Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal

The objective of this analysis was to describe the pharmacokinetic characteristics of anidulafungin in patients with serious fungal disease based on pharmacokinetic data collected during four recently completed or ongoing Phase II/III clinical studies. A total of 600 anidulafungin plasma samples from 225 patients across the four studies were available for analysis. Patients received daily intravenous infusions of 50, 75, or 100 mg anidulafungin, preceded by a loading dose that was twice the daily dose. The analysis population consisted of 129 patients with esophageal candidiasis, 87 with invasive candidiasis, 7 with invasive aspergillosis, and 2 with azole refractory mucosal candidiasis. A population analysis approach was used to develop a steady-state pharmacokinetic model for anidulafungin, assess the significance of possible covariates, and determine the amount of intersubject and random residual variability. A two-compartment model with first-order elimination provided the best fit to the data. The clearance of anidulafungin was influenced by weight and gender, and subjects in the invasive candidiasis study had a typical clearance that was approximately 30% higher than subjects from other studies. Weight was determined to be a predictor of the central volume of distribution. The covariates on clearance accounted for less than 20% of the intersubject variability and therefore are deemed to be of little clinical relevance. There was no evidence that the presence of rifampin or metabolic substrates, inhibitors, or inducers of cytochrome p450 influenced the clearance of anidulafungin. This indicates that dosing adjustments are not necessary when anidulafungin is administered in the presence of medications falling into these classifications.     

Population approaches/sparse data analysis for human variability in kinetics and dynamics

The application of sparse data analysis techniques, otherwise known as the population approach, to the assessment of pharmacokinetic and pharmacodynamic variability is reviewed. Using software that has recently become available it is now possible to analyse heterogeneous, sparse data from a variety of clinical trials, particularly during drug development. Therefore the pharmacokinetics and pharmacodynamics of a drug can be studied in the target population and this information can be used to guide dosage for optimal therapeutic benefit.     

PEGylation of interferon-β-1a: a promising strategy in multiple sclerosis

Achieving optimal patient benefit from biological therapies can be hindered by drug instability, rapid clearance requiring frequent dosing or potential immune reactions. One strategy for addressing these challenges is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are covalently attached to a biological or small-molecule drug, effectively transforming it into a therapy with improved pharmacokinetic and pharmacodynamic properties. Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. A PEGylated form of interferon-β-1a (PEG-IFNβ-1a) is being developed to address an unmet medical need for safer, more effective and more convenient therapies for multiple sclerosis (MS). Phase I study data suggest that PEG-IFNβ-1a should provide patients with a first-line therapy with a more convenient dosing regimen while maintaining the established efficacy, safety and tolerability of presently available IFNβ-1a. The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNβ-1a in patients with relapsing MS.     

Estimation of population characteristics of pharmacokinetic parameters from routine clinical data

A general data analysis technique estimates average population values of pharmacokinetic parameters and their interindividual variability from clinical pharmacokinetic data gathered during the routine care of patients. Several drug concentration values from each individual, along with dosage information and the values of other routinely assessed variables suffice for purposes of analysis. The Maximum Likelihood principle estimates underlying population values without the necessity for the intermediate estimation of individual parameter values. The approach is quite general, permitting the use of nonlinear statistical models with both fixed and random effects. Complex expressions involving physiological variables can be used to define the pharmacokinetic parameters. Thus, the relationship of physiological factors to parameter values can be assessed. The generality and appropriateness of the analysis technique are demonstrated by analysis of a set of data derived from 141 patients receiving the drug digoxin.This work was supported in part by NIH Grant GM 16496.     

