Methods to Account for Inaccuracies in the Dosing History When Performing Population Pharmacokinetic Analysis

Purpose  To develop and assess methods to account for missing dose history (MDH). Methods  A simulation study was performed with different doses, dose times and formulations using NONMEM. Four methods were used to account for MDH, these were the ideal dose method (IDM) which uses the actual dose history, the concentration minimum method (CMM) which assumes that the nominal dose history is accurate, the extrapolation subtraction method (ESM) which estimates the residual concentration at the time of the study dose and the concentration time method (CTM) where the time of the previous dose event is estimated. The CTM is a new method. Results  The CTM was superior to ESM and CMM and provided parameter estimates that were comparable in accuracy to the IDM. Conclusions  When the nominal dosing history is available then the CTM is a simple and effective method to account for potential inaccuracies in the dose history.     

A Simple Dosing Scheme for Intravenous Busulfan Based on Retrospective Population Pharmacokinetic Analysis in Korean Patients

Busulfan is an antineoplastic agent with a narrow therapeutic window. A post-hoc population pharmacokinetic analysis of a prospective randomized trial for comparison of four-times daily versus once-daily intravenous busulfan was carried out to search for predictive factors of intravenous busulfan (iBu) pharmacokinetics (PK). In this study the population PK of iBu was characterized to provide suitable dosing recommendations. Patients were randomized to receive iBu, either as 0.8 mg/kg every 6 h or 3.2 mg/kg daily over 4 days prior to hematopoietic stem cell transplantation. In total, 295 busulfan concentrations were analyzed with NONMEM. Actual body weight and sex were significant covariates affecting the PK of iBu. Sixty patients were included in the study (all Korean; 23 women, 37 men; mean [SD] age, 36.5 [10.9] years; weight, 66.5 [11.3] kg). Population estimates for a typical patient weighing 65 kg were: clearance (CL) 7.6 l/h and volume of distribution (V_d) 32.2 l for men and 29.1 L for women. Inter-individual random variabilities of CL and V_d were 16% and 9%. Based on a CL estimate from the final PK model, a simple dosage scheme to achieve the target AUC_0-inf (defined as median AUC_0-inf with a once-daily dosage) of 26.18 mg/l·hr, was proposed: 24.79·ABW^0.5 mg q24h, where ABW represents the actual body weight in kilograms. The dosing scheme reduced the unexplained interindividual variabilities of CL and Vd of iBu with ABW being a significant covariate affecting clearance of iBU. We propose a new simple dosing scheme for iBu based only on ABW.     

Population Pharmacokinetics of Sibrotuzumab, A Novel Therapeutic Monoclonal Antibody, in Cancer Patients

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5 mg/m(2) to an absolute dose of 100 mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1 ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6 ml/h (9.6); for the nonlinear clearance Vmax was 0.0338 mg/h (25) and Km 0.219 microg/ml (57). At serum concentrations between approximately 20 ng/ml and 7 microg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7 microg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration-time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.     

Assumption Testing in Population Pharmacokinetic Models: Illustrated with an Analysis of Moxonidine Data from Congestive Heart Failure Patients

Deriving a population pharmacokinetic model from real data is always associated with numerous assumptions. Violations of these assumptions, especially if undetected, may lead to inappropriate conclusions being made from the analysis. Routinely, only a few of the assumptions are explicitly stated and justified in the reporting of a population model. Here, we attempt to be exhaustive in the presentation of the assumptions made in the course of an analysis of moxonidine pharmacokinetics. The different ways that assumptions were justified, through experience, graphical examination, or additional modeling, are outlined. Models for relaxing assumptions regarding the covariate and statistical submodels, not previously reported in the area of population pharmacokinetic modeling, are also described.     

Population pharmacokinetics of antifibroblast activation protein monoclonal antibody F19 in cancer patients

AIMS: The population pharmacokinetics of 131I-mAbF19, a radiolabelled murine monoclonal antibody against fibroblast activation protein and a potential antitumour stroma agent, were investigated during two phase I studies in cancer patients. METHODS: 131I-mAbF19 serum concentration-time data were obtained in 16 patients from two studies involving imaging and dosimetry in colorectal carcinoma and soft tissue sarcoma. Doses of 0.2, 1 and 2 mg antibody were administered as 60 min intravenous infusions. The data were analysed by nonlinear mixed effect modelling. RESULTS: The data were described by a two-compartment model. Population mean values were 109 ml h(-1) for total serum clearance, 3.1 l for the volume of distribution of the central compartment, and 4.9 l for the volume of distribution at steady state. Mean terminal half-life was 38 h. Intersubject variability was high, but no patient covariates could be identified that further explained this variability. In particular, there was no influence of tumour type or mAbF19 dose. CONCLUSIONS: The pharmacokinetics of antistromal mAbF19 were well defined in these two studies with different solid tumour types, and were comparable with those of other murine monoclonal antibodies that do not bind to normal tissue antigens or blood cells.     

