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Polymorphism refers to the simultaneous and frequent existence of two or more discontinuous variants or genotypes or alleles in a biological population, also known as genetic polymorphisms or genes Polymorphism. This gene polymorphism may have a certain degree of influence on the pharmacokinetics and pharmacodynamics of the drug. The study of genomics plays an important role in realizing personalized, patient-oriented precision medicine treatment. Population model analysis is to use a modeling method to quantitatively describe the correlation and variability between pharmacokinetic and pharmacodynamic parameters and individual characteristics and to quantify the impact of covariates. At present, this method has been widely used. This paper systematically introduces the application examples of using the population model approach to assess the effects of genetic polymorphisms on the drug PK/PD.
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Rituximab, a chimeric human-mouse monoclonal antibody, has been used as a first-line treatment for CD20
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AIM: To compare the results calculated by population pharmacokinetic analysis tools Phoenix NLME, Monolix, R nlmixr package and CPhaMAS cloud platform with the gold standard sofeware NONMEM. METHODS: Fifty sparse sampling data sets based on a one-compartment model and fifty dense sampling data sets based on a two-compartment model were simulated, and the above five analysis tools were used to calculate the population typical value, individual variability and individual pharmacokinetic parameters. RESULTS: The population typical value and individual variability calculated by CPhaMAS and Phoenix NLME had the highest matching degree with NONMEM, followed by nlmixr. Monolix had the lowest matching degree, but Monolix and nlmixr might be more robust. The correspondence between clearance and distribution volume was better than the absorption rate constant. Except the absorption rate constant calculated by Monolix and intercompartmental clearance calculated by nlmixr, the correlation coefficients of individual pharmacokinetic parameters calculated by all analytical tools were greater than 0.99. CONCLUSION: The results calculated by the above four population pharmacokinetic analysis tools are highly correlated with that of NONMEM.
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Linezolid is an antibacterial agent for the treatment of multi-resistant Gram-positive bacterial infections， which is widely used in clinical practice. However， there are large individual differences in the pharmacokinetic characteristics of the drug in patients， and it is difficult to obtain the optimal therapeutic effect when the drug is administered according to the conventional dose in the instructions. Therefore， it is necessary to carry out therapeutic drug monitoring （TDM） for linezolid， and guide and optimize its antibacterial treatment plan by using population pharmacokinetics （PPK） and pharmacodynamics principles. This paper summarizes the PPK changes and the research progress of individualized administration of linezolid in various populations， and recommends that the patient’s steady-state blood concentration is kept at 2-8 mg/mL through TDM when using linezolid clinically. It is recommended to appropriately reduce the dosage for patients with liver and kidney dysfunction， appropriately increase the dosage for obese， burned and children patients， and provide pharmaceutical monitoring during the medication process to promote rational drug use.
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OBJECTIVE To analyze influential factors for dabigatran exposure in elderly patients with non-valvular atrial fibrillation. METHODS The clinical information of 75 elderly patients diagnosed with non-valvular atrial fibrillation was collected from our hospital in Jan. 2019-Jun. 2020. One or two steady-state blood drug concentration samples were collected from each patient. NONMEM 7.2.0 software was used to establish a population pharmacokinetics model of dabigatran； the effects of different covariates on the apparent clearance of dabigatran were investigated， and the final model was verified by goodness of fit and Bootstrap method； NONMEM 7.2.0 software was used to analyze the drug exposure of ordinary elderly patients and elderly patients after taking dabigatran ester in different disease states. RESULTS Totally 122 blood concentration samples of dabigatran were collected. Advanced age， creatinine clearance and history of chronic heart failure were screened out as three significant covariates that influenced the clearance of dabigatran in elderly patients. The exposure of population with advanced age increased by about 50% compared with the general elderly， the exposure of population with history of chronic heart failure increased by nearly 30% compared with population without， and the exposure of population with moderate and severe renal injury increased by about 30% and 80% compared with mild. CONCLUSIONS Advanced age， renal injury and history of chronic heart failure are influential factors for elevated systemic exposure of dabigatran.
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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.
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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. .