Population pharmacokinetics. Theory and clinical application

Good therapeutic practice should always be based on an understanding of pharmacokinetic variability. This ensures that dosage adjustments can be made to accommodate differences in pharmacokinetics due to genetic, environmental, physiological or pathological factors. The identification of the circumstances in which these factors play a significant role depends on the conduct of pharmacokinetic studies throughout all stages of drug development. Advances in pharmacokinetic data analysis in the last 10 years have opened up a more comprehensive approach to this subject: early traditional small group studies may now be complemented by later population-based studies. This change in emphasis has been largely brought about by the development of appropriate computer software (NONMEM: Nonlinear Mixed Effects Model) and its successful application to the retrospective analysis of clinical data of a number of commonly used drugs, e.g. digoxin, phenytoin, gentamicin, procainamide, mexiletine and lignocaine (lidocaine). Success has been measured in terms of the provision of information which leads to increased efficiency in dosage adjustment, usually based on a subsequent Bayesian feedback procedure. The application of NONMEM to new drugs, however, raises a number of interesting questions, e.g. 'what experimental design strategies should be employed?' and 'can kinetic parameter distributions other than those which are unimodal and normal be identified?' An answer to the later question may be provided by an alternative non-parametric maximum likelihood (NPML) approach. Population kinetic studies generate a considerable amount of demographic and concentration-time data; the effort involved may be wasted unless sufficient attention is paid to the organisation and storage of such information. This is greatly facilitated by the creation of specially designed clinical pharmacokinetic data bases, conveniently stored on microcomputers. A move towards the adoption of population pharmacokinetics as a routine procedure during drug development should now be encouraged. A number of studies have shown that it is possible to organise existing, routine data in such a way that valuable information on pharmacokinetic variability can be obtained. It should be relatively easy to organise similar studies prospectively during drug development and, where appropriate, proceed to the establishment of control systems based on Bayesian feedback.     

Predicting the outcome of phase III trials using phase II data: a case study of clinical trial simulation in late stage drug development

Abstract: Maximizing the likelihood of success in Phase III is the ultimate goal of the use of modelling and simulation in the drug development process. The success in Phase III depends primarily on two questions: 1) Is the drug regimen actually efficacious and safe in the targeted patient population?, and 2) Will the planned Phase III clinical trial(s) be successful in demonstrating this? Traditionally, the first question is addressed in a qualitative, overall interpretation of available study results. Integrating this information into a formal statistical model of the action of the drug, allows running simulations to investigate the impact of uncertainties and imprecision in this knowledge. The second question is related to having an adequately designed clinical trial. Clinical trial simulation, using a drug action model, supplemented with appropriate models for disease progression and trial execution, allows assessing the impact of typical design features such as doses, sample size, in‐/exclusion criteria, drop‐out and trial duration on the trial outcome and thus optimising trial design. In this contribution, the use of modelling and simulation in the Phase II to Phase III transition is illustrated using real data of a drug for symptom relief in a chronic condition. A dose‐response model of the clinical response was developed using data from Phase II. Simulations were performed to 1) generate the range of possible outcomes of ongoing Phase III trials and compare these to the blinded data being generated from these trials; 2) assess the robustness of the ongoing Phase III trials with respect to uncertainty of the true dose‐response, patient variability in baseline severity and drug‐response, and 3) assess the likelihood of achieving a clinically relevant response with a dose lower than those included in the trials.     

Stereoselective drug disposition: potential for misinterpretation of drug disposition data.

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration-effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.     

Assessment of acyclovir intraindividual pharmacokinetic variability during continuous hemofiltration, continuous hemodiafiltration, and continuous hemodialysis.

The use of intravenous acyclovir can be particularly complicated in pediatric patients with evolving renal impairment, because of intraindividual pharmacokinetic variability linked to the patient's clinical condition. The objective of this study was to use therapeutic drug monitoring data to assess acyclovir intraindividual pharmacokinetic variability during several types of renal replacement therapy. Bayesian adaptive control of acyclovir dosage regimen was performed in a pediatric patient with bone marrow transplant who developed severe renal impairment. Acyclovir pharmacokinetic parameter values corresponding to the different techniques and periods of renal replacement therapy were estimated using USCPACK PC Clinical Programs and therapeutic drug monitoring data. Results showed a wide intraindividual pharmacokinetic variability during CAVH, CAVHDF, and CVVHD, reflecting not only the performance of each dialysis technique but also the difficulty in making use of each one. The acyclovir elimination rate constant was higher during CVVHD compared to CAVH or CAVHDF. Bayesian method appears to be valuable in assessing intraindividual pharmacokinetic variability, as it allows the clinician to deal with sparse routine patient data.     

Pharmacokinetic and pharmacodynamic modeling of cibenzoline plasma concentrations and antiarrhythmic effect

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.     

