Application of physiologically based pharmacokinetic model in drug development and several questions being thought / 中国临床药理学与治疗学

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.

Pharmacokinetic/pharmacodynamic modeling of the antitumor action of bispecific CD3/EpCAM antibody M701 in human colorectal cancer xenograft mice / 药学学报

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.

Evolving role of modeling and simulation in drug development

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.

Population pharmacodynamics of cilostazol in healthy Korean subjects

Cilostazol is used for the treatment of intermittent claudication, ulceration and pain. This study was conducted to develop a population pharmacodynamic (PD) model for cilostazol's closure time (CT) prolongation effect in healthy Korean subjects based on a pharmacokinetic (PK) model previously developed. PD data were obtained from 29 healthy subjects who participated in a study conducted in 2009 at Severance Hospital. The PK model used was a two-compartment model with first order absorption. CT data were best described by a turnover model with a fractional turnover rate constant (K(out)) inhibited by drug effects (Eff), which were represented by a sigmoid E(max) model [Eff = E(max) · C(γ) / (EC₅₀(γ)+C(γ))] with E(max) being maximum drug effect, EC₅₀ drug plasma concentration at 50% of E(max), C drug plasma concentrations, and γ the Hill coefficient. For the selected PD model, parameter estimates were 0.613 hr⁻¹ for K(out), 0.192 for E(max), 730 ng/ml for EC₅₀ and 5.137 for γ. Sex and caffeine drinking status significantly influenced the baseline CT, which was 85.36 seconds in male non-caffeine drinkers and increased by 15.5% and 16.4% in females and caffeine drinkers, respectively. The model adequately described the time course of CT. This was the first population PD study for cilostazol's CT prolongation effect in a Korean population.

Pharmacodynamics of a combination of remifentanil and propofol for ultrasound-guided transvaginal oocyte retrieval / 临床麻醉学杂志

Objective To evaluate the clinical anesthetic efficacy of a combination of propofol and remifentanil for ultrasound-guided transvaginal oocyte retrieval.Pharmacodynamic (PD) model was established and its characteristics were analyzed based on the simulated concentrations of propofol and remifentanil in respective pharmacokinetic models, so as to guide further study.Methods Forty-two female patients undergoing transvaginal oocyte retrieval were divided into groups PR15 (n=24) and PR10 (n=18), who were received intravenous bolus of remifentanil 1.5 μg/kg + propofol 1.5 mg/kg and remifentanil 1.0 μg/kg+propofol 1.0 mg/kg, respectively.The anesthesia quality evaluation was based on the following indicators: onset time (loss of eyelash reflex), recovery time of orientation, the incidence of hypoxemia (SpO2 < 92%) and adverse reactions.Nonlinear mixed-effects model was used to evaluate the time courses of the simulated propofol and remifentanil concentrations-effect and to establish the PD model with NONMEM software.Results The time of recovering orientation in the patients of group PR10 was significantly faster compared with the patients in group PR15;the time of loss of eyelash reflex , incidence of hypoxemia (12.5% vs 16.7%) and cough (16.7% vs 11.1%) had no significant differences between the both groups.With the final PD model, the estimated parameters as following: EC50 of propofol and remifentanil for effective sedation and analgesia were 1.71 μg/ml and 2.57 ng/ml, respectively.EC95 of propofol and remifentanil for effective sedation and analgesia were 4.30 g/ml and 4.57 ng/ml, respectively.The effect site concentration of propofol 1 mg/kg was lower than EC50, but the effect site concentration of 1.5 mg/kg was higher than EC50.The peak effect site of 1.0 μg/kg and 1.5 μg/kg remifentanil was higher than EC50, and 1.5 μg/kg concentration was close to EC95.Conclusion Based on patients' recovery time, propofol 1.0 mg/kg combined with fentanyl 1.0 μg/kg is appropriate in patients undergoing transvaginal oocyte retrieval.

Evaluation of the protective effect of salvianolic acid A on ischemic heart failure by a multi-target pharmacokinetic-pharmacodynamic model / 中国药科大学学报

@#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.

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.

Pharmacokinetic-pharmacodynamic study on antipyretic effects of baicalin on carrageenan-induced pyrexia of rats / 中草药

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.

Pharmacokinetic and pharmacodynamic modeling in anesthetic field

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.

Analysis and strategy on pharmacokinetic/pharmacodynamic correlation of Chinese materia medica based on multi-components and multi-targets / 中草药

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.