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Humans , Antineoplastic Agents/therapeutic use , Drug Development , Lung NeoplasmsABSTRACT
Caspofungin is the firs t echinocandin antifungal drug approved for serious fungal infections caused by Candida or Aspergillus. Currently ，caspofungin has been recommended as the first-line treatment for invasive Candida and the second-line treatment for invasive Aspergillus，for its safety and tolerability. However ，there are still probability of pharmacokinetic variability and the risk of low exposure in different populations. Herein the population pharmacokinetics-pharmacodynamics studies of caspofungin in children and adults were reviewed. The results indicate that the body surface area was the main factor affecting the distribution and clearance of caspofungin in pediatric patients. In adults ，the two-compartment model fits the caspofungin behavior best in vivo with the primary covariates of body weight and albumin level. The efficacy of caspofungin might be related to pharmacokinetics-pharmacodynamics parameters ，such as the ratio of area under blood concentration time curve to minimum inhibitory concentration （AUC/MIC），the ratio of peak concentration to minimum effective concentration （cmax/MEC）.
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Imipenem-cilastatin is a broad-spectrum carbapenem antibiotic drug that has been widely used in clinical practice ， but there is a lack of guidelines and expert consensus on the development of individualized regimens for special status populations [e.g. continuous renal replacement therapy （CRRT）patients，extracorporeal membrane oxygenation （ECMO）patients， critically ill burn patients ，neonates and children]. In this paper ，by searching population pharmacokinetics research of imipenem- cilastatin in special status populations ，it is recommended that imipenem-cilastatin is given 1 to 3 g/d for CRRT patients ；500 mg to 1 g，q6 h for burn patients ；750 mg to 1 g，q6 h for ECMO patients ；20 mg/kg or 25 mg/kg，q8 h for neonates ；and 25 mg/kg，q6 h for children.
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AIM: To develop software for individualizing dosage regimens of vancomycin (VCM) according to the established population pharmacokinetics (PPK) models. METHODS: VCM dosing software was developed using MyEclipse, SQL Server, and JRE. The software developing schemes included requirement analysis, general design, detailed design, software coding, software test, software maintenance and software redevelopment. RESULTS: The developed software achieved the functions such as input and management of patient information, prediction of trough concentrations under various dosing regimens which could help initial dosage design, and prediction of trough concentrations more accurately based on therapeutic drug monitoring results and Bayesian method which could help dosage adjustment. The software was utilized in the interpretation of VCM serum concentration, pharmacists proposed the suggestions for adjusting dosage regimens. The rechecked serum concentrations all reached the expected target blood concentration range in the group of adopting advice. CONCLUSION: The new developed software based on our established PPK models can provide a useful tool in the clinical setting to facilitate the individualized therapy for the adult and elderly infected patients.
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AIM: To investigate the population pharmacokinetic characteristics of capecitabine and its possible influencing factors in Chinese patients of breast cancer. METHODS: 78 cases of Chinese patients with breast cancer were chosen as the objects in this study. Following treatment with capecitabine (0.6 g, 0.15 g/piece, 4 pieces, orally), blood samples were collected and concentrations of capecitabine in plasma were analyzed by high performance liquid chromatography-mass spectrometry (HPLC-MS/MS) method. The nonlinear mixed-effects software (NONMEM) was used to analyze the data and the population pharmacokinetic model was constructed accordingly. RESULTS: The final established model of absorption and elimination is one-compartment model. The clearance (CL/F) in pharmacokinetic formula of the model is as follows: CL/F=291×e
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AIM: To establish a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases who developed neutropenia. METHODS: Patients from department of hematology with neutropenia in our hospital were taken into oue study.The patients (n=77) were performed trough and peak serum concentration of vancomycin, and their clinical data and medication information were collected. The Nonlinear mixed effect modeling approach (NONMEM) was used to establish the PPK model of those patients and model assessment and validation was carried out. Goodneess of fit plots and visual predictive check plus Bootstrap approach were used to assess validate our model. RESULTS: The model was a two compartment model, the final formulas were: clearance rate CL=6.84×(BW/70)
