Pharmacokinetic/Pharmacodynamic Modeling of Total Lymphocytes and Selected Subtypes After Oral Budesonide

In the present pharmacokinetic/pharmacodynamic (PK/PD) evaluation, cortisol, total lymphocytes, and lymphocyte subpopulations were monitored following single oral doses of two oral formulations of 3 mg budesonide (BUD) (Dosage Forms A and B) in order to assess the differential effects that BUD may have on cortisol suppression and the modulation of blood lymphocyte subtypes. On a single occasion, five subjects received one 3 mg capsule of Dosage Form A, four received three capsules of Dosage Form A (single dose of 9 mg), and five received three capsules of Dosage Form B (single dose of 9 mg). Placebo capsules were administered to six subjects in the study. Cortisol concentrations, total lymphocyte counts, and lymphocyte subpopulation counts for the CD3, CD4, CD8, CD19, and CD56/16 were fitted to an in direct PK/PD response model that described the effects of BUD on serum cortisol concentrations as well as the combined effects of BUD and cortisol on total lymphocytes and the CD3, CD4, CD8, CD19, and CD56/16 subtypes. Data were also analyzed using noncompartmental methods. The PK/PD model fitted the data with the exception of data for CD56/16. The IC₅₀ value for unbound BUD acting on total lymphocytes was 0.276 ng/ml while the IC₅₀ values for unbound BUD acting on lymphocyte subtypes ranged from 0.150 ng/ml for CD4 to 0.364 ng/ml for CD8. The IC₅₀ values for the effects of BUD on serum cortisol were lower (0.079 ng/ml). The results of PK/PD modeling and noncompartmental analysis indicate that BUD has a smaller effect on the CD8 subtype and larger effects on the CD4 and CD19 subtypes, relative to the effect on total lymphocytes, and that cortisol suppression, although not a direct immunological biomarker, may be a more sensitive marker for the systemic effect of corticosteroids.     

A Pharmacokinetic/Pharmacodynamic Approach to Predict Total Prednisolone Concentrations in Human Plasma

Prednisolone and prednisone are two widely used corticosteroids for various inflammatory and immune diseases. Prednisolone is the active form of prednisone in vivo. Total prednisolone in plasma exhibits nonlinear pharmacokinetics mainly due to its nonlinear protein binding. Other factors such as reversible metabolism (or interconversion between prednisolone and prednisone), competitive protein binding from endogenous cortisol, cortisol circadian rhythm, and prednisolone mediated cortisol suppression complicate prednisolone pharmacokinetics. This study was aimed to develop a new approach to describe the nonlinear pharmacokinetics of total prednisolone and predict total prednisolone concentrations in plasma. Based on literature datasets, a linear two-compartment pharmacokinetic model was developed to adequately describe the reversible metabolism between free prednisone and prednisolone. Cortisol and prednisolone protein binding were described via the sum of a Langmuir and linear type binding. The endogenous cortisol circadian rhythm and cortisol suppression during prednisone or prednisolone exposure were described with a previously reported linear release rate pharmacokinetic/pharmacodynamic (PK/PD) model. By combining the pharmacokinetic models for free prednisone and prednisolone, the linear release rate model for cortisol suppression, and competitive protein binding between cortisol and prednisolone, we were able to predict total prednisolone concentrations in plasma. The predicted total prednisolone concentrations in plasma were in good agreement with the literature reported data. Thus, this PK/PD approach shows that the combination of nonlinear protein binding, cortisol circadian rhythm, and cortisol suppression could account for the nonlinearity of total prednisolone. In addition, it also allows a valid prediction of total prednisolone in plasma after either prednisone or prednisolone administration.     

Grey-box Modelling of Pharmacokinetic /Pharmacodynamic Systems

Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling consists of using stochastic differential equations (SDEs) where the stochastic term in the differential equations represents unknown or incorrectly modelled dynamics of the system. The methodology behind the grey-box PK/PD modelling framework for systematic model improvement is illustrated using simulated data and furthermore applied to Bergmans minimal model of glucose kinetics using clinical data from an intravenous glucose tolerance test (IVGTT). The grey-box estimates of the stochastic system noise parameters indicate that the glucose minimal model is too simple and should preferably be revised in order to describe the complicated in vivo system of insulin and glucose following an IVGTT.     

