Quantitative assessment of the relevance of organic-anion-transporting-polypeptide 1B1 and 2B1 polymorphisms in fexofenadine pharmacokinetic variants via pharmacometrics / 药物分析学报

Fexofenadine is useful in various allergic disease treatment.However,the pharmacokinetic variability information and quantitative factor identification of fexofenadine are very lacking.This study aimed to verify the validity of previously proposed genetic factors through fexofenadine population pharmaco-kinetic modeling and to explore the quantitative correlations affecting the pharmacokinetic variability.Polymorphisms of the organic-anion-transporting-polypeptide(OATP)1B1 and 2B1 have been proposed to be closely related to fexofenadine pharmacokinetic diversity.Therefore,modeling was performed using fexofenadine oral exposure data according to the OATP1B1-and 2B1-polymorphisms.OATP1B1 and 2B1 were identified as effective covariates of clearance(CL/F)and distribution volume(V/F)-CL/F,respectively,in fexofenadine pharmacokinetic variability.CL/F and average steady-state plasma con-centration of fexofenadine differed by up to 2.17-and 2.20-folds,respectively,depending on the OATP1B1 polymorphism.Among the individuals with different OATP2B1 polymorphisms,the CL/F and V/F differed by up to 1.73-and 2.00-folds,respectively.Ratio of the areas under the curves following single-and multiple-administrations,and the cumulative ratio were significantly different between OATP1B1-and 2B1-polymorphism groups.Based on quantitative prediction comparison through a model-based approach,OATP1B1 was confirmed to be relatively more important than 2B1 regarding the degree of effect on fexofenadine pharmacokinetic variability.Based on the established pharmacokinetic-pharmacodynamic relationship,the difference in fexofenadine efficacy according to genetic poly-morphisms of OATP1B1 and 2B1 was 1.25-and 0.87-times,respectively,and genetic consideration of OATP1B1 was expected to be important in the pharmacodynamics area as well.This population phar-macometrics study will be a very useful starting point for fexofenadine precision medicine.

Application of quantitative pharmacology in vaccine research and development: overview and prospect / 中国临床药理学与治疗学

This article introduces the mechanism including antigen presentation, adjuvant, lymphatic system and the characteristics of vaccine, and then summarizes the key applications of core pharmacometrics approaches including QSP, PK/PD, dose response analysis, MBMA, in dose-response, preclinical and clinical translation, and correlation between biomarkers and efficacy of vaccines. It is expected that the successful application of model informed drug development can promote model informed vaccine development so that pharmacometrics makes its due contributions to the development of safer, more effective and more controllable vaccine products.

Interpretation of pharmacokinetic-based criteria for supporting alternative dosing regimens of programmed cell death receptor-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) blocking antibodies for treatment of patients with cancer guidance for industry / 中国临床药理学与治疗学

In recent years, modeling and simulation technology based on pharmacometrics has received increasing attention in the development of innovation drugs. In August of 2021, FDA issued a guidance named Pharmacokinetic-Based Criteria for Supporting Alternative Dosing Regimens of Programmed Cell Death Receptor-1 (PD-1) or Programmed Cell Death-Ligand 1 (PD-L1) Blocking Antibodies for Treatment of Patients with Cancer Guidance for Industry, claiming the necessity of using population PK-based simulation method for the optimization of dosing regimens, and the corresponding implementation standards. This article first summarized the existing therapeutic regimens of PD-1/PD-L1 blocking antibodies in clinic as well as the main content of the guidance, and then cited some actual examples where population PK-based simulation method did contribute to the approval of the alternative dosing regimens. Besides, some critical considerations for the dosing regimen optimization of PD-1/PD-L1 blocking antibodies were also analyzed. In our view, this guidance would have positive impacts on the development of PD-1/PD-L1 blocking antibodies in the future. We hope that this article may provide some references for the colleagues in China.

Model-informed drug development for immune checkpoint inhibitors / 药学学报

With a deepening understanding of cancer treatment, immune checkpoint inhibitors are recognized widely as a novel fundamental remedy for various malignancies with effectiveness and safety. With the development of pharmacometrics, model-informed drug development (MIDD) has emerged to accelerate the process of clinical research for new drugs and improve the accuracy of decision-making in new drug research, especially for immune checkpoint inhibitors. As a typical illustration, the research development of pembrolizumab is presented in this review to highlight the application of MIDD, which may provide a reference for the development of other new antitumor drugs.

Dose selection of obeticholic acid in hepatic impairment patients and the review consideration of FDA / 中国临床药理学与治疗学

The clinical trial of OBCA (OCALIVA) in the treatment of primary biliary cirrhosis (PBC) shows its efficacy. As it is difficult to conduct sufficient clinical studies in moderate and severe hepatic impairment population, the applicant and the FDA theorem have different opinions based on the same model, such as population PK, exposure-response and physiologically-based PK (PBPK). The applicant considers that the increase in the exposure of drug in liver tissue is limited, and there is no need for dose adjustment, that is, 5 mg, once a day. FDA believes that the influencing factors of the PBPK model have not been fully taken into account and the validation of the PBPK is not robust with a wide variability, and there is also a risk of high blood drug exposure in patients. It is recommended to significantly reduce the dose, that is, 5 mg, once a week, no more than 10 mg, per week at least 3 days interval, and accordingly written into the medication instructions. After approval many patients with hepatic impairment did not take medicine according to the instructions, therefore overdosed, resulting in death. The results fully prove that the original considerations and decisions of FDA have been verified, and the experience and lessons of this example once again suggest that modeling and simulation need bold assumptions and careful verification.

