Development and application progress of physiologically based pharmacokinetic modeling and its combined use with other modeling methods / 中国临床药理学与治疗学

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.

Pharmacodynamic Estimate of Propofol-Induced Sedation and Airway Obstruction Effects in Obstructive Sleep Apnea-Hypopnea Syndrome

PURPOSE: Sedatives must be carefully titrated for patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) as oversedation may lead to disastrous respiratory outcomes. This study aimed to investigate the relations between the effect-site concentration (Ce) of propofol and sedation and airway obstruction levels in patients with OSAHS. MATERIALS AND METHODS: In 25 patients with OSAHS, sedation was induced by 2% propofol using target-controlled infusion. Sedation and airway obstruction levels were assessed using the Observer's Assessment of Alertness/Sedation Scale and a four-category scale, respectively. The relationships between propofol Ce and sedation and airway obstruction were evaluated using a sigmoid Emax model. Pharmacodynamic modeling incorporating covariates was performed using the Nonlinear Mixed Effects Modeling VII software. RESULTS: Increased propofol Ce correlated with the depth of sedation and the severity of airway obstruction. Predicted Ce50(m) (Ce associated with 50% probability of an effect> or =m) for sedation scores (m> or =2, 3, 4, and 5) and airway-obstruction scores (m> or =2, 3, and 4) were 1.61, 1.78, 1.91, and 2.17 microg/mL and 1.53, 1.64, and 2.09 microg/mL, respectively. Including the apnea-hypopnea index (AHI) as a covariate in the analysis of Ce50(4) for airway obstruction significantly improved the performance of the basic model (p<0.05). CONCLUSION: The probability of each sedation and airway obstruction score was properly described using a sigmoid Emax model with a narrow therapeutic range of propofol Ce in OSAHS patients. Patients with high AHI values need close monitoring to ensure that airway patency is maintained during propofol sedation.

Neuromuscular blockade and pharmacokinetic-pharmacodynamic modeling

A major goal in pharmacokinetic-pharmacodynamic (PK/PD) modeling of neuromuscular blockade (NMB) is to quantitatively estimate the dose-response relationship.Our PK/PD model consists of three submodels:PK, link kinetics, and PD.A virtual effect compartment in which the drug concentration is in equilibrium with the observed concentration is used to extract the kinetic component (keo) from the pharmacodynamic data alone.Parameters of this model are keo, Ce(50), and gamma.The underlying structural pharmacokinetics and pharmacodynamics for NMB have been well understood, and new novel PK/PD models have been substituted for the gold standard PK/PD model for NMB.The purpose of this review was to describe progress in the field of PK/PD modeling of NMB from the first model, a simultaneous PK/PD model developed by Sheiner et al in the 1970s, to some of the more complicated models.Specific PK/PD models, which accurately described the behaviors of rocuronium, mivacurium, atracurium, and cisatracurium, include the recirculatory model, the peripheral link model, the peripheral elimination model, and a nonparametric model for link kinetics.

Appliance of PK/PD modeling in traditional chinese medicine research / 中国药理学通报

Pharmacokinetic-pharmacodynamic(PK/PD)modeling,as an available tool accounting for the interrelated dynamic connection between the dosage and efficiency of drugs,plays an important role in the field of studying the mechanism and optimizing the clinical administration of traditional Chinese medicine(TCM).Based on the general illustration on the foregoing application of PK/PD modeling,the present work investigates the involving challenges in the field,such as the selection of the target chemical composition and effect mark.In accordance with the unique properties of TCM,further,the related suggestions,mainly focusing on determining the substances based on the effect and establishing the multi-index appraise system,are put forward as reference for the following research work.