Investigação da atividade antihiperglicemiante da farinha da casca de Passiflora edulis Sims, Passifloraceae, em ratos diabéticos induzidos por aloxano / Investigation of antihyperglycemic activity of Passiflora edulis Sims, Passifloraceae, in alloxan-induced diabetic rats

O presente estudo objetivou a modelagem farmacodinâmica da ação antihiperglicemiante da farinha da casca de maracujá (Passiflora edulis Sims, Passifloraceae) em ratos diabéticos induzidos por aloxano. Os animais foram divididos em três grupos (n = 9): grupo diabético tratado com 20 mg/kg, 40 mg/kg ou 160 mg/kg da farinha. As amostras sanguíneas foram coletadas da veia lateral da cauda e a glicemia foi determinada com auxílio de um glucômetro em 0, 1, 2, 4 e 6 h após o tratamento via oral. Observou-se que o efeito antihiperglicemiante da farinha da casca de maracujá foi dependente da dose, obtendo um efeito expressivo observado em quatro horas para todas as doses, sendo mais pronunciado na dose de 160 mg/kg. O efeito, expresso como redução da glicemia basal em relação ao tempo zero, pode ser modelado através de um modelo dose-efeito clássico, o qual permitiu a determinação do efeito máximo (Emax) e da dose necessária para alcançar 50 por cento deste efeito (DE50). Após a modelagem dos dados, obteve-se um valor de Emax = 58,41 por cento e de DE50 = 23,61 mg/kg. Esta abordagem pode permitir a comparação do efeito antihiperglicemiante de Passiflora edulis com outras espécies que apresentem atividade sobre a redução da glicemia, mediada pela presença de fibras solúveis.

This study goals the pharmacodynamic modeling of anti hyperglycemic action of flour of Passion fruit bark (Passiflora edulisSims, Passifloraceae) in alloxan-induced diabetic rats. The animals were divided into three groups (n = 9) that received different doses: 20, 40 or 160 mg/kg of flour. The blood samples were collected from the tail vein and the blood glucose was determined using a glucometer Prestige IQ in 0, 1, 2, 4 and 6 h after the oral treatment. It was observed that the effect of the flour of Passion fruit bark was dose dependent, getting an expressive effect observed in four hours from all doses tested, being more pronounced at the 160 mg/kg dose. This effect was expressed as reduction of basal blood glucose in respect to zero time and can be modeled through a classic dose effect model. It allowed the determination of maximum effect (Emax) and the necessary dose to reach 50 percent of this effect (ED50). After the data modeling, it was gotten a value of Emax = 58,41 percent and ED50 = 23,61 mg/kg. This approach allows the comparison of antyhyperglicemic effect of Passiflora eduliswith other species that present activity lowering the glycemia, through the presence of soluble fibers.

Development of an Adequate Propofol Sedation Model in Elderly Patients for Elective Surgery under Regional Anesthesia

BACKGROUND: Propofol, an ultrashort-acting anesthetic agent, is being increasingly used for sedation during regional anesthesia. The goal of this study was to characterize the pharmacodynamic relation between the effect site concentration of propofol and the occurrence of loss of consciousness (LOC) and apnea in elderly patients undergoing regional anesthesia. METHODS: Twenty patients aged 65 years or older presenting for elective surgery requiring regional anesthesia were enrolled. After performing spinal anesthesia, the target effect site concentration of propofol was set at 1.0 microg/mL. Effect site concentration was increased by 0.2 or 0.3 microg/mL until LOC and apnea were observed. LOC was determined by the loss of response to verbal command ("open your eyes") and apnea as the loss of spontaneous breathing for 20 seconds. The pharmacodynamic relation between effect site concentrations of propofol and LOC or apnea was characterized by population analysis using nonlinear mixed effects model. Approximate entropy (ApEn) as a surrogate measure of central nervous effect of propofol was calculated from raw electroencephalogram, retrospectively. The correlation between effect site concentration of propofol and ApEn was tested. RESULTS: The estimates (standard error) of Ce50 for LOC and apnea (the effect site concentration of propofol associated with 50% probability of LOC and apnea) were 1.74 (0.09) and 2.35 (0.11) microg/mL, respectively. The Spearman correlation coefficient between effect site concentration of propofol and ApEn was -0.8164 (p<0.0001). CONCLUSION: These results provide an adequate guidance for sedation in elderly patients for elective surgery under regional anesthesia.

Kinetics of Isoniazid Transfer into Cerebrospinal Fluid in Patients with Tuberculous Meningitis

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.