Data Supplementation: A Pharmacokinetic/Pharmacodynamic Knowledge Creation Approach for Characterizing an Unexplored Region of the Response Surface

No HeadingPurpose. To develop a data supplementation [i.e., a pharmacokinetic/pharmacodynamics (PK/PD) knowledge creation] approach for generating supplemental data to be used in characterizing a targeted unexplored segment of the response surface.Methods. The procedure for data supplementation can be summarized as follows: 1) statement of the objective of data supplementation for PK/PD knowledge creation, 2) performance of PK knowledge discovery, 3) PK data synthesis for target dose group(s), 4) covariate data synthesis for virtual subjects in the target dose group(s), 5) discovery of hidden knowledge from real data set to which supplemental data will be added, 6) implementation of a data supplementation methodology, and 7) discovery and communication of the created knowledge. A nonparametric approximate Bayesian multiple supplementation and its modification, structure-based multiple supplementation, which is an adaptation of the approximate Bayesian bootstrap, is proposed as a method of data supplementation for PK/PD knowledge creation. The structured-based multiple supplementation methodology was applied to characterize the effect of a target dose of 100 mg that was unexplored in a previously concluded study that investigated the effect of 200- and 600-mg doses on biomarker response.Results. The target dose of 100 mg was found to produce a response comparable with that of the 200 mg and better than that obtained with the 600 mg.Conclusions. Implementation of the PK/PD knowledge creation process through data supplementation resulted in gaining knowledge about a targeted region of a response surface (i.e., the effect of a target dose) that was not previously studied in a completed study without expending resources in conducting a new study.     

泰比培南对小鼠肺炎克雷伯菌大腿感染模型的PK/PD研究

目的：通过泰比培南对小鼠大腿克雷伯菌感染模型PK/PD研究,预测最佳PK/PD参数。方法：选用临床肺炎克雷伯菌1株,采用琼脂二倍稀释法检测药物的最低抑菌浓度（MIC）;构建小鼠的肺炎克雷伯菌大腿感染模型,分三种剂量（50、15、3 mg·kg-1）给予受试药物,观察给药24 h后大腿组织感染量变化,并采用HPLC法检测血药浓度。结果：体外测得MIC为0.03μg· mL-1;在小鼠的肺炎克雷伯菌大腿感染模型中,50、15、3 mg·kg-1三种剂量均对感染有治疗作用, PK/PD参数AUC/MIC、Cmax/MIC、T〉MIC的相关系数r2分别为0.8、0.75、0.54。结论：体内PK/PD研究表明,AUC/MIC、Cmax/MIC参数是反映泰比培南对小鼠的肺炎克雷伯菌大腿感染治疗效果主要的PK/PD参数。     

Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog,TAK-448, for its anti-tumor efficacy in a rat xenograft model

TAK-448 is the investigational metastin/kisspeptin analog, which is known to have an anti-tumor effect through suppression of androgen hormones (luteinizing hormone and testosterone) levels. This study developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat vertebral-cancer of the prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. A potential contribution of the hormone-independent direct effects of TAK-448 to the tumor growth inhibition was also investigated in the in vivo rat xenograft model, because our in vitro experiments revealed that TAK-448 may also directly suppress VCaP cellular proliferation. The PK/PD model successfully described the time course of tumor growth inhibition after drug treatment as well as the development of resistance to the inhibition of androgen hormones, following drug treatment or castration. The EC₅₀ of the hormone-dependent inhibitory effect of TAK-448 was much lower than that of TAP-144, and TAK-448 also has a faster onset of anti-tumor effect than TAP-144, demonstrating that TAK-448 has a stronger overall anti-tumor effect than TAP-144. In addition, model inference, by incorporating a hormone-independent inhibition pathway of TAK-448 into the PK-PD model, suggested that such a direct inhibition pathway for TAK-448 cannot be excluded, as also indicated by in vitro studies, but its EC₅₀ would be approximately three orders of magnitude higher than that of the hormone-dependent pathway. This study helps to understand the potential and mechanism of TAK-448 as a prostate cancer treatment.     