Optimizing the preclinical/clinical interface: an Informa Life Sciences conference 12-13 December, 2006, London, UK

The primary goal of this meeting was to propose strategies for expediting the Phase 0 drug research process for valuable drug candidate identification by taking full advantage of innovative technologies and cost-effective decision-making procedures. A theme that recurred throughout the meeting was the identification, validation and full exploitation of specific integrated biomarkers, which serve as quantifiable indicators of normal biologic processes, pathophysiological states and responses to therapeutics. These are indispensable tools for generating reliable data from proof-of-mechanism, proof-of-principle and proof-of-concept investigations. Real-life biomarkers can also be obtained from modeling and simulating preclinical and early clinical findings. The successful migration of these and other pertinent data into predictive models of efficacy, toxicity and diseases is a sine qua non for translation medicine to become a discipline that realistically predicts clinical outcomes. Indeed, the discovery of novel, efficacious drug treatments for neurological and psychiatric diseases is intrinsically dependent on reliable translation medicine approaches. Novel microdosing technologies that enable Phase 0 pharmacokinetic profiling of drug candidates in humans improve the success rate of the drug development process. In addition, the clear identification of risk, the calculation of its probability, the assessment of its severity in relation to medical need and the availability of a management strategy can help to establish realistic safety goals. Performing in vitro and in vivo cardiac safety evaluation earlier in Phase 0 research can substantially reduce the number of drug candidates that eventually fail on the basis of unacceptable cardiac harm. Emerging 'omics' technologies allow the identification of species-specific toxicity and the reliable extrapolation of non-clinical observations to humans. Regulatory perspectives on the use of non-clinical information to gain approval for Phase I studies were given special consideration. In particular, key recommendations for preventing tragic events, such as those that resulted from a cytokine storm caused by the CD28 tumour antibody, TGN-1412, in healthy volunteers, were the subject of detailed scrutiny. Interestingly, the bispecific CD9/CD3 tumour antibody MT-103 produces target antigen-redirected lysis without causing notable adverse effects. In conclusion, this conference provided participants with state-of-the-art approaches for improving the present low predictive power of non-clinical information regarding clinical outcome.     

Dichloroacetate: population pharmacokinetics with a pharmacodynamic sequential link model

Dichloroacetate (DCA) is a small molecule that reduces ambient concentrations of lactate in man. It was the purpose of this study to develop pharmacokinetic and pharmacodynamic models for determination of a dose for a pivotal Phase III clinical trial of DCA in patients with traumatic brain injury (TBI). Population pharmacokinetic and pharmacodynamic models were developed for DCA using NONMEM software. The pharmacokinetic data were fit to a physiologic two-compartment model, and the pharmacodynamic data were fit to an indirect physiologic response model. Simulations were employed to evaluate various dosing strategies for consideration in a pivotal Phase III clinical trial of DCA. For the pharmacokinetic model, it was discovered that the clearance of DCA decreased on multiple dosing from 4.82 L/h to 1.07 L/h and that the pharmacokinetics and pharmacodynamics in TBI patients could not be predicted from normal volunteers. Population pharmacokinetic modeling and simulation of the expected effects of several dosing strategies were useful procedures for designing a Phase III trial.     

A population pharmacokinetic profile of imazodan in congestive heart failure patients

Conclusions Population pharmacokinetic profiling during early Phase I/Phase II testing has provided pharmacokinetic information early in the clinical development of an investigational cardiotonic compound. While development of a population pharmacokinetic profile can be a continuous evolutionary process, initial analyses suggest imazodan clearance to be influenced by hemodynamic and hepatic status in severe congestive heart failure patients. Volume of distribution appears to be proportional to body size, but the magnitude of this relationship is probably not clinically significant. Following oral administration, imazodan is generally rapidly absorbed; however, interindividual variability in this process is large. Imazodan bioavailability appears to be good considering the severity of congestive heart failure and altered hemodynamics in this patient population.     

信息管理系统在I期临床试验质量控制中的作用

目的探讨药物临床试验信息管理系统在Ⅰ期临床试验质量控制中的作用。方法在2017年8月-2018年8月的4个Ⅰ期临床试验项目中应用药物临床试验信息管理系统,根据"药物临床试验数据现场核查要点"分析机构质控员与申办方监查员在原始数据核查及质量控制中发现的问题,与传统纸质记录管理模式的4个Ⅰ期临床试验项目分析比较。结果使用药物临床试验信息管理系统后的Ⅰ期临床试验项目中发生的受试者的筛选/入组数据链完整性、临床试验检查/化验等数据的溯源、试验用药品管理过程与记录、受试者的管理等方面存在问题均明显低于系统使用前(χ^2=11.922,P<0.001)。结论药物临床试验信息管理系统在I期临床试验项目中的应用对受试者信息完整性,药品管理规范性,临床试验的真实性、完整性、可信性及可溯源性都有较大提升,能提升Ⅰ期临床试验的质量。     