基于群体药动学模型的奥卡西平个体化给药软件研制

目的 研制基于群体药动学（population pharmacokinetics,PPK）模型的奥卡西平（oxcarbazepine,OXC）个体化给药软件。方法 根据已建立的成人和儿童OXC活性代谢物10,11-二氢-10-羟基卡马西平（monohydroxycarbazepine,MHD）的PPK模型信息,运用MyEclipse、SQL Server、JRE等工具研制OXC给药软件。软件开发方案包括软件需求分析、软件概要设计、软件详细设计、软件编码、软件测试以及软件维护和二次开发。结果 研制的OXC给药软件可实现患者信息输入和管理,能自动调用NONMEM软件,能预测多种具体给药方案下的MHD血药浓度,供临床制定初始给药方案参考,而且能结合已有的血药浓度监测信息和Bayesian反馈法更精准地预测血药浓度,辅助临床进一步优化给药方案。结论 基于MHD的PPK模型研制的给药软件能快捷方便地辅助成人和儿童癫痫患者OXC的个体化给药。     

Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer

The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC₅₀ values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.     

Efficacy and safety of trastuzumab

The human epidermal growth factor receptor (HER) 2 is overexpressed in ～ 20 – 25% of human breast cancers and is an independent adverse prognostic factor. Targeted therapy directed against this receptor has been developed in the form of a humanised monoclonal antibody, trastuzumab. This antibody has shown activity as a single agent in metastatic breast cancer both prior to chemotherapy and in heavily pretreated patients. A pivotal Phase III trial has demonstrated that its use in combination with an anthracycline or paclitaxel results in a significant improvement in survival, time to progression, and response. This has recently been reinforced by another trial with docetaxel. The HER2 status of a tumour is a critical determinant of response to trastuzumab-based treatment. Those that express HER2 at the highest level on immunohistochemistry (IHC), 3+, derive more benefit from treatment with trastuzumab than those with overexpression at the 2+ level. Benefit correlates best with tumours that are positive on fluorescence in situ hybridisation for HER2, regardless of IHC status. Treatment with trastuzumab is generally well tolerated with a low incidence of adverse events. Some patients may experience fever, chills, dyspnoea and pain, particularly with the first administration. Unexpectedly, cardiac toxicity has developed in some patients treated with trastuzumab, and this has a higher incidence in those treated in combination with an anthracycline. ‘Cross-talk’ between the oestrogen receptor and HER2 pathway has stimulated interest in using trastuzumab in combination with endocrine therapy. Current clinical trials are investigating the role of this agent in the adjuvant setting.     

Population Pharmacokinetic Analysis of Mizolastine and Validation from Sparse Data on Patients Using the Nonparametric Maximum Likelihood Method

A population analysis of the kinetics of mizolastine was performed from concentrations on 449 allergic patients, using the nonparametric maximum likelihood method (NPML). A two-compartment open model with zero-order absorption was used to describe the kinetics of mizolastine after oral administration. A heteroscedastic variance model was assumed for the error. To explain the kinetic variability, eight covariates were introduced in the analysis: gender, pharmaceutical dosage form, age, body weight, serum creatinine concentration, creatinine renal clearance, plasma levels of hepatic transaminases ASAT and ALAT. Their relationships to the kinetic parameters were studied by means of the estimated distribution of each kinetic parameter conditional on different levels of each covariate. An important interindividual kinetic variability was found for all parameters. Moreover, several kinetic parameters among which the duration of absorption were found to be influenced by pharmaceutical dosage form and gender. Body weight and creatinine renal clearance were found to have a little influence on the oral clearance and the smallest disposition rate constant. This population analysis was validated on a separate group of 247 other patients. For each observed concentration of this sample, a predictive distribution was computed using the individual covariates. Predicted concentrations and standardized prediction errors were deduced. The mean and variance of the standardized prediction errors were, respectively, 0.21 and 2.79. Moreover, in the validation sample, the predicted cumulative distribution function of each observed concentration was computed. Empirical distribution of these values was not significantly different from a uniform distribution, as expected under the assumption that the population model estimated by NPML is adequate.     

