群体药物动力学简介

介绍了群体药物动力学的定义及统计理论、群体参数估计方法及在临床药理学与新药开发中的应用     

A Systematic Approach to Evaluating Closed System Drug-Transfer Devices During Drug Product Development

The use of Closed System Drug-Transfer Devices (CSTDs) has increased significantly in recent years due to NIOSH and USP recommendations to use them during preparation of hazardous drugs. Mechanistic and material differences between CSTDs and traditional in-use components warrant an assessment of their impact on product quality and dosing accuracy. Using a combination of prevalent CSTDs with biologic molecules, we performed an extensive assessment of the effect of using CSTDs for dose preparation and observed no negative impact on product quality attributes. Additionally, we found that the CSTD hold-up volume is 2 to 4-fold higher than conventional in-use components and exhibited a strong dependence on the CSTD brand used. We also found that the CSTD brand and dosing volume have a major influence on dosing accuracy with suboptimal protein recovery at very low dosing volumes. We identified entrapment of product in the CSTD spike as the root cause for this sub-optimal recovery and found that flushing the CSTD spike with a brand-new syringe and not the dosing syringe aided in complete protein recovery. Taken together we present a systematic approach to evaluate the risks and impact of CSTD to drug product quality, dose preparation, and dosing accuracy.     

An Application of Ito's Lemma in Population Pharmacokinetics and Pharmacodynamics

Pharmaceutical Research -     

Applied Pharmacokinetics in Drug Development

The process of discovering, developing, and marketing new drugs has changed considerably in the last decade; however, the cost associated with this process remains staggeringly high. Although there are many reasons for this high cost, one reason appears to be the continuing high attrition rates of drugs during costly early- and late-stage human clinical trials. To address this problem, drug discovery organizations are striving to rapidly identify high-potential drug candidates and eliminate as early as possible those with inferior potency, poor pharmacokinetic properties, and toxicity problems, so that these deficient drug candidates do not incur the high costs of clinical trials. During the last 5 years, a decision-making go/no-go strategy has been introduced into the drug discovery process, using pharmacokinetic principles to minimize the risks and maximize the benefits of selecting superior drug candidates. Pharmacological deficiencies are related in part to pharmacokinetic properties. To understand this process, a brief review of pharmacokinetic properties including oral bioavailability, half-life, absorption, clearance, and volume of distribution is presented. We examine in vitro — in vivo (human) and/or in vivo (animals) — in vivo (human) correlations for several of these pharmacokinetic properties, followed by a discussion of how this preclinical information is collected and used in drug discovery at the various stages to select drug candidates. Finally, we summarize how these methods are used to make go/no-go decisions in each step of the drug discovery process.     

The Application of Virtual Therapeutic Drug Monitoring to Assess the Pharmacokinetics of Imatinib in a Chinese Cancer Population Group

PurposeImatinib is used in gastrointestinal stromal tumours (GIST) and chronic myeloid leukaemia (CML). Oncology patients demonstrate altered physiology compared to healthy adults, e.g. reduced haematocrit, increased α-1 acid glycoprotein, decreased albumin and reduced glomerular filtration rate (GFR), which may influence imatinib pharmacokinetics. Given that Chinese cancer patients often report raised imatinib plasma concentrations and wider inter-individual variability reported in trough concentration when compared to Caucasian cancer patients, therapeutic drug monitoring (TDM) has been advocated.MethodThis study utilised a previously validated a Chinese cancer population and assessed the impact of imatinib virtual-TDM in Chinese and Caucasian cancer populations across a dosing range from 200-800 mg daily.ResultsStaged dose titration to 800 mg daily, resulted in recapitulation to within the target therapeutic range for 50 % (Chinese) and 42.1% (Caucasian) subjects possessing plasma concentration < 550 ng/mL when dosed at 400 mg daily. For subjects with plasma concentrations >1500 ng/mL when dosed at 400 mg daily, a dose reduction to 200 mg once daily was able to recover 67 % (Chinese) and 87.4 % (Caucasian) patients to the target therapeutic range.ConclusionVirtual TDM highlights the benefit of pharmacokinetic modelling to optimising treatments in challenging oncology population groups.     

Alternatives to Drug Use: An Alternative Approach to Drug Education

The Alcohol and Drug Education Course, a secondary prevention program for drug-abusing adolescents, was evaluated. The program provided some drug information, but primarily emphasized alternatives to drug and alcohol use for achieving altered states of consciousness. Students were found to be relatively knowledgeable about the effects of drugs, but were also misinformed on some issues. The program was successful in increasing the students' awareness of alternatives to drug use and the hazards of drug abuse, and in decreasing their reported reliance on drugs for achievement of altered states of consciousness.     

An Alternative Approach to the Analysis of Animal Carcinogenicity Studies

Long-term animal carcinogenicity studies are an important part of the risk analysis process assessing the carcinogenic potential of products to humans. Results from the statistical analysis of the data from such studies are generally presented as a series of hypothesis tests indicating whether there was a significant rise in the number of tumors at given sites. The conclusion from such an analysis depends on the size of the experiment. In particular, the number of false-negative results can be high when tumors are rare. In this paper, a test for equivalence fixing the proportion of false negatives is proposed. The effect on the required sample size is also discussed.     