A population pharmacokinetic profile of imazodan in congestive heart failure patients

Population pharmacokinetic profiling during early Phase I/Phase II testing has provided pharmacokinetic information early in the clinical development of an investigational cardiotonic compound. While development of a population pharmacokinetic profile can be a continuous evolutionary process, initial analyses suggest imazodan clearance to be influenced by hemodynamic and hepatic status in severe congestive heart failure patients. Volume of distribution appears to be proportional to body size, but the magnitude of this relationship is probably not clinically significant. Following oral administration, imazodan is generally rapidly absorbed; however, interindividual variability in this process is large. Imazodan bioavailability appears to be good considering the severity of congestive heart failure and altered hemodynamics in this patient population.     

Aspects of the clinical pharmacology of nifedipine, a dihydropyridine calcium-entry antagonist

Although nifedipine has been characterized in terms of its general vasodilatory effects, this dihydropyridine must still be regarded as investigational with regard to available pharmacokinetic and pharmacodynamic data. Although limited studies are available, it is clear that the pharmacokinetic and pharmacodynamic data reported are quite variable among subjects. Further, it appears that single dose elimination kinetics may be of little predictive value with regard to the kinetic characteristics present during chronic drug administration. It is also possible that the plasma level-effect correlations for the drug may differ with single and sustained dosing regimens. At the present time the lack of definitive data to define the relationships between plasma levels of nifedipine and associated drug effects suggests that measurement of drug levels in plasma serves primarily as a research tool and to identify patient noncompliance or abnormal absorption of the drug. Finally, since the prototype of this class, nifedipine, has been shown to have the potential for non-linear kinetics during chronic dosing, dihydropyridine analogs should be subject to extensive pharmacokinetic and pharmacologic evaluation during both single and chronic dosing studies, prior to widespread clinical use.     

A novel Bayesian decision procedure for early-phase dose-finding studies

Phase I first-in-man studies in normal, healthy volunteers are performed to define a maximum safe dose and to identify a range of acceptable doses for later drug development studies in patients. Analysis of pharmacokinetic and pharmacodynamic data using mixed-effects modeling can be used to fit an overall dose-response relationship. By expressing prior information as pseudodata, the same methodology can be used to perform a Bayesian analysis and to determine posterior modal estimates for the model parameters. Decision theory can then be applied to maximize a chosen gain function, utilizing real-time data capture for choosing safe doses in a way that will provide more informative responses, thus accelerating study completion. The methodology is introduced elsewhere (1). The purpose of this paper is to describe software currently in development and to illustrate the method using an example from a recent study.     

A phase I trial of ametantrone acetate (NSC-287513)

Ametantrone acetate is an intensely blue anthracenedione undergoing clinical trials in man. In this Phase I study, 20 patients received 39 courses of drug as a single IV dose given daily for five days and repeated every three weeks (21 days). Dosage escalations proceeded from 15 mg/m² to 35 mg/m². Predictable and reversible leukopenia was the dose limiting toxicity. One previously untreated patient with renal cell carcinoma metastatic to the lungs and right arm experienced a partial response of 51 days duration. Nine patients had pharmacokinetic studies performed during the study. Ametantrone was extensively distributed (apparent volume of distribution, 26.3 1/m²) and demonstrated a short half-life (harmonic mean half-life, 0.38 hour). The maximum tolerated dose in this study was 35 mg/m². Recommended doses for Phase II trials are 30 mg/m² in good risk patients and 25 mg/m² in poor risk patients. Because of the partial response seen in one patient with renal cell carcinoma, Phase II trials should include this tumor category in order to better define the activity of ametantrone in this disease. In addition, since the total amount of drug that could be given to patients receiving the five day schedule (125–150 mg/m²) was approximately the same amount that could be administered as a single dose (140 mg/m²), it would appear that the only advantage of the daily times five day dosage schedule would be in the lower incidence of bluish skin discoloration.     

