ABSTRACT
M701 is a bispecific CD3/EpCAM T-cell engager antibody for the treatment of malignant ascites. We developed a population pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively describe and predict the antitumor effect of M701 in human colorectal cancer xenograft mice. We developed the M701 PK model based on plasma concentration data after i.v. administration. A tumor growth model for human colorectal cancer xenograft was developed to evaluate the antitumor effect of M701. We additionally simulated the inhibitory effect of M701 on tumor volume under different dose regimens based on a PK/PD model. A two-compartment model was developed to predict the PK in human colorectal cancer xenograft mice. The relationship between the M701 concentration and tumor growth inhibition was characterized by a combined Simeoni tumor growth/transit compartment model. The estimated pharmacodynamic parameters were related to the tumor growth characteristics λ0 (0.212 d-1) and λ1 (0.044 7 cm3·d-1), to the drug potency k2 (0.071 5 mL·ng-1·d-1), and to the kinetics of tumor cell death k1 (2×10-5 d-1). A model visual predictive check showed that both the PK model and the tumor growth model closely fit the observed data. Simulated tumor growth after administration of M701 (0.5 mg·kg-1 every 6 days and 0.25 mg·kg-1 every 3 days) could be effectively inhibited. This population PK/PD model of M701 provides insight into the antitumor effect of M701 and supports the further therapeutic development of M701.
ABSTRACT
Physiologically based pharmacokinetic (PBPK) model is based on physiology, anatomy, enzymes for drug metabolism, characteristic of drug transport, physicochemical property of drug and drug-body interaction. Thus, PBPK model may quantitatively predict: concentration-time profiles of drug and its metabolites in plasma and tissues; pharmacokinetics of drug under disease status; pharmacokinetics of drug in special population; pharmacokinetics of drugs in human derived from experimental animals; in vivo pharmacokinetics of drugs based on in vitro parameters for metabolism and transport; pharmacokinetics of drugs from different formations; pharmacodynamics or toxicity of drugs based on in vitro parameters for metabolism, transport, activity or toxicity of drug; drug-drug interaction; individual contributions of enzymes and transporters to in vivo drug disposition. Here, we would review applications of PBPK model in drug development and several questions which should be thought through a series of examples.
ABSTRACT
Pharmacokinetic-pharmacodynamic model is a kind of language that quantitatively describes the drug-related outcomes in the form of mathematical formula. Various outcomes can be subjected to modeling analysis if they can be expressed in numbers. Empirical models have been widely and successfully applied in drug development and research. However, a more competitive drug development environment requires more accurate and predictive models in the early stages of drug development. Accordingly, the subjects of PK-PD modeling have been extended from clinical data to preclinical and in vitro data in the discovery stage. More mechanistic and predictive models, such as physiologically based pharmacokinetic and quantitative system-based pharmacology models, are being increasingly used owing to the growing need to characterize drugs more accurately at the earliest. This tutorial briefly introduces the essential concepts of PK-PD modeling and simulation and describes the recent changing roles of PK-PD model for application in novel drug development process.
Subject(s)
In Vitro Techniques , PharmacologyABSTRACT
@#The aim of this study was to develop a multi-target pharmacokinetic-pharmacodynamic(PK-PD)model for the evaluation of the protective effect of salvianolic acid A(Sal A)on ischemic heart failure based on a metabolic balance model. The rats were assigned to 3 groups: sham-operated group(saline), ischemic heart failure group(saline)and Sal A-treated group(Sal A, 1 mg/(kg ·d), ip). The concentrations of brain natriuretic peptide(BNP), angiotensin II(Ang II), malondialdehyde(MDA), asymmetric dimethylarginine(ADMA)and the activity of glutathione peroxidase(GSH-Px)in rat plasma were determined before and at 1, 2, 3, and 4 weeks after ligation in all the groups. A multi-target PK-PD model was developed based on the change rate of metabolic disruption parameter k and was eventually used to integrally evaluate the protective effect of Sal A on ischemic heart failure. Sal A showed improvement effects on multiple biomarkers and the correlation study demonstrated a good relationship between dynamic parameter k and left ventricular ejection fraction(LVEF). More importantly, the multi-target model well fitted the relationship between AUC and the change rate. The multi-target PK-PD model provides a novel method to integrally evaluate the protective effect of Sal A, which might offer a new strategy for the establishment of a PK-PD model that embodies the characteristics of traditional Chinese medicine.
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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.