Population Pharmacokinetic/Pharmacodynamic Modeling of Systemic Corticosteroid Inhibition of Whole Blood Lymphocytes: Modeling Interoccasion Pharmacodynamic Variability

Purpose To develop a population pharmacokinetic/pharmacodynamic (PK/PD) model that characterizes the effects of major systemic corticosteroids on lymphocyte trafficking and responsiveness. Materials and Methods Single, presumably equivalent, doses of intravenous hydrocortisone (HC), dexamethasone (DEX), methylprednisolone (MPL), and oral prednisolone (PNL) were administered to five healthy male subjects in a five - way crossover, placebo - controlled study. Measurements included plasma drug and cortisol concentrations, total lymphocyte counts, and whole blood lymphocyte proliferation (WBLP). Population data analysis was performed using a Monte Carlo-Parametric Expectation Maximization algorithm. Results The final indirect, multi-component, mechanism-based model well captured the circadian rhythm exhibited in cortisol production and suppression, lymphocyte trafficking, and WBLP temporal profiles. In contrast to PK parameters, variability of drug concentrations producing 50% maximal immunosuppression (IC₅₀) were larger between subjects (73–118%). The individual log-transformed reciprocal posterior Bayesian estimates of IC₅₀ for ex vivo WBLP were highly correlated with those determined in vitro for the four drugs (r ²  = 0.928). Conclusions The immunosuppressive dynamics of the four corticosteroids was well described by the population PK/PD model with the incorporation of inter-occasion variability for several model components. This study provides improvements in modeling systemic corticosteroid effects and demonstrates greater variability of system and dynamic parameters compared to pharmacokinetics. Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Population pharmacokinetics/pharmacodynamics of anesthetics

In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of modeling need careful attention. Key articles from the anesthesiology literature are selected to discuss the modeling of typical anesthesiological PD end points, such as level of consciousness and analgesia, interactions between hypnotics and analgesics, estimation with poor and sometimes rich data sets from populations of various sizes, covariate detection, covariances between random effects, and Bayesian forecasting.     

利奈唑胺的PK/PD与给药方案优化设计研究进展

通过CNKI、PUBMED等文献库查阅相关文献进行分析,介绍利奈唑胺在不同疾病中PK/PD特点,从而为临床合理应用提供参考.以PK/PD参数为依据,对给药方案进行优化,可以更好地发挥抗菌药物的临床治疗效果,降低不良反应和耐药性的发生率,减轻患者经济负担.利奈唑胺具有强大的抗革兰阳性菌活性,由于不同病理生理因素与其PK/PD特点,研究优化给药方案、促进合理用药具有重大意义.     

Pharmacokinetic/Pharmacodynamic Evaluation of Deflazacort in Comparison to Methylprednisolone and Prednisolone

Purpose. The pharmacokinetics and pharmacodynamics of deflazacort after oral administration (30 mg) to healthy volunteers were determined and compared with those of 20 mg of methylprednisolone and 25 mg of prednisolone. Methods. Methylprednisolone, prednisolone and the active metabolite of deflazacort, 21-desacetyldeflazacort, were measured in plasma using HPLC. For the assessment of pharmacodynamics, differential white blood cell counts were obtained over 24 hours. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was applied to link corticosteroid concentrations to the effect on lymphocytes and granulocytes. Results. Deflazacort is an inactive prodrug which is converted rapidly to the active metabolite 21-desacetyldeflazacort. Maximum concentrations of 21-desacetyldeflazacort averaged 116 ng/ml and were observed after 1.3 h. The average area under the curve was 280 ng/ml · h, and the terminal half-life was 1.3 h. 21-Desacetyldeflazacort was cleared significantly faster than both methylprednisolone and prednisolone. The PK-PD-model was suitable to describe time course and magnitude of the observed effects. The results were consistent with reported values for glucocorticoid receptor binding affinities for the investigated compounds. Conclusions. Due to the short pharmacokinetic half-life of its active metabolite, pharmacodynamic effects of deflazacort are of shorter duration than those of methylprednisolone and prednisolone. The PK-PD model allows good prediction of pharmacodynamic effects based on pharmacokinetic and receptor binding data.     

构建沙格列汀PK/PD模型——模拟其在健康人群和肝损伤患者的药动学和药效学

在本次研究中,我们旨在开发和评价沙格列汀的全身生理药代动力学(WB-PBPK)/药效学(PD)模型,模拟其在健康成人及肝功能损害患者中的药代动力学和药效学特性,为特殊患者的临床药学研究提供新方法.基于文献中获取的如logD和血浆蛋白结合率等药物特征参数,建立WB-PBPK模型和PD模型.将模拟所得的血药浓度-时间曲线及...     