Drug–drug interactions of new active substances: mibefradil example

Introduction: Mibefradil was approved as a novel calcium antagonist in Switzerland in 1996. Following its launch as an antihypertensive and anti-anginal agent, there were reports about serious pharmacokinetic and pharmacodynamic interactions occurring with other drugs frequently administered to patients with cardiovascular diseases. Despite appropriate modifications of the prescribing information, such interactions continued to occur. The drug was finally withdrawn after a study in patients with congestive heart failure showed a trend to higher mortality with mibefradil. This increase in mortality could again be due to multiple interactions between mibefradil and other drugs. In retrospect, it can be concluded that several of the interactions, including the theoretical risk of severe toxicity in some patients, could have been and in fact were predicted on the basis of the data available before introduction to the market. Depending on the benefits, these problems would however not necessarily represent an unacceptable risk for a new active compound. Results and conclusion: The most important points revealed by this analysis were: (1) when interpreting the results of interaction studies, it is important to consider not only the mean of the interaction effect but also the observed and the theoretically conceivable extreme effects in individual subjects and (2) a drug with a high interaction potential may represent a high risk even if an adequate warning is included in the product information. The need for specific pharmacokinetic and pharmacodynamic interaction studies with new drugs and the limitations of the pivotal clinical efficacy and safety studies during phase III in order to reveal such interactions are discussed. Received: 19 March 1999 / Accepted in revised form: 29 July 1999     

Regulatory Aspects of Pharmacokinetic Profiling in Special Populations

The clinical efficacy and safety profile of a new medicinal product is established in phase III studies, which are usually restricted to a well defined patient population. This population may not fully represent the population in which the product will be used once it is on the market. Pharmacokinetic studies in special populations are performed to estimate drug exposure in subpopulations of patients with characteristics that may affect drug exposure. The clinical consequences of altered exposure are then assessed, taking pharmacokinetic/pharmacodynamic relationships into consideration. If needed, specific treatment recommendations should be developed.Recommendations regarding pharmacokinetic characterization in special populations are given in a number of European guidelines. The pharmacokinetic characteristics, therapeutic window and intended use of the medicinal product influence the need for pharmacokinetic studies of a new medicinal product. There are a number of methodological issues to be considered when designing pharmacokinetic studies in special populations: the study design, study population and control group, the dosing regimen to be used, the analytes to be measured, and the distribution and range of the factor to be studied. The data should be presented in sufficient detail to enable assessment by regulatory authorities of the conducted analysis and conclusions drawn. Assessment of the data should include an evaluation of how and to what extent the pharmacokinetics in specific subpopulations deviate from the exposure at the therapeutic dose in the clinical efficacy and safety studies, and if there is a need for specific treatment recommendations. Based on the available information on the pharmacokinetic/pharmacodynamic relationships for efficacy and safety and/or the exposure at the therapeutic dose in the phase III population where efficacy and safety have been demonstrated, target criteria (a target exposure range) should be defined. Within the target exposure range, there should be no clinically relevant difference in efficacy and safety. Should the exposure in a specific group fall outside the defined target criteria, appropriate treatment recommendations need to be developed. The aim should be to develop dosing recommendations that will allow the majority of the patients to obtain exposure within the defined target range. If it is not possible to develop suitable dosing recommendations in a subgroup of patients, there may be a need for specific warnings or wordings regarding monitoring of the patients. It may also be an option to exclude that patient group from the indication. The resulting treatment recommendations should ensure safe and effective use of the drug in the entire population for which it has been approved.     

Microdosing: current and the future

The concept of microdosing has been around for approximately 10 years. In this time there have been an increasing number of drugs reported in the literature where the pharmacokinetics at a microdose have been compared with those observed at a therapeutic dose. Currently, approximately 80% of the microdose pharmacokinetics available in the public domain have been shown to scale to those observed at a therapeutic dose, within a twofold difference. Microdosing is now being extended into areas of drug development other than purely pharmacokinetic prediction. Microdosing has been applied to the study of drug-drug interactions by giving human volunteers a microdose of the candidate drug before and after the administration of a drug known to inhibit or induce certain enzymes, such as the cytochrome P450s. Early data on the metabolism of a drug candidate can be obtained by administering a (14)C-drug to human volunteers and comparing the plasma concentration-time curves for total (14)C and unchanged parent compound. Full metabolic profiles can be generated as an early indication of the drug's metabolism in humans, prior to Phase 1 clinical studies. Microdosing is also being applied to situations where the concentration of a drug in cell or tissue types is key to its efficacy. The application of microdosing as a tool in drug development is therefore widening into new and previously unforeseen fields.