A Population Pharmacokinetic Modelling Approach to Unravel the Complex Pharmacokinetics of Vincristine in Children

Pharmaceutical Research - Vincristine, a chemotherapeutic agent that extensively binds to β-tubulin, is commonly dosed at 1.4–2.0&nbsp;mg/m2 capped at 2&nbsp;mg. For infants,...     

Mixed Effect Modeling of Sumatriptan Pharmacokinetics During Drug Development. I: Interspecies Allometric Scaling

Allometric scaling is an empirical examination of the relationships between the pharmacokinetic parameters and size (usually body weight), but it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%). and its metabolic pathway undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. These similarities across species suggested the possible relevance of an allometric analysis. Toxicokinetic data were collected from rats, pregnant rabbits, and dogs in animal pharmacokinetic studies where sumatriptan was administered intravenously to the animals at doses of 5 mg/kg. 0.25 mg/kg, and 1 mg, kg, respectively. Animal data were pooled and analyzed in one step using a mixed effect modeling (population) approach. The kinetic parameters predicted in any species were close to the observed values by species: 77 L/hr vs. 80 L/hr in man for total clearance, 137 L vs. 119 L for distribution volume at steady state. The value of the mixed effect modeling approach compared to the two-step method was demonstrated especially with the possibility of including covariates to describe the status of animal (e.g., pregnancy) in the model. Knowledge of the animal kinetics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the first-dose-in-man study may emerge from more creative data analysis based on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.     

Editorial: A Systems Approach to Drug Development and to Drug Therapy

Pharmaceutical Research -     

An Alternative Approach to Drug Policy Outcome Measurement

The wide range of benefits from drug policy interventions makes evaluation complex. Existing outcome instruments do not provide an overall assessment of 'value', which limits their usefulness. Multiple attribute utility theory can address these aggregation issues. Being explicitly preference based, it has the advantage of transparency. Data were collected in order to investigate the feasibility of preference elicitation and use of alternative methods for outcome evaluation. The results of this investigation are promising. The data provided are consistent and intuitive. Using students' preferences for the 'end products' of drug interventions, the value attached to a premature death is found to outweigh that of averting a house burglary by between 100:1 and 550:1. This ratio is substantially higher than that implied by current resource allocation between different policy approaches. A simulated application of preference data to a published study is shown for demonstration purposes.     

Integrated Pharmacokinetics and Pharmacodynamics in Drug Development

Drug development is a complex, lengthy and expensive process. Pharmaceutical companies and regulatory authorities have recognised that the drug development process needs optimisation for efficiency in view of the return on investments. Pharmacokinetics and pharmacodynamics are the two main principles determining the relationship between dose and response. This article provides an update on integrated approaches towards drug development by linking pharmacokinetics, pharmacodynamics and disease aspects into mathematical models. Gradually, a transition is taking place from a rather empirical approach towards a modelling- and simulation-based approach to drug development. The main learning phases should be phases 0, I and II, whereas phase III studies should merely have a confirmatory purpose. In model-based drug development, mechanism-based mathematical models, which are iteratively refined along the path of development, incorporate the accumulating knowledge of the investigational drug, the disease and their mutual interference in different subsets of the target population. These models facilitate the design of the next study and improve the probability of achieving the projected efficacy and safety endpoints. In this article, several theoretical and practical aspects of an integrated approach towards drug development are discussed, together with some case studies from different therapeutic areas illustrating the application of pharmacokinetic/pharmacodynamic disease models at different stages of drug development.     

Population Pharmacokinetics of Cycloplatam. II. Clinical Monitoring of the Drug Pharmacokinetics Upon Short and Long-Term Infusion

Pharmaceutical Chemistry Journal -     

群体药代动力学在儿科临床药理学研究中的应用

儿童是一特殊人群,他们的各种生理指标与成人有很大的不同。但在临床实践中,人们往往是参照成人剂量来指导儿童的用药,这严重的威胁着儿童的身体健康,个体化给药方案的建立刻不容缓。在这一方面,群体药代动力学是其强有力的工具。     

Metrics for External Model Evaluation with an Application to the Population Pharmacokinetics of Gliclazide

Purpose The aim of this study is to define and illustrate metrics for the external evaluation of a population model.Materials and Methods In this paper, several types of metrics are defined: based on observations (standardized prediction error with or without simulation and normalized prediction distribution error); based on hyperparameters (with or without simulation); based on the likelihood of the model. All the metrics described above are applied to evaluate a model built from two phase II studies of gliclazide. A real phase I dataset and two datasets simulated with the real dataset design are used as external validation datasets to show and compare how metrics are able to detect and explain potential adequacies or inadequacies of the model.Results Normalized prediction errors calculated without any approximation, and metrics based on hyperparameters or on objective function have good theoretical properties to be used for external model evaluation and showed satisfactory behaviour in the simulation study.Conclusions For external model evaluation, prediction distribution errors are recommended when the aim is to use the model to simulate data. Metrics through hyperparameters should be preferred when the aim is to compare two populations and metrics based on the objective function are useful during the model building process.     