Investigation of Drug Delivery in Rats via Subcutaneous Injection: Case Study of Pharmacokinetic Modeling of Suspension Formulations

With the rising cost of drug research, “do more with less” has become a new emphasis in the pharmaceutical industry. Consequently, the early analysis of pharmacokinetic/pharmacodynamic, efficacy, and safety parameters for a new drug target is critical for ensuring informed decision-making as soon as possible during the drug discovery process. When absorption, distribution, metabolism, and excretion properties of compounds are suboptimal which is especially true during the early stages of drug discovery, obtaining the desired exposure can be challenging via the most common routes (oral, intravenous). Therefore, subcutaneous (SC) injection is often explored as an alternate route of delivery. Although SC injection is used widely in the industry, information about how to model and predict the absorption of drugs administered via SC injection is not readily available. In the current research, we analyzed the absorption behavior of 12 model compounds covering a wide range of physicochemical properties following SC injection. We introduced a compound-specific parameter, the absorption factor from single SC injections of suspension doses of each compound, to aid in modeling and predicting of drug absorption profiles. The pharmacokinetic models derived in this study are capable of describing and predicting the absorption properties of SC injection for individual compounds.     

Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats

Although the mechanism of action for peroxisome proliferator‐activated receptor gamma (PPARγ) agonists has been extensively explored, the impact of the pharmacokinetic (PK) profile on the pharmacodynamic (PD) effects of PPARγ agonists has not been elucidated in detail. The importance of the PK profile of PPARγ agonist was evaluated for its PD effect based on population PK/PD analysis. Pioglitazone hydrochloride, the PPARγ agonist, was administered orally to Wistar fatty rats once a day (q.d.) or once every other day (q.2d.) as double the amount for the q.d. treatment. The plasma glucose lowering effect was selected as a surrogate PD effect for an anti‐diabetic effect. The model fitting was conducted using the non‐linear mixed effect modeling (NONMEM) method. The indirect response model described well the plasma glucose concentration–time profile. The q.d. treatment showed a stronger impact on the plasma glucose lowering effect than did the q.2d. treatment. The results of PK/PD modeling suggested that the sensitivity (i.e. EC ₅₀) between each group was comparable. On the other hand, the time above the effective concentration in the q.d. treatment group was longer than that in the q.2d. treatment group. The simulation of various dose regimens suggested that the much longer exposure duration within the effective level showed a stronger plasma glucose lowering effect, even with identical exposure to pioglitazone in the plasma. The PK/PD analysis clarified that the PK profile affected the pharmacological response and that continuous exposure at an appropriate effective level would be efficient for the anti‐diabetic effect of the PPARγ agonist.     

Pharmacokinetic/pharmacodynamic analyses of chymase inhibitor SUN13834 in NC/Nga mice and prediction of effective dosage for atopic dermatitis patients

A chymase inhibitor SUN13834 has been shown to improve skin condition in animal models for atopic dermatitis. In the present study, effective dosages of SUN13834 for atopic dermatitis patients were predicted by pharmacokinetic/pharmacodynamic (PK/PD) analyses of SUN13834 in NC/Nga mice, which spontaneously develop atopic dermatitis-like skin lesions. For the PK/PD analyses, we utilized the minimum effective plasma concentration of unbound SUN13834 in late-phase reaction of trinitrochlorobenzene (TNCB)-induced biphasic dermatitis in mice, based on the assumption that the minimum effective plasma concentrations are the same among the two animal models. In late-phase reaction of biphasic dermatitis, SUN13834 was most effective when its plasma concentration was highest at the elicitation, and the minimum effective plasma concentration of unbound SUN13834 at the elicitation was calculated to be 0.13–0.2 ng/mL. Oral administration of SUN13834 improved dermatitis in NC/Nga mice at 15 mg/kg (twice a day; bid) and 30 mg/kg (once a day; qd), but not at 60 mg/kg (every other day; eod). At the three dosages, the duration times over the plasma level of 0.13–0.2 ng/mL were 16.1–20.3, 10.7–12.2 and 7.8–8.8 h, respectively, suggesting an importance of maintenance of the minimum effective plasma concentration for at least about 10–12 h. The clinical effective dosage predicted in this paper is also discussed in relation to a recently conducted Phase 2a study.     

