Application status and development trend of virtual clinical trials / 中国胸心血管外科临床杂志

@#Virtual clinical trials are clinical trials conducted through computer simulation technology, which breaks through the limitations of traditional clinical trials and has the advantages of saving time, reducing costs, and reducing the risk of human trials. With the application of new computer technologies such as population pharmacokinetics, physiologically-based pharmacokinetics, quantitative systems pharmacology, and artificial intelligence, the field of virtual clinical trials in healthcare has become an important development direction. This article will give a preliminary review of the connotation, methods and future development trends of virtual clinical trials, aiming to provide reference for the application of new technologies and methods in clinical trials.

Advances and applications of quantitative systems pharmacology modeling and virtual clinical trials in modern drug development / 药学学报

Quantitative systems pharmacology (QSP) modeling is an emerging computational medicine approach with growing applications and significance in modern drug development. QSP models are generally formulated based on multiscale disease mechanisms and drug-target interactions, which makes them capable of integrating multimodal data from the preclinical and clinical space. This also enables them to generate quantitative characterization of the dynamic disease progression as well as high-throughput predictions of drug-induced efficacy and toxicity signals. Therefore, QSP modeling and model-based virtual clinical trials have been widely implemented to guide drug development, in scenarios such as target identification and assessment, clinical trial design, evaluation of combination therapy and biomarkers, and personalized medicine. In US and Europe, QSP modeling has been developing rapidly in the past 10 years and is now an integral part of the model-informed drug development paradigm; however, in China it is still a nascent field. Here we will present a comprehensive review of the recent advancements of QSP and its impact in modern drug development through a number of case studies. This review will provide guidance for the future drug development efforts and the growth of QSP practice in China.

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.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Application of MIDD in Clinical Research of Antitumor Drugs / 中国肺癌杂志

The antitumor drug has become one of the focused areas in new drug research and development. Their clinical research generally consumes a long period of time, with high cost and high risk. Model-informed drug development (MIDD) integrates and quantitatively analyzes physiological, pharmacological, and disease progression information through modeling and simulation, which can reduce the cost of drug development and improve the efficiency of clinical research. In this essay, Osimertinib and Pembrolizumab are given as examples to illustrate the specific application of MIDD in different phases of clinical research, aiming to provide references for the application of MIDD to guide the clinical research of 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.

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.

Applications of model-informed drug development (MIDD) on new drug research and development / 中国临床药理学与治疗学

Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.

Application of model-informed drug development approach in dose optimization: Insights from the modification of nivolumab dosage regimen / 中国临床药理学与治疗学

Nivolumab is a humanized monoclonal antibody that blocks the programmed death 1 (PD-1) receptor. The initially recommended dose was 3 mg/kg every 2 weeks (Q2W) when nivolumab was firstly approved by the US FDA in 2014. A flat dose of 240 mg Q2W was approved in 2016, and subsequently 480 mg Q4W in 2018. Model-informed drug development (MIDD) approach was applied for the analyses of drug exposure, safety and efficacy based on the data from existed clinical studies, and the model-informed analyses became the key evidences supporting approval of new dosage regimens. Relevant studies and regulatory considerations related to the nivolumab dose selection and subsequent modification were reviewed in this paper. The application of MIDD approach in dose optimization is additionally discussed.