万古霉素在重症监护患者的群体药代动力学模型建立与验证

目的建立适合重症监护患者的万古霉素群体药代动力学模型,用以指导其给药方案调整。方法收集54例重症监护患者的112个常规血药浓度监测数据,用NONMEM软件以非线性混合效应模型进行群体分析,建立单房室药代动力学模型。通过拟合优度评价及自举验证法进行模型的内部验证;收集35例重症监护患者的95个常规血药浓度监测数据,通过拟合优度参数法进行模型的外部验证。以评价最终模型的拟合性能。结果模型内部验证及外部验证的结果表明,模型结构稳定,能较好地预测万古霉素浓度的动态变化规律。结论万古霉素静脉注射给药后的体内过程符合单房室药代动力学的特征,美罗培南对万古霉素的清除率有显著影响。     

Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill intensive care unit patients

Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5-7-fold difference in peak serum concentration (C_max) (mean ± standard deviation 15.70 ± 6.58 mg/L) and 12-h area under the serum concentration-time curve (AUC_0-12) (96.73 ± 56.45 mg h/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC_0-24/MIC (range 31.66-216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T > MIC) (range 53.4-100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC_0-24/MIC and T > MIC values, the clinical and microbiological responses of patients were primarily affected by the individual's pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient's specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria.     

Ceftazidime dosage regimen in intensive care unit patients: from a population pharmacokinetic approach to clinical practice via Monte Carlo simulations

AIM

To predict the ceftazidime dosage regimen as a function of the glomerular filtration rate expressed by the modification of the diet in renal disease (MDRD), reason for admission and mechanical ventilation in intensive care unit (ICU) patients to treat Pseudomonas aeruginosa pneumonia.

METHOD

A published and qualified population pharmacokinetic model was used to perform Monte Carlo simulations of ceftazidime concentrations. The serum target of 40–100 mg l⁻¹ was defined based on the minimal inhibitory concentration (MIC), the European break point (EBP), the pulmonary drug diffusion and toxicity. The recommended dosage regimens were based on the maximum percentile of the patients with simulated steady state concentrations reaching the target.

RESULTS

Steady-state was reached at 72 h whatever the MDRD. The simulations of serum concentrations generated higher percentiles of the population reaching the target after continuous administration. We recommend a 4 g continuous dose after the usual 2 g loading dose for patients with MDRD from 10 to 30 ml min⁻¹, 6 g for MDRD between 40 and 80 ml min⁻¹, 8 g for MDRD from 90 to 110 ml min⁻¹, 10 g for MDRD from 120 to 190 ml min⁻¹ and 12 g day⁻¹ for patients with MDRD higher than 200 ml min⁻¹.

CONCLUSION

Our study demonstrated that in ICU patients for a given MDRD, steady-state takes longer to reach in polytrauma patients than in patients with medical or post surgery reasons for admission. Continuous infusion ensures that a higher percentage of patients reaches the target than the same dose given by discontinuous administration and this only depends on MDRD.     

Indications for a ceftriaxone dosing regimen in Japanese paediatric patients using population pharmacokinetic/pharmacodynamic analysis and simulation

Objectives The objective of this study was to build a ceftriaxone population pharmacokinetic model for Japanese paediatric patients and to examine the dosing regimen of ceftriaxone based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. Methods The population pharmacokinetic analysis using NONMEM was based on published serum concentrations of ceftriaxone. A Monte Carlo simulation was examined to evaluate the time above the minimum inhibitory concentration (TAM) in 20 and 60 mg/kg body weight dose regimen using the population pharmacokinetic parameters. Key findings The time course of the serum concentration of ceftriaxone in paediatric patients was fitted to a two‐compartment model and body weight was incorporated to pharmacokinetic parameters as the covariate. Based on the percent TAM estimated from the final population pharmacokinetic model and the minimum inhibitory concentration (MIC) of ceftriaxone in 2004, we have predicted that the once daily administration of 20 mg/kg ceftriaxone would be effective on various infecting organisms. Conclusions A population pharmacokinetic model of ceftriaxone was built for Japanese paediatric patients based on the available data. The estimated PK/PD result confirmed the appropriateness of once daily dose of 20 mg/kg. In some patients for whom no efficacy was observed at 20 mg/kg, an increase to 60 mg/kg may be required.     

Evaluation of Bayesian estimation in comparison to NONMEM for population pharmacokinetic data analysis: Application to pefloxacin in intensive care unit patients

The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PFCLfor a patient with median covariates values was similar in both BE/ MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PFCLby both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL,respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CLin the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CLin the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CLfor actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL(decrease of CL for weight <65 kg) whereas the BE/MLR analysis predicted an increase of CLin patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.     

药动药效联合模型定量分析方法的研究现状

药动药效联合模型在药理学研究中正在发挥越来越重要的作用。本文介绍了近年来该领域定量计算方面的一些新概念和新进展，包括药动学和药效学模型、药动药效联合模型的四个属性、Sheiner效应室理论应用时应该注意的问题及药动药效联合模型的计算程序等。     

Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative,ECMO and hypothermia patients

Introduction: Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment.

Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations.

Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment.     

An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study

AIMS

To describe ibuprofen pharmacokinetics in preterm neonates with patent ductus arteriosus (PDA) and to establish relationships between doses, plasma concentrations and ibuprofen efficacy and safety.

METHODS

Sixty-six neonates were treated with median daily doses of 10, 5 and 5 mg kg⁻¹ of ibuprofen-lysine by intravenous infusion on 3 consecutive days. A population pharmacokinetic model was developed with NONMEM. Bayesian individual pharmacokinetic estimates were used to calculate areas under the curve (AUC) and to simulate doses. A logistic regression was performed on PDA closure.

RESULTS

Ibuprofen pharmacokinetics were described by a one-compartment model with linear elimination. Mean population pharmacokinetic estimates with corresponding intersubject variabilities (%) were: elimination clearance CL = 9.49 ml h⁻¹ (62%) and volume of distribution V = 375 ml (72%). Ibuprofen CL significantly increased with postnatal age (PNA): CL = 9.49*(PNA/96.3)^1.49. AUC after the first dose (AUC1D), the sum of AUC after the three doses (AUC3D) and gestational age were significantly higher in 57 neonates with closing PDA than in nine neonates without PDA closure (P = 0.02). PDA closure was observed in 50% of the neonates when AUC1D < 600 mg l⁻¹ h (or AUC3D < 900 mg l⁻¹ h) and in 91% when AUC1D > 600 mg l⁻¹ h (or AUC3D > 900 mg l⁻¹ h) (P = 0.006). No correlation between AUC and side-effects could be demonstrated.

CONCLUSIONS

To achieve these optimal AUCs, irrespective of gestational age, three administrations at 24 h intervals are recommended of 10, 5, 5 mg kg⁻¹ for neonates younger than 70 h, 14, 7, 7 mg kg⁻¹ for neonates between 70 and 108 h and 18, 9, 9 mg kg⁻¹ for neonates between 108 and 180 h.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Ibuprofen is a nonsteroidal anti-inflammatory agent that induces closure of the patent ductus arteriosus in neonates.
• Few studies of ibuprofen pharmacokinetics have been performed and were limited to small groups of preterm infants, showing a large intersubject variability and an increase in clearance with either postnatal or gestational age.

WHAT THIS STUDY ADDS

• A population pharmacokinetic study was performed on 66 neonates to characterize the concentration-time courses of ibuprofen.
• Ibuprofen clearance significantly increased from postnatal age day 1 to day 8, but not with gestational age.
• A relationship was shown between ibuprofen area under the curve (AUC) and patent ductus arteriosus closure rate, and an effective threshold AUC was evidenced.
• Dosing schemes were proposed as a function of postnatal age, to achieve this AUC and to improve the efficacy of treatment for patent ductus arteriosus in neonates.

     

Population pharmacokinetic/pharmacodynamic modeling of valproate in Chinese children with epilepsy

AIM： To establish a population pharmacokinetic/pharmacodynamic （PK/PD） model for valproate （VPA） in children with epilepsy in China, and promote reasonable use of antiepileptic drug in clinical practice. METHODS： Sparse data of VPA serum concentrations from 417 pediatric children were collected. These patients were divided into three groups： Population PK-Index group, n = 317; Population PK-Valid group, n = 100; 115 of the total 417 subjects were also included in the Population PD group. Population PK parameters of VPA were estimated based on the data from population PK-Index group. In the validation procedure, the serum concentrations of VPA from the population PK-Valid group were predicted by base and final models respectively. To assess the accuracy and precision of the predictions, mean prediction error （MPE）, mean squared prediction error （MSPE）, root mean squared prediction error （RMSPE）, weight-residues （WRES） and its 95 % confidence intervals （95 % CI） were all calculated, then compared between the two models. For population PD group, all of the ! 15 patients were VPA monotherapy. Efficacy of epilepsy treatment was divided into 5 grades according to the percentage of seizure frequency decreased （ PSFD% ）. The value of PSFD% 100%, 75% - 100%, 50% - 75%, 25% - 50%, or less than 25 % are corresponding to grade 1 to 5. For population PD group, the quantitative relationship between the VPA serum concentrations and the probability for its efficacy score was characterized by logistic regression.[第一段]     

重症监护患者营养支持用药分析

目的 调查我院重症监护患者使用营养制剂情况,为临床合理用药提供参考.方法 统计我院重症监护患者使用营养支持药品的数据,对重症监护患者使用营养支持药品的品种、总金额及各种营养支持药品的用药频度,利用限定日剂量方法进行相关计算和分析.结果 重症监护患者使用的肠外营养制剂共16种,总用药频度是5978,总金额是561 042.54元;使用的肠内营养制剂共4种,总用药频度是1093,总金额276 591.97元.复方氨基酸类、脂肪乳类和肠内营养制剂的金额构成比分别为27.0％、32.9％、33.0％,总金额构成比为92.9％.重症监护患者使用最多的前10位营养支持药品中,肠外营养制剂有9种,而肠内营养制剂仅1种,即肠内营养混悬液(TPF),但是其用药频度达到897,占肠内营养制剂总用药频度(1093)的82.1％,并且在所有营养制剂中排在首位.结论 我院重症监护患者的营养支持方式以肠外营养为主,而肠内营养混悬液是临床易于接受的一种营养制剂.临床为重症监护患者选择营养支持药物,应综合考虑各种因素.     

