Pharmacokinetic/pharmacodynamic integration in drug development and dosage-regimen optimization for veterinary medicine

Pharmacokinetic (PK)/pharmacodynamic (PD) modeling is a scientific tool to help developers select a rational dosage regimen for confirmatory clinical testing. This article describes some of the limitations associated with traditional dose-titration designs (parallel and crossover designs) for determining an appropriate dosage regimen. It also explains how a PK/PD model integrates the PK model (describing the relationship between dose, systemic drug concentrations, and time) with the PD model (describing the relationship between systemic drug concentration and the effect vs time profile) and a statistical model (particularly, the intra- and interindividual variability of PK and/or PD origin). Of equal importance is the utility of these models for promoting rational drug selection on the basis of effectiveness and selectivity. PK/PD modeling can be executed using various approaches, such as direct versus indirect response models and parametric versus nonparametric models. PK/PD concepts can be applied to individual dose optimization. Examples of the application of PK/PD approaches in veterinary drug development are provided, with particular emphasis given to nonsteroidal anti-inflammatory drugs. The limits of PK/PD approaches include the development of appropriate models, the validity of surrogate endpoints, and the acceptance of these models in a regulatory environment.     

CCR2拮抗剂研究进展

细胞表面趋化因子受体2(CCR2)属于G蛋白偶联受体(GPCR)超家族成员,并且是单核细胞趋化蛋白1～4(MCP1～4)的受体.MCP1～4是促炎症反应的化学诱导物,CCR2和MCP-1在人类侵蚀性疾病模型如动脉粥状硬化、多发性硬化症中均起显著作用.大量研究证明CCR2和MCP-1拮抗剂可以减少临床炎症模型的发病率,这些化学拮抗剂的结构多样,主要包括γ-氨基丁酰胺类、甘胺酰胺类、噻唑类、吲哚类、二取代双哌啶醇类、季铵盐类和不饱和杂环类等,它们表现出不同的药理活性.CCR2拮抗剂对各种与趋化因子相关的疾病具有较好的疗效,部分药物已经进入临床试验阶段,综述CCR2及其受体拮抗剂的研究进展.     

定量药理学与儿童药物研发和合理用药

1引言 儿童合理用药是摆在世界各国临床药理学工作者和儿科医生面前一个亟待解决而又悬而难决的课题。长期以来，儿童作为弱势群体和人类的未来是社会大众的保护对象，伦理上不接受儿童作为药物试验的受试者。即使是常用于儿童的药物，也很少在儿童中试验过。     

Translational PK–PD modeling in pain

The current gap between animal research and clinical development of analgesic drugs presents a challenge for the application of translational PK–PD modeling and simulation. First, animal pain models lack predictive and construct validity to accurately reflect human pain etiologies and, secondly, clinical pain is a multidimensional sensory experience that can’t always be captured by objective and robust measures. These challenges complicate the use of translational PK–PD modeling to project PK–PD data generated in preclinical species to a plausible range of clinical doses. To date only a few drug targets identified in animal studies have shown to be successful in the clinic. PK–PD modeling of biomarkers collected during the early phase of clinical development can bridge animal and clinical pain research. For drugs with novel mechanism of actions understanding of the target pharmacology is essential in order to increase the success of clinical development. There is a specific interest in the application of human pain models that can mimic different aspects of acute/chronic pain symptoms and serves as link between animal and clinical pain research. In early clinical development the main objective of PK–PD modeling is to characterize the relationship between target site binding and downstream biomarkers that have a potential link to the clinical endpoint (e.g. readouts from the human pain models) so as to facilitate the selection of doses for proof of concept studies. In patient studies, the role of PK–PD modeling and simulation is to characterize and confirm patient populations in terms of responder profiles with the aim to find the right dose for the right patient.     

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.     

药代动力学药效动力学结合模型研究进展

药代动力学和药效动力学共同构成了现代药理学研究的基础。PK/PD模型是将两者相结合,以说明给予某一剂量后所引起的药理作用的时间过程。研究PK/PD关系不但有助于正确指导临床用药,还可以用于探讨药物作用机制、新药评估以及新制剂的开发等。本文就近些年来PK/PD模型在药理学和毒理学,临床应用以及新药开发等方面的研究进展作一简要的综述。     

Tools to define the relevance of PK/PD parameters to the efficacy, toxicity and emergence of resistance of antimicrobials

In vitro and in vivo pharmacokinetic (PK) and pharmacodynanmic (PD) modeling have been effectively utilized in early drug development across a range of therapeutic disciplines to define the relationship between efficacy-related active drug concentrations in the serum and plasma. In addition to phase I and phase II PK data, human clinical trials enhance the PK and PD information gained from preclinical research. More recently, PK/PD models have been utilized to evaluate the potential for the targets of specific drug classes to develop drug resistance. In addition, PK/PD modeling tools have been used to address the issues associated with relationship of drug exposure to toxicity in preclinical and clinical settings. As more clinical data is collected on new classes of antibiotics, or specific compounds, there will be a need to perform PK/PD assessments to evaluate the in vitro and preclinical in vivo data because the compilation of both sets of information relates to human clinical outcome data.     

Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50 and KeO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.     