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AIM: To provide reference for the clinical application of tigecycline and subsequent population pharmacokinetic-pharmacodynamics study in the future. METHODS: The Chinese and English keywords of "Tigecycline", "population pharmacokinetics", "population pharmacokinetic model", "pharmacodynamics" or "Tigecycline" pharmacokinetics "were used to search the relevant references published from the time of self-establishment to June 1, 2021 in PubMed, China Knowledge Infrastructure, Wanfang and other databases. The research progress of population pharmacokinetics and pharmacodynamics of tigecycline was reviewed. RESULTS & CONCLUSION: A total of 73 relevant references were retrieved, including 8 tigecycline PPK studies and 7 tigecycline PK/PD studies. At present, tigecycline PPK models had been established in patients with complex intra-abdominal infections, skin and skin and soft tissue infections, community-acquired pneumonia, nosocomial pneumonia, septic shock and other severe infections, including 8 two-compartment models. The main covariates affecting tigecycline plasma clearance were weight-related, liver function and renal function-related parameters. Body weight was also an important factor influencing the apparent volume of distribution. The effect of different disease types on the pharmacokinetics of tigecycline was different, and it needed to be considered and selected in combination with the specific circumstances of patients when formulating clinical dosing regimens. Pharmacodynamics studies should consider not only the type of disease, pathogens and patient factors themselves, but also the characteristics of atypical nonlinear plasma protein binding of tigecycline. In order to accurately understand the efficacy of different dose regimens, it was necessary to monitor the therapeutic drugs of tigecycline.
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The goal of this work was to establish a population pharmacokinetics (PPK) model of tacrolimus in idiopathic membranous nephropathy (IMN) patients and to identify potential covariates that influence pharmacokinetic of tacrolimus. A total of 610 data points on the blood concentration of tacrolimus were collected from 96 IMN patients in routine clinical settings. Nonlinear mixed-effect modeling (NONMEM) was used to investigate the effects of CYP3A5 genotype, age, gender, weight, laboratory tests and co-therapy medications on the pharmacokinetic of tacrolimus. The PPK model was evaluated by the goodness-of-fit (GOT), bootstrap and prediction corrected visual predictive check (pc-VPC). The pharmacokinetic of tacrolimus was described by a one-compartment model. The apparent clearance (CL/F) of CYP3A5*1/*3 and *1/*1 were 1.57 and 1.86 times of that of *3/*3, respectively. The CL/F of tacrolimus was 73.6% in patients undergoing co-therapy with Wuzhi capsules, and 1.2 times than that of the patients undergoing co-therapy with Jinshuibao capsules. The evaluation of the model shows that the model is stable and has satisfactory predictive performance. The clinical trial was approved by the Society of Ethics and conducted in Binzhou Medical University Hospital. The established PPK model can describe the pharmacokinetic characteristics of tacrolimus in Chinese patients with IMN, and can facilitate individualized therapy with tacrolimus.
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OBJECTIVE: To compare all published sodium valproate population pharmacokinetic models of epileptic children in China and assess them by external validation to determine their predictive performance. METHODS: The published population pharmacokinetic model of sodium valproate in children with epilepsy in China was collected by database retrieval. By retrospectively collecting patients' information, we performed an external validation to evaluate the power of prediction. RESULTS: Four sodium valproate models were published before. The external validation of 101 samples showed that the MPE, MAE, RMSE of the four model were similar. All of them showed good adequacy between predicted concentrations and observed concentrations. Comparing with other models, the model established by Ding has better prediction error coincidence rate in most interval, which is more targeted for the prediction of individualized dosage regimen for epileptic children in our hospital. However, the overall prediction accuracy of the four models is not significantly different. CONCLUSION: By the evaluation of four published population pharmacokinetic models of sodium valproate model B performs better than others, while the overall accuracy of the four models did not differ much. Racial difference may be an important factor affecting the accuracy of the model, which needs to be further explored in subsequent studies.