基于PK/PD理论临床药师参与临床万古霉素治疗血流感染患者的药学实践

目的:探究万古霉素日剂量和日给药频次在治疗革兰阳性球菌败血症中对血药(谷)浓度的影响程度.方法:临床药师分别通过参与1例万古霉素日剂量不变、增加给药频次治疗粪肠球菌败血症的治疗实践和1例万古霉素增加日剂量、减少给药频次治疗人葡萄球菌败血症的治疗实践,观察日剂量和给药频次对万古霉素血药(谷)浓度的影响程度.结果:万古霉素...     

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic–pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?     

Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

Background and purpose:Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice.Experimental approach:Serum and whole brain drug concentrations, cortical SERT occupancy and 5-HTP-potentiated behavioral syndrome were measured over 6 h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [(3)H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([(3)H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect-compartment model was applied to collapse the hysteresis and predict the steady-state relationship between drug exposure and PD response.Key results:The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18 ng mL(-1), 18 ng mL(-1) and 24 ng mL(-1), respectively, with corresponding responses in the 5-HTP behavioral model being between 20-40% of the maximum.Conclusions and implications:Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6-21 ng mL(-1), 21-95 ng mL(-1) and 20-48 ng mL(-1) for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5-HTP-potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values.British Journal of Pharmacology (2008) 155, 276-284; doi:10.1038/bjp.2008.243; published online 16 June 2008.     

Evaluating biapenem dosage regimens in intensive care unit patients with Pseudomonas aeruginosa infections: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation

This study was conducted to identify optimal dosage regimens and estimate pharmacokinetic/pharmacodynamic (PK/PD) characteristics of short-infusion (SI) versus extended-infusion (EI) biapenem against Pseudomonas aeruginosa infections in Chinese intensive care unit (ICU) patients. A total of 85 strains of P. aeruginosa were collected, and the minimum inhibitory concentration (MIC) of biapenem was measured by the serial two-fold agar dilution method. We designed four frequently used clinical regimens: biapenem 300?mg I.V. q12h, q8h, and q6h, and 600?mg q12h. The Monte Carlo Simulation (MCS) was performed using previously published pharmacokinetic data to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of these regimens as an SI (0.5?h) and an EI (1?h, 2?h, 3?h, and 4?h).For a target of 40%fT_>MIC (serum drug concentration remains above the MIC for a dosing period), none of the regimens achieved any CFRs>90% for P. aeruginosa, multidrug–resistant P. aeruginosa (MDR-PA) and even non–MDR-PA. The traditional biapenem SI regimens most commonly seen in clinical practice were insufficient in treating both MDR and non-MDR P. aeruginosa in ICU patients. However, biapenem 600?mg q12h over 2–4?h EI regimens could achieve CFR>90% with 20%fT_>MIC. Clinical trials should aim to validate the potentially greater PK/PD index with higher, more frequent doses and longer extended infusions.     

Dose optimization of piperacillin/tazobactam in patients with renal dysfunction based on population pharmacokinetic and pharmacodynamic simulations

In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.     

A physiologically based pharmacokinetic model for atrazine and its main metabolites in the adult male C57BL/6 mouse

Atrazine (ATR) is a chlorotriazine herbicide that is widely used and relatively persistent in the environment. In laboratory rodents, excessive exposure to ATR is detrimental to the reproductive, immune, and nervous systems. To better understand the toxicokinetics of ATR and to fill the need for a mouse model, a physiologically based pharmacokinetic (PBPK) model for ATR and its main chlorotriazine metabolites (Cl-TRIs) desethyl atrazine (DE), desisopropyl atrazine (DIP), and didealkyl atrazine (DACT) was developed for the adult male C57BL/6 mouse. Taking advantage of all relevant and recently made available mouse-specific data, a flow-limited PBPK model was constructed. The ATR and DACT sub-models included blood, brain, liver, kidney, richly and slowly perfused tissue compartments, as well as plasma protein binding and red blood cell binding, whereas the DE and DIP sub-models were constructed as simple five-compartment models. The model adequately simulated plasma levels of ATR and Cl-TRIs and urinary dosimetry of Cl-TRIs at four single oral dose levels (250, 125, 25, and 5 mg/kg). Additionally, the model adequately described the dose dependency of brain and liver ATR and DACT concentrations. Cumulative urinary DACT amounts were accurately predicted across a wide dose range, suggesting the model's potential use for extrapolation to human exposures by performing reverse dosimetry. The model was validated using previously reported data for plasma ATR and DACT in mice and rats. Overall, besides being the first mouse PBPK model for ATR and its Cl-TRIs, this model, by analogy, provides insights into tissue dosimetry for rats. The model could be used in tissue dosimetry prediction and as an aid in the exposure assessment to this widely used herbicide.