A review of three years' experience of the first pharmacometrics company in Korea

As the pharmaceutical industry in Korea is reaching the golden era of drug discovery due to increased investments in research and development and government funds, the need for a more efficient tool for the quantitative analysis has emerged. Therefore, the demand for pharmacometrics (PMx) consultancy services increased. Higher quality service suitable for regulatory submission and out-licensing deals were desired. In this analysis, we compiled and summarized 3 years of experiences of Q-fitter, the first PMx consultancy service company providing PMx analysis to the pharmaceutical industry in Korea. The projects were organized by companies, company types, indications, therapeutic areas, drug development stages, purposes, and scope of services. Within each category, we subcategorized the sections and assessed proportions and a year-over-year trend. As a result, we observed an increase in the number of projects in an average of ~170% per year, with the most frequent types of companies collaborated being the domestic pharmaceutical companies. Among the projects, ~72% involved modeling and simulation using population pharmacokinetic (PK) models, and the other included non-compartmental analysis (NCA), drug-drug interaction (DDI) prediction, and interpretation of the modeling results. The most sought-after purpose in PMx analysis was first-in-human (FIH) dose prediction followed by PK analysis, next clinical trial prediction, and scenario-based simulation. Oncology has been the top therapeutic area of interest every year consisting of ~38% of total projects, followed by Neurology (~13%). From this review, we were able to characterize the PMx service needs and spot the trend of current PMx practices in Korea.

Latest Progress of Clinical Pharmacology in Innovative Drug Development / 世界科学技术-中医药现代化

Under the traditional “empirical trial design”,innovative drug development cannot make comprehensive use of the existing information from previous studies.The development efficiency is low.And it is easy to cause safety issues.Therefore,it is particularly necessary to explore and establish new models,more efficient and safer strategies for the clinical development of innovative drugs.In recent years,the “knowledgeable” clinical research strategy for new drug has been proposed and practiced by the FDA and EMEA.It employed the model and the simulation technology to quantitatively analyze and predict exposure/response relationships of innovative drug and its influence factors in patients.It helped in obtaining sufficient information from clinical data at the same time,to minimize the required number of subjects,and to ensure the safety of subjects in clinical trials.

Pharmacometric models simulation using NONMEM, Berkeley Madonna and R

In this tutorial, we introduce a differential equation simulation model for use in pharmacometrics involving NONMEM, Berkeley Madonna, and R. We report components of the simulation code and similarities/differences between software, rather than how to use each software. Depending on the purpose of the simulation, an appropriate tool can be selected for effective communication.

Tips for the choice of initial estimates in NONMEM

The importance of precise information and knowledge on the initial estimates (IEs) in modeling has not been paid its due attention so far. By focusing on the IE, this tutorial may serve as a practical guide for beginners in pharmacometrics. A 'good' set of IEs rather than arbitrary values is required because the IEs where NONMEM kicks off its estimation may influence the subsequent objective function minimization. To provide NONMEM with acceptable IEs, modelers should understand the exact meaning of THETA, OMEGA and SIGMA based on physiology. In practice, problems related to the value of the IE are more likely to occur for THETAs rather than the random-effect terms. Because it is almost impossible for a modeler to give a precise IE for OMEGAs at the beginning, it may be a good practice to start at relatively small IEs for them. NONMEM may fail to converge when too small IEs are provided for residual error parameters; thus, it is recommended to give sufficiently large values for them. The understandings on the roles, meanings and implications of IEs even help modelers in troubleshooting situations which frequently occur over the whole modeling process.

Comparative Study of First-in-Human Dose Estimation Approaches using Pharmacometrics

OBJECTIVE: First-in-human dose estimation is an essential approach for successful clinical trials for drug development. In this study, we systematically compared first-in-human dose and human pharmacokinetic parameter estimation approaches. METHODS: First-in-human dose estimation approaches divided into similar drug comparison approaches, regulatory guidance based approaches, and pharmacokinetic based approaches. Human clearance, volume of distribution and bioavailability were classified for human pharmacokinetic parameter estimation approaches. RESULTS: Similar drug comparison approaches is simple and appropriate me-too drug. Regulatory guidance based approaches is recommended from US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding no-observed-adverse-effect level (NOAEL) or minimum anticipated biological effect level (MABEL). Pharmacokinetic based approaches are 8 approaches for human clearance estimation, 5 approaches for human volume of distribution, and 4 approaches for human bioavailability. CONCLUSION: This study introduced and compared all methods for first-in-human dose estimation. It would be useful practically to estimate first-in-human dose for drug development.

Application of pharmacometrics in drug development and therapeutic drug monitoring / 中国药科大学学报

Pharmacometrics,developed from the conventional pharmacokinetics,is the science of applying mathe-matical and statistical methods to characterize,understand,and predict a drug's pharmacokinetic,phannacodyna-mic,and biomarker-outcome behaviors.Pharmacometrics has been widely valued for its utility of modeling and simulation in drug research and development,therapeutic drug monitoring and individualized therapy.This paper reviewed the advances of pharmacometrics employed in new drug research and development and therapeutic drug monitoring both at home and abroad.