Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters

Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram-negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.     

Comparison of pharmacokinetic parameters determined by four different methods

Pharmacokinetic evaluation was performed using RESID, NONLIN84, KINPAK and AUC-RPP programs for a crossover hydromorphone study involving I.V., P.O. and rectal administration in humans. It was observed that when the curve fitting was difficult by using compartment model dependent methods, pharmacokinetic parameters could still be estimated by compartment model independent analysis.     

Comparison of some practical sampling strategies for population pharmacokinetic studies

Using population analysis, sparsely sampled Phase 3 clinical data can be utilized to determine the pharmacokinetic characteristics of the target population. Data arising from such studies are likely to be constrained to certain sampling windows, i.e., the visiting hours at the study clinic. When the sampling window is narrow compared to the half-life of the drug, the advantage of taking more than one sample is not obvious. Study designs with one or two samples per visit have been compared with respect to (i) precision and bias of the population parameter estimates, (ii) the ability to identify the underlying pharmacokinetic model, and (iii) the estimation of individual parameter values. The first point was assessed using simulated data while the latter two were studied using a real data set. Results show: (i) Parameter estimates are more biased and imprecise when only one sample is taken compared to when two samples are obtained, this is true irrespective of the time span between the two samples. (ii) Ability to identify a more complex model is increased if two samples are taken. Specifically, the variability between occasions can be quantified. (iii) Two-sample designs are generally better with respect to prediction of individual parameter values. Even minor changes to commonly employed study designs, in this case the addition of one sample at each study occasion, can improve quality and quantity of the information obtained. During the course of this study E. Niclas Jonsson was paid by a grant from ASTRA AB.     

Comparison of pharmacokinetic parameters of intravenous quinidine and quinine in dogs

The pharmacokinetic parameters of quinidine and quinine were determined and compared in seven mongrel dogs. Both drugs were given intravenously, with a minimum of 4 weeks between protocols, and blood samples collected for 20-24 h. Depending on the distribution phase, both two- and three-compartment models were used to describe the kinetics. The volumes of distribution, intercompartmental clearance rates, and volumes of the central and peripheral compartments were similar. The total body clearance (ClT) of quinidine, 3.58 +/- 1.96 (SD) ml/kg/min, was 56% slower than that of quinine, 8.11 +/- 3.03 ml/kg/min, with p less than 0.02. Quinine half-life (t1/2), 6.58 +/- 3.3 h, was 54% less than that of quinidine, 14.4 +/- 4.10 h, p less than 0.02.     

不同组方氯沙坦口服制剂药代动力学参数及影响因素分析

目的:分析不同组方、不同来源氯沙坦钾口服制剂药代动力学参数差异,寻找引起药代动力学差异的影响因素.方法:搜集山东大学齐鲁医院药理研究所近几年氯沙坦钾口服制剂氯沙坦药代动力学试验数据;检索国内外相关文献,获取不同研究氯沙坦药代动力学参数.采用SPSS 24软件对数据进行汇总、聚类分析与评价.结果:不同厂家不同组方、相同厂...     

兔体内动静脉血中氨茶碱药动学参数比较

本文借助于房室模型理论和统计矩理论对动静脉血中药代动力学的差异进行了理论性探讨,并对iv氨茶碱后,兔体内动静脉血中药代动力学参数进行比较。结果表明用静脉血估算的平均驻留时间和稳态分布容积都比用动脉血估算结果要大,但差异不显著。     

左氧氟沙星药代动力学/药效动力学参数与金黄色葡萄球菌耐药的相关性研究

目的：探讨左氧氟沙星药代动力学/药效动力学（PK/PD）参数与金黄色葡萄球菌耐药的相关性。方法：建立兔组织笼金黄色葡萄球菌感染模型,给予不同剂量的左氧氟沙星灌胃治疗。抽取组织笼内组织液进行药代动力学测定,计算PK/PD参数,同时监测组织笼内细菌药物敏感性变化。结果：PK/PD参数AUC24/MIC、AUC24/MPC、Cmax/MIC、Cmax/MPC、T〉MPC和Tmsw和耐药发生相关（MIC：最小抑菌浓度,MPC：防耐药变异浓度,MSW：耐药突变选择窗）,T〉MIC与耐药的发生无相关性。当AUC24/MIC在20～150h时,容易发生耐药,保持药物AUC24/MPC〉25h可以限制耐药的发生。体内MSW的上、下限分别为AUC24/MPC=25h和AUC24/MIC=20h。结论：AUC24/MPC、Cmax/MPC和T〉MPC可能是预测耐药发生的独立参数。     

Accuracy of allometrically predicted pharmacokinetic parameters in humans: role of species selection.

