and subcutaneous injection in human

Prediction of the plasma/serum mAb concentration–time profile in human is important to determine the required dose regime. This study proposes an approach for predicting the plasma/serum mAb concentration–time profile after intravenous and subcutaneous injection in human based on comprehensive analysis of reported pharmacokinetic data. Optimal scaling exponents from cynomolgus monkey to human for CL, Q, V_c, and V_p were estimated as 0.8, 0.75, 1.0, and 0.95, respectively. The estimated exponents were used to predict plasma/serum mAb concentration–time profile in human from pharmacokinetic data in cynomolgus monkey, and the results had reasonable accuracy with symmetric variability of prediction. Then, data reported for pharmacokinetics in human were used to estimate optimal k_a and F after subcutaneous injection. The geometric mean of k_a was suitable to predict T_max, and F which was estimated from CL was suitable to predict C_max. Our approach is useful for predicting the plasma/serum mAb concentration–time profile after intravenous and subcutaneous injection in human. Moreover, the study also investigated the possibility of predicting pharmacokinetic parameters of mAbs with increased FcRn binding mutations in human and found that our approach of prediction based on reported pharmacokinetic data may also be applicable to mAbs with these mutations.     

Dosage Adjustment for Ceftazidime in Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling

Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment.     

基于Excel函数设计抗菌药物间歇静脉滴注给药方案

目的:设计抗菌药物间歇静脉滴注给药方案。方法:以头孢唑啉钠、头孢曲松钠、阿米卡星为例,采用多剂量函数法处理相关药动学数据,将药动学与药效学(PK/PD)参数相结合,应用Excel软件编写计算程序,设计合理给药方案。结果:时间依赖性抗菌药物的杀菌效应主要取决于血药浓度高于细菌最低抑菌浓度(MIC)的时间;对于血浆消除半衰期短的抗菌药物宜采取小剂量均匀分次给药,甚至持续给药;半衰期较长者12～24h给药1次即可。浓度依赖性抗菌药物优化临床抗菌疗效的最佳PK/PD参数为Cmax/MIC,适宜日剂量单次给予。结论:基于PK/PD,应用Excel函数设计抗菌药物间歇静脉滴注给药方案,方法简便、可靠、直观。