A Population Pharmacokinetic Analysis of Milrinone in Pediatric Patients After Cardiac Surgery

The purpose of this study was to ascertain the optimal pharmacokinetic model for milrinone in pediatric patients after cardiac surgery when milrinone was administered as a slow loading dose followed by a constant-rate infusion. The data used for pharmacokinetic analysis were collected in a prospective, randomized, placebo-controlled multi-center trial of milrinone as prophylaxis for the development of low cardiac output syndrome after surgery for repair of complex congenital cardiac defects. Two blood samples were randomly collected from each patient for determination of plasma milrinone concentrations with subsequent population pharmacokinetic modeling. The pharmacokinetics of milrinone in pediatric patients under 6 year's age were best described by a weight-normalized one compartment model after a slow loading dose followed by a constant-rate infusion. The volume of distribution was 482 ml kg(-1) and was independent of age. Clearance was a linear function of age given by Cl = 2.42 ml kg(-1) min(-1) [1 + 0.396*age].     

Anti-EGFR strategies as an incremental step for the treatment of colorectal cancer patients: moving from scientific evidence to clinical practice

The epidermal growth factor receptor (EGFR) is a 170,000 Da transmembrane glycoprotein involved in signalling pathways affecting cellular growth, differentiation and proliferation. An abnormal overexpression of the EGFR has been described in many human tumours and implicated in the development and prognosis of malignancies, thus representing not only a possible prognostic marker, but primarily a rational molecular target for a new class of anticancer agents. Several clinical trials have been reported with the use of EGFR-targeted monoclonal antibodies and tyrosine kinase inhibitors, mainly in combination with chemotherapy for advanced colorectal cancer patients. Taken together, results available so far suggest that anti-EGFR treatment strategies represent an incremental step for the the treatment of colorectal cencer patients with a manageable and acceptable toxicity profile. Nevertheless, many critical issues are yet unresolved, such as the optimal chemotherapy regimen to combine with anti-EGFR treatment and the most adequate patients setting. Moreover, the biological selection of colorectal tumours most likely to benefit from this treatment approach is still to be defined.     

Diazepam Pharamacokinetics from Preclinical to Phase I Using a Bayesian Population Physiologically Based Pharmacokinetic Model with Informative Prior Distributions in Winbugs

Modelling is an important applied tool in drug discovery and development for the prediction and interpretation of drug pharmacokinetics. Preclinical information is used to decide whether a compound will be taken forwards and its pharmacokinetics investigated in human. After proceeding to human little to no use is made of these often very rich data. We suggest a method where the preclinical data are integrated into a whole body physiologically based pharmacokinetic (WBPBPK) model and this model is then used for estimating population PK parameters in human. This approach offers a continuous flow of information from preclinical to clinical studies without the need for different models or model reduction. Additionally, predictions are based upon single parameter values, but making realistic predictions involves incorporating the various sources of variability and uncertainty. Currently, WBPBPK modelling is undertaken as a two-stage process: (i) estimation (optimisation) of drug-dependent parameters by either least squares regression or maximum likelihood and (ii) accounting for the existing parameter variability and uncertainty by stochastic simulation. To address these issues a general Bayesian approach using WinBUGS for estimation of drug-dependent parameters in WBPBPK models is described. Initially applied to data in rat, this approach is further adopted for extrapolation to human, which allows retention of some parameters and updating others with the available human data. While the issues surrounding the incorporation of uncertainty and variability within prediction have been explored within WBPBPK modeling methodology they have equal application to other areas of pharmacokinetics, as well as to pharmacodynamics.     

基于群体药动学模型的万古霉素个体化给药辅助决策平台的研制及应用

目的 研发一款适合临床实际应用场景的万古霉素个体化给药辅助决策平台,并为万古霉素的合理使用提供个体化给药建议。方法 基于当前已构建并验证可行的万古霉素群体药动学模型,运用Idea2019、JDK1.8、ETL等软件研发万古霉素个体化给药辅助决策平台。平台开发历经①需求分析;②模块设计;③软件测试、优化完善3个主要阶段。结果 成功研制并应用的万古霉素个体化给药辅助决策平台具有页面简约,功能完善,操作便捷的优势,按功能分为4个主要模块,分别是检索模块、信息模块、浓度预测模块以及报告模块。该平台可以连接医院内网平台,自动获取患者信息、用药信息、血药浓度检测结果等,并基于内嵌的群体药动学模型,结合患者个体信息,计算出个体药动学参数用于后续的万古霉素浓度预测。浓度预测模块将贝叶斯反馈法与患者用药信息、药物浓度测定结果及相关协变量参数值相结合,以指南推荐的谷浓度及AUC范围为目标值,计算满足目标浓度范围下的个体化给药方案,并考虑临床实际应用场景,设定自定义模拟功能,更具推广应用价值。结论 基于前期已构建的万古霉素群体药动学模型,在Idea2019、JDK1.8、ETL等软件工具辅助下,成功建立了万古霉素个体化给药辅助决策平台,该平台能更高效、便捷地辅助药师,为临床使用万古霉素提供个体化给药建议。     