A general equation was derived, which directly describes the mathematical relationship between the allometrically predicted pharmacokinetic (PK) parameters in humans and the body weights of animal species (along with their corresponding measured PK parameters). It was shown, with use of the derived equation, that the predicted values in humans, based on combinations of animal species commonly used in allometry, are heavily dependent on certain species, for example, the dog. In contrast, parameter values from the rat made no contribution to the predicted human values, as long as the rat was not the smallest species used. Monte Carlo simulations were further performed to examine the species or weight dependence. The cost-effective combinations of animal species, in terms of number and species type, were theoretically examined through simulations. Finally, literature data demonstrated the species or weight dependence predicted from the equation and as illustrated through the Monte Carlo simulations. Appreciation of this species or weight dependence should guide researchers in selecting animal species and designing optimal experiments in the application of allometric scaling.     

Glutathione S-transferase polymorphisms are not associated with population pharmacokinetic parameters of busulfan in pediatric patients

High busulfan exposure is associated with increased toxicity, for example veno-occlusive disease, whereas low exposure results in less efficacy such as lower engraftment rates. Despite adjusting dose to body weight, interindividual variability in pharmacokinetics and thus drug exposure remained rather large. In this report, the contribution of genetic polymorphisms in the glutathione-S-transferases (GST) isozymes GSTA1, GSTM1, GSTP1, and GSTT1 to the pharmacokinetics of busulfan is studied retrospectively. Seventy-seven children, undergoing myeloablative conditioning for allogeneic hematopoietic stem cell transplantation, were treated with busulfan (Busulvex) during 4 days, receiving busulfan either in one single dose or dived in four doses every 6 hours. Genetic variants of GSTA1, GSTM1, GSTP1, and GSTT1 were determined by pyrosequencing. Pharmacokinetic parameters were estimated by using nonlinear mixed-effect modeling (NONMEM). Subsequently, a combined population pharmacokinetic-pharmacogenetic model was developed describing the pharmacokinetics of busulfan taking into account the GST polymorphisms. In the presented pediatric population, body weight appeared to be the most important covariate and explained a major part of the observed variability in the pharmacokinetics of busulfan. None of the studied polymorphisms in the genes encoding GSTA1 GSTM1, GSTP1, and GSTT1 nor combinations of genotypes were significant covariates. It was concluded that in children, variability in pharmacokinetics of busulfan could not be related to polymorphisms in GST.     

Impact of genetic polymorphisms of transporters on the pharmacokinetic, pharmacodynamic and toxicological properties of anionic drugs

As the importance of drug transporters in the clinical pharmacokinetics of drugs is recognized, genetic polymorphisms of drug transporters have emerged as one of the determinant factors to produce the inter-individual variability of pharmacokinetics. Many clinical studies have shown the influence of genetic polymorphisms of drug transporters on the pharmacokinetics and subsequent pharmacological and toxicological effects of drugs. The functional change in a transporter in clearance organs such as liver and kidney affects the drug concentration in the blood circulation, while that in the pharmacological or toxicological target can alter the local concentration at the target sites without changing its plasma concentration. As for the transporters for organic anions, some single nucleotide polymorphisms (SNPs) or haplotypes occurring with high frequency in organic anion transporting polypeptide (OATP) 1B1, multidrug resistance 1 (MDR1), and breast cancer resistance protein (BCRP) have been extensively investigated in both human clinical studies and in vitro functional assays. We introduce some examples showing the relationship between haplotypes in transporters and pharmacokinetics and pharmacological effects of drugs. We also discuss how to predict the effect of functional changes in drug transporters caused by genetic polymorphisms on the pharmacokinetics of drugs from in vitro data.     