Subject(s)
PhysiologyABSTRACT
Objective: Pharmacokinetic-pharmacodynamic (PK-PD) modeling is used to characterize the antipyretic effects of baicalin (BA) in rats. Methods: Twelve healthy male Sprague-Dawley (SD) rats were randomly divided into two groups, each with six. The rats in the first group were sc injected with carrageenan (1 mL per rat) alone to make the inflammation model. The rats in the second group were given BA (180 mg/kg) by ig administration after carrageenan injection. Body temperature was measured while orbital sinus blood sample was collected at different time points. The blood concentration of BA was determined by high performance liquid chromatography-mass spectrometry. PK-PD modelings were fitted with ADAPT 5.1 software. The model with advantage was selected by the fitting goodness. Results: The concentration-time curve was best and fitted by double-site absorption with enterohepatic circulaion of Pk model and the antipyretic responses of Sigmoid-Imax PD model could be well confirmed. The PK and PD models were reconnected by the antipyretogenetic inhibition with effect compartment. The fitting results indicated that the Imax of antipyretic effect by BA was 0.56 °C and shape parameter (H) for PD was 10.67. Conclusion: The dose-effect relationship range in the antipyretic activity of BA on carrageenan-induced pyrexia of rats is narrow and its efficiency is low.
ABSTRACT
Models are simplified descriptions of true biological processes. Pharmacokinetic/pharmacodynamic (PK/PD) modeling is a mathematical description on the relationship between pharmacokinetics and pharmacodynamics. The PK/PD modeling allows estimation of PK/PD parameters and it can establish dose-concentration-response relationships which describe and predict the effect-time courses of a drug. PK/PD modeling has recently emerged as a major tool in clinical pharmacology in order to optimize drug uses by designing rational dosage forms. Population analysis is used to estimate the variability in the population and also to establish guidelines for the individualization of drug dosage regimen. Non-linear mixed effect model is the basis of population approach. This approach permits the simultaneous analysis for all the data of the studied population, by using either PK or PD models to describe the typical trends (population means) and individual profiles. The target controlled infusion system is based on the population PK models which describe the inter-individual PK variability by individualizing the PK parameters according to the patient's covariate. The PK/PD modeling is highly useful for the development of drugs as well as for pharmacotherapy.
Subject(s)
Biological Phenomena , Dosage Forms , Drug Therapy , Pharmacokinetics , Pharmacology, ClinicalABSTRACT
To analyze the correlation of pharmacokinetic/pharmacodynamic (PK/PD) of Chinese materia medica (CMM) based on the multi-components and multi-targets, through the example of demonstrative research, we brought forward some innovative strategies. The research requires to use a medicated serum in parallel at a pathologic state. The experiments included the determination of multi-components PK parameters, the establishment of serum dynamic fingerprints and multi-targets PD models, the research on PK/PD binding model, the selection of the analytic program, the representation of internal relations among the concentration, time, and effect in the effective component group, the analyses on the correlation between fingerprint and PD, the tracing of the rule of PD from the chemical fingerprints and metabolic fingerprints, and the construction of a spectrum which could represent the characterization of the correlation between the retention time and the effect and the characterization of dose-effect fingerprint spectrum of the correlation between peak area growth and effects. The multi-dimensional characteristics of fingerprint-pharmacophore fingerprints (feature effect peak and dose-effect fingerprint spectrum)-fingerprint spectrum of PK are integrated, processed, and edited and a multi-dimensional image of "active integration fingerprint" in the active component group was built. A new research method on the combination of the PK/PD of CMM was explored. Only by this way, we will really understand the interaction in active component group in vivo and clearly explain the material base which truly works.
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For the pharmacokinetic analysis of isoniazid transfer into CSF, steady-state isoniazid concentrations of plasma and CSF were measured in eleven tuberculous meningitis patients confirmed with findings of CSF and neuroimazing. Peak plasma levels (4.17-21.5 micrograms/mL) were achieved at 0.25 to 3 hours after multiple isoniazid dose (600 mg/day). Terminal half-life, total clearance (CI/F) and volume of distribution (Vd/F) were 1.42 +/- 0.41 hr, 0.47 +/- 0.22 L/kg/hr and 0.93 +/- 0.48 L/kg, respectively. Isoniazid concentrations in CSF collected intermittently were highest at 3 hr (Mean, 4.18 micrograms/mL) and were 0.54 +/- 0.21 micrograms/mL at 12 hrs after the last dose of isoniazid 10 mg/kg/day. CSF/plasma partitioning of isoniazid and equilibration rate were estimated using modified pharmacokinetic/pharmacodynamic model. Disposition rate constant from CSF to plasma and CSF/plasma partitioning ratio of isoniazid were estimated to be 0.39 h-1 and 1.17, respectively.