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OBJECTIVE: To establish a population pharmacokinetics(PPK) model of teicoplanin(TEC) in Chinese adult patients and investigate the factors influencing TEC pharmacokinetic parameters. METHODS: A total of 222 blood samples and related information were prospectively collected from 139 inpatients with Gram-positive bacterial infection receiving TEC intravenously. A one-compartment model with first order elimination was used to perform the PPK analysis and the PPK model of TEC was developed via nonlinear mixed effects modeling(NONMEM) approach. The stability and prediction of the final model were evaluated by Bootstrap and normalized predictive distribution error (NPDE). Monte Carlo simulation was used to evaluate the effective of currently recommended dosing regimen. RESULTS: The creatinine clearance(CLcr) and albumin(ALB) were identified as the most significant covariate on the clearance rate of TEC. The established final model was: CL(L•h-1)=1.24×(CLcr/77)0.564×31/ALB;V(L)=69.2. It is verified that the established final model is stable, effective and predictable. For most patients with different serum albumin concentration and CLcr, the initial loading dose of 400 mg/q12h, iv, 3 times, and the maintenance dose of 400-800 mg•d-1 can achieve effective treatment of trough concentration. Severe infections need to adjust the loading dose to 800 mg/q12h, iv, 3 times, and maintain a dose of 400-800 mg•d-1 of the dosing regimens to ensure that the blood concentration reached 15 mg•L-1. CONCLUSION: This study reports that CLcr, ALB has a significant effect on TEC clearance and the model has important value for the individualization of TEC therapy in Chinese adult patients.
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Multiple target tyrosine kinase inhibitors are commonly used in clinical as anti-tumor drugs, which can promote tumor cell apoptosis by inhibiting cell signal transduction, with high selectivity and few side effects. At present, it is widely used in the treatment of non-small cell lung cancer, metastatic renal cancer, thyroid cancer and hematological malignancies. However, the clinical efficacy and pharmacokinetic characteristics of these drugs are affected by many factors, and there are great individual differences. In recent years, the study of population pharmacokinetics is emerging and is widely used in the study of many drugs. In this paper, the pharmacokinetic characteristics and influencing factors of axitinib, imatinib, erlotinib and sunitinib in cancer patients and healthy people were summarized through the retrieval of relevant literature, and then the progress of pharmacokinetic research of tyrosine kinase inhibitors(TKIs) was reviewed. The pharmacokinetic characteristics in different tumor types were analyzed and the related covariates were summarized. The results showed that demographic factors, gene polymorphism, blood biochemical indexes, combined use of drugs and liver and kidney function were important factors affecting metabolism in vivo. Factors such as experimental design and model construction may be the important reasons for the differences in research results. The purpose of this study is to provide a reference for making a reasonable and safe drug therapy plan.
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Ribavirin is a widely used nucleoside antiviral drug. During the epidemic of coronavirus disease 2019 (COVID-19), ribavirin was recommended for empirical treatment in the Clinical Management of Human Infection with COVID-19 (trial guidance v6). However, due to the large inter-individual variations in dose-response relationship, and extremely long terminal half time, it is necessary to perform therapeutic drug monitoring and individualized dose adjustment for ribavirin in special populations. In this article, the pharmacokinetics and therapeutic drug monitoring of ribavirin in different populations are reviewed in order to provide reference for clinical rational use and individualized medication of ribavirin for treatment of COVID-19.
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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.
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Physiologically based pharmacokinetics (PBPK) is one of the main research fields of pharmacometrics, and it plays an important role at all the stages of drug development and clinical practice. In early drug discovery and development, human pharmacokinetics (PK) could be predicted by PBPK modeling using in silico, in vitro and preclinical in vivo data. During clinical studies, PBPK model could be used to investigate the effects of various physiological and pathological factors on PK, such as age, gender, liver/kidney impairment, and to guide dose adjustment of special population (pregnant women, children, etc.). Furthermore, PBPK modeling is now becoming more appealing with the ability to predict drug-drug interaction (DDI) in the case of co-administration of multiple drugs. In recent years, the application of PBPK modeling in industry has increased widely. Also, regulatory agencies have recognized the potential of PBPK and its impact on labeling recommendations. As the popularity of model-informed drug development, the combination of PBPK modeling with other commonly used modeling methods, such as population pharmacokinetics (PopPK), pharmacokinetic/pharmacodynamic (PK/PD) modeling and model-based meta-analysis (MBMA), has shown attractive advantages. In this paper, the origin and development, as well as the application status of PBPK are introduced briefly, and the application of PBPK modeling merged with PopPK, PK/PD and MBMA is reviewed.