利用SPSS和Excel拟合血管外给药药动学参数的效果比较

目的：考察SPSS和Excel对血管外给药的药动学参数的拟合效果。方法：采用SPSS，Excel对参数理论值产生的血药浓度和实测血药浓度进行曲线拟合。结果：通过理论参数和实例分析，显示Excel规划求解法的拟合效果良好，基本上与SPSS法相近。结论：Excel规划求解法可作为获取血管外给药药动学参数有效而简便的方法。     

Factors influencing the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa

The influence of various covariates (including weight, race, smoking, gender, age, mild-to-moderate alcohol intake, and body surface area) on the population pharmacokinetic parameters of phenytoin in adult epileptic patients in South Africa was investigated. The parameters were the maximum metabolic rate (Vm) and the Michaelis-Menten (MM) constant (Km) of phenytoin. The study population comprised 332 black and colored epileptic patients (note: "black" refers to indigenous people of South Africa, who speak one of the Bantu languages as their native language; "colored" refers to people considered to be of mixed race, classified as such by the apartheid former government of South Africa). The influence of covariates on Vm and Km estimates was determined using nonlinear mixed-effects modeling (NONMEM). Parameter models describing the factors that could potentially influence Vm and Km were tested using the Michaelis-Menten parallel MM and first-order elimination models, to which 853 steady state dose-to-serum concentration pairs were fitted. The results indicated that body weight, smoking, race, and age (65 years or older), in descending order of importance, significantly influenced Vm (p < 0.05). Although a significant difference (p = 0.03) in Km was found between black and colored patients, incorporating the influence of race in Km in the final regression model did not improve the fit of the model to the data, which indicated that the variability in Km was accounted for by Vm. The scaling factors for smoking, colored patients and age (65 years or older) in Vm were 1.16, 1.10, and 0.88, respectively. These factors should be taken into account when adjusting phenytoin dose.     

瑞格列奈药代动力学特征及有关基因多态性对其药代和药物相互作用的影响

瑞格列奈是一种具有氨基酸结构的非磺脲类促胰岛素分泌的口服降糖药,降血糖作用快而短,模拟胰岛素生理性分泌,主要用于控制高血糖,同时减少低血糖的发生。本文将对瑞格列奈的药代动力学特征、基因组学研究进展、药物相互作用作一综述。以期为指导瑞格列奈的临床用药打下坚实的理论基础,确保临床用药的安全性和有效性,真正实现临床上的个体化给药。     

Comparison of nonlinear pharmacokinetic parameters estimated from the sinusoidal perfusion and venous equilibrium models

It is shown that the intrinsic and steady-state clearances and the values of Vm and Km of the Michaelis-Menten equation estimated via the sinusoidal perfusion model are different from the corresponding values estimated via the venous equilibration model. The liver blood flow rates estimated by two theories (from plasma data) are identical. The comparison was made using the single dose oral and intravenous and steady-state oral plasma concentration-time data for verapamil in six subjects previously published.     

A general model-based design of experiments approach to achieve practical identifiability of pharmacokinetic and pharmacodynamic models

The use of pharmacokinetic (PK) and pharmacodynamic (PD) models is a common and widespread practice in the preliminary stages of drug development. However, PK–PD models may be affected by structural identifiability issues intrinsically related to their mathematical formulation. A preliminary structural identifiability analysis is usually carried out to check if the set of model parameters can be uniquely determined from experimental observations under the ideal assumptions of noise-free data and no model uncertainty. However, even for structurally identifiable models, real-life experimental conditions and model uncertainty may strongly affect the practical possibility to estimate the model parameters in a statistically sound way. A systematic procedure coupling the numerical assessment of structural identifiability with advanced model-based design of experiments formulations is presented in this paper. The objective is to propose a general approach to design experiments in an optimal way, detecting a proper set of experimental settings that ensure the practical identifiability of PK–PD models. Two simulated case studies based on in vitro bacterial growth and killing models are presented to demonstrate the applicability and generality of the methodology to tackle model identifiability issues effectively, through the design of feasible and highly informative experiments.     