Modeling delayed drug effect using discrete-time nonlinear autoregressive models: a connection with indirect response models

Indirect response (IDR) models have been widely applied to pharmacodynamic (PD) modeling, particularly when delayed response (hysteresis) is present. This paper proposes a class of nonlinear discrete-time autoregressive (AR) models with drug concentrations acting as a time-varying covariate on the asymptote parameter or the autocorrelation parameter of the AR models as an alternative modeling approach for delayed response data. The mathematical derivations revealed the inherent connection between IDR models and nonlinear AR models, and showed that the nonlinear AR models approximate the IDR models when the time interval between response data is small. Simulations demonstrate that the IDR models and the corresponding AR models produce similar temporal response profiles, and as the time interval decreased (i.e., more intensive sampling designs), the AR model based parameter estimates were more comparable to those estimated from the IDR models. In conjunction with mixed-effects modeling, the nonlinear AR models have been shown to well describe a set of simulated longitudinal PK/PD data for a clinical study. Further extensions of the proposed nonlinear AR models are warranted to model irregular and sparse PK/PD data.     

药代动力学-药效动力学结合模型在中药研究中的应用

药代动力学-药效动力学(Pharmacokinetic-pharmacodynamic,PK/PD)结合模型是研究中药体内代谢过程、药物效应及二者联系的有效工具,对于中药作用机制研究、临床用药优化有重要的参考价值。建立能体现中医药特色的PK/PD结合模型十分必要。该文针对目前PK/PD结合模型在中药研究领域的应用现状作了系统的阐述,并就中药效应物质基础的确定、效应指标的选择等关键问题进行探讨并提出建议,以期为今后的相关研究提供参考。     

麻醉科毒麻精神药品管理的改进与体会

保证毒麻药品的安全使用是麻醉科药品管理工作的重要内容之一,在工作中发现我院麻醉科毒麻精神药品管理存在一些漏洞。现将解放军总医院麻醉科毒麻精神药品的管理经验与《麻醉药品精神药品管理条例》内容相结合,对我院麻醉科的管理制度进行改进与完善,联合麻醉科护士与手术室护士共同对毒麻药品进行管理,确保毒麻药品精神药品每个使用环节都有监管,杜绝麻醉药品外流。保证毒麻精神药品使用过程中的安全性、合法化、规范化、有序化。     

Pharmacokinetic-pharmacodynamic guided trial design in oncology

The application of pharmacokinetic (PK) and pharmacodynamic (PD) modeling in drug development has emerged during the past decades and it is has been suggested that the investigation of PK–PD relationships during drug development may facilitate and optimize the design of subsequent clinical development. Especially in oncology, well designed PK–PD modeling could be extremely useful as anticancer agents usually have a very narrow therapeutic index. This paper describes the application of the current insights in the use of PK–PD modeling to the design of clinical trials in oncology. The application of PK–PD modeling in each separate stage of (pre)clinical drug development of anticancer agents is discussed. The implementation of this approach is illustrated with the clinical development of docetaxel.     

Preclinical Pharmacokinetic/Pharmacodynamic Modeling and Simulation in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.KEY WORDS: pharmaceutical industry, preclinical pharmacokinetic/pharmacodynamic modeling, simulation     

Model-Based Decision Making in Early Clinical Development: Minimizing the Impact of a Blood Pressure Adverse Event

We describe how modeling and simulation guided program decisions following a randomized placebo-controlled single-rising oral dose first-in-man trial of compound A where an undesired transient blood pressure (BP) elevation occurred in fasted healthy young adult males. We proposed a lumped-parameter pharmacokinetic–pharmacodynamic (PK/PD) model that captured important aspects of the BP homeostasis mechanism. Four conceptual units characterized the feedback PD model: a sinusoidal BP set point, an effect compartment, a linear effect model, and a system response. To explore approaches for minimizing the BP increase, we coupled the PD model to a modified PK model to guide oral controlled-release (CR) development. The proposed PK/PD model captured the central tendency of the observed data. The simulated BP response obtained with theoretical release rate profiles suggested some amelioration of the peak BP response with CR. This triggered subsequent CR formulation development; we used actual dissolution data from these candidate CR formulations in the PK/PD model to confirm a potential benefit in the peak BP response. Though this paradigm has yet to be tested in the clinic, our model-based approach provided a common rational framework to more fully utilize the limited available information for advancing the program.     

PK/PD: new insights for antibacterial and antiviral applications

The path of new compounds from discovery to bedside is long and costly and a large majority of compounds never make it to the market. To improve drug development, better tools are needed to assess efficacy and safety early in the process. One approach that has been suggested by the FDA to help streamlining the drug development process is pharmacokinetic/pharmacodynamic (PK/PD) modeling and simulation. In this approach, a model-based link between PK profiles and corresponding PD is established. Once a suitable model is identified and validated, predictions about efficacy and safety of different dosing regimens can be made. The goal of this review is to examine the current state of PK, PD, and PK/PD in antibiotic and antiviral research and development.     

Quantitative systems pharmacology as an extension of PK/PD modeling in CNS research and development

Quantitative systems pharmacology (QSP) is a recent addition to the modeling and simulation toolbox for drug discovery and development and is based upon mathematical modeling of biophysical realistic biological processes in the disease area of interest. The combination of preclinical neurophysiology information with clinical data on pathology, imaging and clinical scales makes it a real translational tool. We will discuss the specific characteristics of QSP and where it differs from PK/PD modeling, such as the ability to provide support in target validation, clinical candidate selection and multi-target MedChem projects. In clinical development the approach can provide additional and unique evaluation of the effect of comedications, genotypes and disease states (patient populations) even before the initiation of actual trials. A powerful property is the ability to perform failure analysis. By giving examples from the CNS R&D field in schizophrenia and Alzheimer’s disease, we will illustrate how this approach can make a difference for CNS R&D projects.     

Do Plasma Concentrations Obtained from Early Arterial Blood Sampling Improve Pharmacokinetic/Pharmacodynamic Modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC₅₀ ) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC₅₀ and K_eO based on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid E_max ) model could not describe the time course of effect of the NMBAs adequately.