Pharmacokinetics of a Mouse/Human Chimeric Monoclonal Antibody (C-17-1 A) in Metastatic Adenocarcinoma Patients

The pharmacokinetic characteristics of a mouse/human chimeric monoclonal antibody (C-17-1A) were determined in 10 patients with metastatic adenocarcinoma following the administration of either 10-mg or 40-mg infusions as a single or multiple dose. The administration of single 10-mg (n = 5) and 40-mg (n = 5) doses infused over 1 hr resulted in mean apparent steady-state distribution volumes of 4.13 ± 0.97 and 5.16 ± 1.92 liters, respectively, indicating that C-17-1A appears to distribute throughout the vascular compartment and into limited extracellular fluid volume. The disposition of C-17-1A was adequately characterized using a two-compartment open model with mean distribution half-lives of 15.8 and 18.5 hr and mean elimination half-lives of 90.0 and 97.6 hr for the 10- and 40-mg groups, respectively. A linear relationship was observed between AUC and dose (µLg/kg). The clearance of C-17-1A was correlated linearly with total Ig, IgG, and tumor size. Multiple administration of either 10-mg (n = 3) or 40-mg (n = 3) doses of C-17-1A infused over 1 hr every 14 days for a total of three doses resulted in superimposable mean serum concentration versus time data and consistent mean pharmacokinetic characteristics. These data indicate that C-17-1A exhibits linear, nonsaturable distribution and elimination characteristics in man over the dose range studied (i.e., 130 to 880 µg/kg). The multiple-dose pharmacokinetics of C-17-1A were predictable, indicating a lack of an antibody response to C-17-1A over a period of 42 days. The clearance of C-17-1A exhibited large interindividual variability with significant correlations to circulating IgG levels and tumor size.     

Population Pharmacokinetic and Exposure-Response Analyses of Baloxavir Marboxil in Adults and Adolescents Including Patients With Influenza

Baloxavir marboxil, a prodrug that is metabolized to baloxavir acid, suppresses viral replication by inhibiting cap-dependent endonuclease. Our aim is to characterize its pharmacokinetics and exposure-response relationships. Population pharmacokinetic analysis of the baloxavir acid was performed using 8310 plasma concentration data points from 1109 subjects. Exposure-response analyses were performed regarding the time to alleviation of symptoms and the reduction in the influenza virus titer. A 2-compartment model with first-order absorption and lag time well described the plasma concentration data for baloxavir acid, and body weight and race were found to be the most important factors influencing the clearance and distribution volume. A dose regimen based on the body weight (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg) could provide sufficient exposures for expecting efficacy irrespective of body weight or race; however, the exposures were dependent on the body weight and race. Exposure-response analyses suggested that the reduction in the influenza virus titer was greater in any exposure-based groups in baloxavir marboxil treatment than in the oseltamivir phosphate treatment and placebo groups. In conclusion, the population pharmacokinetic model and exposure-response relationships would be useful for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir acid.     

人表皮生长因子受体2、增殖细胞核抗原表达与乳腺癌患者病理特征相关性分析

目的:探讨人表皮生长因子受体2(HER-2)、增殖细胞核抗原(Ki67)表达与乳腺癌患者病理特征的相关性。方法:选取某院乳腺癌患者98例(2018年4月~2019年4月),均行Ki67、HER-2检测,分析HER-2、Ki67阳性率及与乳腺癌患者病理特征(TNM分期)的相关性。结果:乳腺癌Ⅰ、Ⅱ、Ⅲ期Ki67阳性率为57.89%、79.17%、50.00%,HER-2阳性率为55.26%、85.42%、91.67%(P<0.05),Ki67、HER-2与乳腺癌TNM分期均呈正相关(P<0.05)。结论:HER-2、Ki67与乳腺癌患者病理特征有相关性,有助于乳腺癌恶性程度评估。