Population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone with genetic polymorphisms of CYP2D6 and ABCB1

This study estimated the population pharmacokinetics of risperidone and its active metabolite, 9-hydroxyrisperidone, according to genetic polymorphisms in the metabolizing enzyme (CYP2D6) and transporter (ABCB1) genes in healthy subjects. Eighty healthy subjects who received a single oral dose of 2?mg risperidone participated in this study. However, eight subjects with rare genotype variants in CYP2D6 alleles were excluded from the final model built in this study. We conducted the population pharmacokinetic analysis of risperidone and 9-hydroxyrisperidone using a nonlinear mixed effects modeling (NONMEM) method and explored the possible influence of genetic polymorphisms in CYP2D6 alleles and ABCB1 (2677G>T/A and 3435C>T) on the population pharmacokinetics of risperidone and 9-hydroxyrisperidone. A two-compartment model with a first-order absorption and lag time fitted well to serum concentration-time curve for risperidone. 9-hydroxyrisperidone was well described by a one-compartment model as an extension of the parent drug (risperidone) model with first-order elimination and absorption partially from the depot. Significant covariates for risperidone clearance were genetic polymorphisms of CYP2D6*10, including CYP2D6*1/*10 (27.5?% decrease) and CYP2D6*10/*10 (63.8?% decrease). There was significant difference in the absorption rate constant (k ( a )) of risperidone among the CYP2D6*10 genotype groups. In addition, combined ABCB1 3435C>T and CYP2D6*10 genotypes had a significant (P?T as covariates was successfully constructed. The estimated contribution of genetic polymorphisms in CYP2D6*10 and ABCB1 3435C>T to population pharmacokinetics of risperidone and 9-hydroxyrisperidone suggests the interplay of CYP2D6 and ABCB1 on the pharmacokinetics of risperidone and 9-hydroxyrisperidone according to genetic polymorphisms.     

Development of a genetic algorithm and NONMEM workbench for automating and improving population pharmacokinetic/pharmacodynamic model selection

Journal of Pharmacokinetics and Pharmacodynamics - The current approach to selection of a population PK/PD model is inherently flawed as it fails to account for interactions between structural,...     

Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications

Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations. Routine genotyping before drug therapy may enable the identification of responders, nonresponders, or patients at increased risk of toxicity. Automated, high-throughput detecting methods for single-nucleotide polymorphisms (SNPs) are highly desirable in many clinical laboratories. The aim of this study is to develop a high-throughput genotyping method for detecting SNPs influencing drug response in the Japanese population. We have developed three real-time PCR assays for detecting SNPs in the human drug-metabolizing enzymes and drug targets. The assay for simultaneously detecting CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A5, NAT2, TPMT, DPYD, UGT1A1, ALDH2, ADH2, MDR1, CETP, DCP-1, ADRB2, HTR2A, INPP1, SDF1, and mitochondrial DNA polymorphisms takes less than 1.5 h. With the clinical application of NAT2 genotyping, we found statistically significant difference between the incidence of adverse drug reactions (ADRs) and the NAT2 genotype. The incidence of the ADRs was significantly higher in the slow type than the in other two types, as 5 of the 6 patients were of the slowtype, and the other was the intermediatetype, while no patients of the rapidtype has developed any ADRs.     

中国健康人群P450 2C9基因多态性与甲苯磺丁脲代谢的关系

目的 研究甲苯磺丁脲人体代谢过程与中国健康志愿者P450 2C9基因多态性的关系。方法 不同P450 2C9＊1／＊1（n=53）、＊1／＊3（n=9）及＊3／＊3（n=1）基因型的健康志愿者单次口服甲苯磺丁脲500mg后，用HPLC方法测定血和尿中的甲苯磺丁脲及其代谢产物浓度，研究甲苯磺丁脲的药代过程。结果 P450 2C9＊1／＊3与P450 2C9＊3／＊3基因型的受试者与P450 2C9＊1／＊1基因型相比，AUC（0-∞）增加20％和116％，t1/2增加60％和813％，CL0为68％和11％，CLform仅为39％和3％。结论 P450 2C9＊1／＊3对甲苯磺丁脲的代谢活性较P4502C9＊1／＊1显著降低，P4502C9＊3／＊342谢活性更低，并呈现基因剂量关系。