The Population Pharmacokinetics of Citalopram After Deliberate Self-Poisoning: A Bayesian Approach

Defining the pharmacokinetics of drugs in overdose is complicated. Deliberate self-poisoning is generally impulsive and associated with poor accuracy in dose history. In addition, early blood samples are rarely collected to characterize the whole plasma-concentration time profile and the effect of decontamination on the pharmacokinetics is uncertain. The aim of this study was to explore a fully Bayesian methodology for population pharmacokinetic analysis of data that arose from deliberate self-poisoning with citalopram. Prior information on the pharmacokinetic parameters was elicited from 14 published studies on citalopram when taken in therapeutic doses. The data set included concentration–time data from 53 patients studied after 63 citalopram overdose events (dose range: 20–1700 mg). Activated charcoal was administered between 0.5 and 4 h after 17 overdose events. The clinical investigator graded the veracity of the patients’ dosing history on a 5-point ordinal scale. Inclusion of informative priors stabilised the pharmacokinetic model and the population mean values could be estimated well. There were no indications of non-linear clearance after excessive doses. The final model included an estimated uncertainty of the dose amount which in a simulation study was shown to not affect the model’s ability to characterise the effects of activated charcoal. The effect of activated charcoal on clearance and bioavailability was pronounced and resulted in a 72% increase and 22% decrease, respectively. These findings suggest charcoal administration is potentially beneficial after citalopram overdose. The methodology explored seems promising for exploring the dose–exposure relationship in the toxicological settings.     

Mixed Effect Modeling of Sumatriptan Pharmacokinetics During Drug Development: II. From Healthy Subjects to Phase 2 Dose Ranging in Patients

Sumatriptan is indicated for the treatment of migraine attack and cluster headache; it is currently marketed as a subcutaneous injection, nasal spray, and oral tablet. New formulations are under consideration. The knowledge of sumatriptan absorption, combined with PK/PD information would help the design of more efficient formulations. In this perspective, we attempted to model the absorption of sumatriptan by population PK analysis. Data following administration by the intravenous (iv), the subcutaneous (sc), and the oral (po) route in healthy subjects were analyzed. A large database with full kinetic profiles was constituted. Sumatriptan was administered to 215 healthy subjects (iv, sc, and po) and to 143 migraine sufferers (po). The mean age was 31 years (18–86 years) in healthy subject population and was 38 years (18–65 years) in migraine patients. The mean weights were 74kg (54–104 kg) and 66 kg (38–136 kg) in healthy subjects and migraine patients, respectively, and the mean heights were 176cm (157–193 cm) and 164cm (152–183 cm) in healthy subjects and migraine patients, respectively. A NONMEM analysis was performed using a two-compartment disposition model. Oral absorption was modeled with a first-order input followed by a zero-order input. Less biased results were obtained using the FOCE method. The total clearance and the distribution volume at steady state were 71.2 L/hr and 94.5 L after iv dosing and 68.7 L/hr and 109 L after inclusion of the sc and po data. The absorption phase appeared to last for about 5 hr. The interindividual variability of the main PK parameters was low: It was around 20% for the total clearance and around 30% for the distribution volume at steady state. Although significant, the combination of age and height on clearance did not decrease considerably the interindividual variability of this parameter (decrease of 2.2%); nor was it possible to establish clearly if a migraine attack has an effect on drug absorption because of the sampling scheme during absorption. Simulations have shown that it would have been possible to estimate all the PK parameters with a data set reduced to one quarter of its actual number of samples.     

A Rational Approach to Drug Development: The Exploratory Phase

Abstract

Ibuprofen powders were blended with phospholipids to prepare physical mixtures or made into solid dispersions by the solvent method and their comparative dissolution profiles were studied. Ibuprofen exhibited significantly improved dissolution rates in phospholipid coprecipitates compared to either physical mixtures or the pure ibuprofen. the coprecipitates of phospholipid-ibuprofen were made at 1:10, 1:20, 1:30 and 1:40 ratios and dissolution profiles were monitored up to 90 minutes. Marginal increase in dissolution rates were observed by increasing the phosopholipid-ibuprofen ratio from 1:40 to 1:20 and further increase to 1:10 ratio did not produce any difference. the coprecipitates of phosopholipid-ibuprofen at a 1:20 ratio showed more than 2 fold increase in the total amount dissolved in water after 90 minutes compared to ibuprofen alone. No significant difference was observed among the three phospholipids in terms of enhancing dissolution rate of ibuprofen in water. When studies were conducted with 1:20 phospholipid—ibuprofen at pH 2.2 medium, the total amount dissolved in water after 90 minutes varied significantly among the phospholipids studied. DSPC showed best results followed by DPPC and DMPC respectively.