Impact of Shed/Soluble targets on the PK/PD of approved therapeutic monoclonal antibodies

Introduction: Suboptimal treatment for monoclonal antibodies (mAbs) directed against endogenous circulating soluble targets and the shed extracellular domains (ECD) of the membrane-bound targets is an important clinical concern due to the potential impact of mAbs on the in vivo efficacy and safety. Consequently, there are considerable challenges in the determination of an optimal dose and/or dosing regimen.

Areas covered: This review outlines the impact of shed antigen targets from membrane-bound proteins and soluble targets on the PK and/or PD of therapeutic mAbs that have been approved in the last decade. We discuss various bioanalytical techniques that have facilitated the interpretation of the PK/PD properties of therapeutic mAbs and also considered the factors that may impact such measurements. Quantitative approaches include target-mediated PK models and bi- or tri-molecular interaction PK/PD models that describe the relationships between the antibody PK and the ensuing effects on PD biomarkers, to facilitate the mAb PK/PD characterization.

Expert commentary: The proper interpretation of PK/PD relationships through the integrated PK/PD modeling and bioanalytical strategy facilitates a mechanistic understanding of the disease processes and dosing regimen optimization, thereby offering insights into developing effective therapeutic regimens. This review provides an overview of the impact of soluble targets or shed ECD on mAb PK/PD properties. We provide examples of quantitative approaches that facilitate the characterization of mAb PK/PD characteristics and their corresponding bioanalytical strategies.     

Population Pharmacokinetic/ Pharmacodynamic Modeling of Cetrorelix,a Novel LH-RH Antagonist,and Testosterone in Rats and Dogs

Purpose. Population models for thepharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasinghormone (LH-RH) antagonist, and the pharmacodynamic response ontestosterone production were investigated in rats and dogs. Methods. The plasma concentrations of CET and testosterone weredetermined after intravenous and subcutaneous injections. Thepopulation PK/PD-models were developed using P-PHARM software. Results. Absolute bioavailability of cetrorelix was 100% in rats and97% in dogs. In rats, the pharmacokinetics was explained by atwo-compartment model with saturable absorption, while athree-compartment model was used in dogs. Testosterone suppression in both specieswas described by a sigmoid E_max model with maximum effect (E_max)considered as total hormonal suppression. The duration of testosteronesuppression in rats was longer at higher doses. The populationelimination half-lifes after iv-dose were 3.0 h in rats and 9.3 h in dogs.Population mean estimates of IC₅₀ were 1.39 and 1.24 ng/ml in ratsand dogs, respectively. Conclusions. A population pharmacokinetic model was developed toexplain the dissolution rate limited absorption from the injection site.The suppression of testosterone could be described by an indirectinhibitory sigmoid E_max model. In both species 1-2 ng/ml CET inplasma was necessary to suppress testosterone production.     

A novel semi-mechanistic tumor growth fraction model for translation of preclinical efficacy of anti-glypican 3 antibody drug conjugate to human

The growing fraction (GF) of tumor has been reported as one of the predictive markers of the efficacy of chemotherapeutics. Therefore, a semi-mechanistic model has been developed that describes tumor growth on the basis of cell cycle, allowing the incorporation of the GF of a tumor in pharmacokinetic/pharmacodynamic (PK/PD) modeling. Efficacy data of anti-glypican 3 (GPC3) antibody drug conjugate (ADC) in a hepatocellular carcinoma (HCC) patient derived xenograft (PDX) model was used for evaluation of this proposed model. Our model was able to describe the kinetics of growth inhibition of HCC PDX models following treatment with anti-GPC3 ADC remarkably well. The estimated tumurostatic concentrations were used in tandem with human PKs translated from cynomolgus monkey for prediction of the efficacious dose. The projected efficacious human dose of anti-GPC3 ADC was in the range 0.20–0.63 mg/kg for the Q3W dosing regimen, with a median dose of 0.50 mg/kg. This publication is the first step in evaluating the applicability of GF in PK/PD modeling of ADCs. The authors are hopeful that incorporation of GF will result in an improved translation of the preclinical efficacy of ADCs to clinical settings and thereby better prediction of the efficacious human dose.