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J L Steimer

Publications and source records attributed to J L Steimer.

At least 19 recordsLinked to original sources
PubMed2002

Population pharmacokinetic analysis of the major metabolites of capecitabine.

Capecitabine has been developed as an orally administered tumor selective fluoropyrimidine for use in the treatment of breast and colorectal cancer. The metabolic pathway for capecitabine includes 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), which is then converted to the pharmacologically active agent 5-fluorouracil (5-FU). A previous analysis showed that systemic exposure to 5'-DFUR and alpha-fluoro-beta-alanine (FBAL), a catabolite of 5-FU, was predictive of dose limiting toxicities. Therefore, a multi-response population pharmacokinetic (PK) model for the description of plasma concentrations of 5'-DFUR, 5-FU and FBAL following oral administration of capecitabine was developed using NONMEM. PK data from a bioequivalence study in 24 patients with various solid tumors were used to develop the PK structural part of the population PK model. The 5'-DFUR, 5-FU and FBAL plasma concentrations were described by a linear disposition PK model with first order absorption and lag time. Sparse plasma concentration data from 54 phase II breast cancer patients were added to the bioequivalence data and the influence of covariates on the apparent oral clearances of 5'-DFUR, 5-FU and FBAL and on the apparent volume of distribution of FBAL was investigated. This was conducted by including all significant (p < 0.05) single covariate-PK parameter pairs in the full PK model, followed by one by one deletion (p < 0.001) from the population model. Statistically significant effects were found for the influence of gender, body surface area and total bilirubin on 5'-DFUR clearance and the influence of creatinine clearance on FBAL clearance. However, none of these effects were considered to have clinical relevance.

Adult↗
PubMed2001

Role of modelling and simulation in Phase I drug development.

Although the use of pharmacokinetic/pharmacodynamic modelling and simulation (M&S) in drug development has increased during the last decade, this has most notably occurred in patient studies using the population approach. The role of M&S in Phase I, although of longer history, does not presently have the same impact on drug development. However, trends such as the increased use of biomarkers and clinical trial simulation as well as adoption of the learn/confirm concept can be expected to increase the importance of modelling in Phase I. To help identify the role of M&S, its main advantages and the obstacles to its rational use, an expert meeting was organised by COST B15 in Brussels, January 10-11, 2000. This article presents the views expressed at that meeting. Although it is clear that M&S occurs in only a minority of Phase I clinical trials, it is used for a large number of different purposes. In particular, M&S is considered valuable in the following situations: censoring because of assay limitation, characterisation of non-linearity, estimating exposure-response relationship, combined analyses, sparse sampling studies, special population studies, integrating PK/PD knowledge for decision making, simulation of Phase II trials, predicting multiple dose profile from single dose, bridging studies and formulation development. One or more of the following characteristics of M&S activities are often present and severely impede its successful integration into clinical drug development: lack of trained personnel, lack of protocol and/or analysis plan, absence of pre-specified objectives, no timelines or budget, low priority, inadequate reporting, no quality assurance of the modelling process and no evaluation of cost-benefit. The early clinical drug development phase is changing and if these implementation aspects can be appropriately addressed, M&S can fulfill an important role in reshaping the early trials by more effective extraction of information from studies, better integration of knowledge across studies and more precise predictions of trial outcome, thereby allowing more informed decision making.

Clinical Trials, Phase I as Topic↗
PubMed2000

Population pharmacokinetics of tolcapone in parkinsonian patients in dose finding studies.

AIMS: To use pharmacostatistical models to characterize tolcapone's pharmacokinetics in parkinsonian patients, and to identify any demographic subpopulations which may be at risk of either under- or over-exposure to this catechol-O-methyltransferase (COMT) inhibitor. METHODS: Four hundred and twelve patients participated in three multicentre, parallel, double-blind, placebo-controlled, dose-finding studies and received either placebo or tolcapone (50, 200 or 400 mg three times daily) in addition to levodopa/decarboxylase inhibitor therapy. Sparse blood samples were obtained from 275 patients for tolcapone assay and the concentrations (1414 in total) were analysed using the NONMEM program. RESULTS: The pharmacokinetic model which best described the data was a two-compartment open model with first-order absorption and possibly a lag-time. Tolcapone pharmacokinetics were shown to be stable, with no systematic trend between 2 and 6 weeks of treatment. The absorption of the drug was shown to be rapid and concomitant food intake had only a minor effect on the relative bioavailability (10-20% reduction compared with fasting). The overall clearance of tolcapone could be estimated with good precision (approximately 4. 5-5 l h-1 ), and none of the investigated covariates (e.g. sex, age, body weight) had any clinically significant influence on this parameter. The volume of distribution showed relatively high variability and was calculated to be approximately 30 l, leading to an estimated half-life in patients of approximately 5-8 h. CONCLUSIONS: Using sparse concentrations and mixed effect-effects modelling analysis it is possible to describe the pharmacokinetics of tolcapone in parkinsonian populations. The parameter estimates obtained agreed with those obtained from conventional pharmacokinetic studies and no subpopulation was shown to be at risk of either under- or over-exposure to tolcapone.

Adult↗
PubMed2000

Population pharmacokinetics of levodopa in patients with Parkinson's disease treated with tolcapone.

OBJECTIVE: To use pharmacostatistical models to evaluate the overall exposure of patients with Parkinson's disease to levodopa in the presence and absence of tolcapone. METHODS: Four hundred twelve patients with Parkinson's disease with fluctuating and nonfluctuating responses to levodopa participated in three multicentered, parallel, double-blind, placebo-controlled dose-finding studies and received either placebo or tolcapone in addition to levodopa-decarboxylase inhibitor therapy. Sparse blood samples were obtained from 393 patients for levodopa and 3-O-methyldopa assay, and the data were analyzed with use of the NONMEM program. RESULTS: The fraction of levodopa metabolized to 3-O-methyldopa was substantially reduced by the co-administration of tolcapone (by 65%, 74%, and 84% with tolcapone doses of 50, 200, and 400 mg, respectively, in fluctuators, and by 50% and 90% with doses of 200 and 400 mg, respectively, in nonfluctuators). This led to an overall reduction in levodopa clearance (CL) of approximately 15% to 25% in fluctuators and 20% to 30% in nonfluctuators. Because this was partly compensated for by a reduction in levodopa dose in these studies, the total daily exposure of patients to levodopa was only slightly increased (11% to 16%). The peak-trough fluctuations of plasma levodopa (Cmax-Cmin) were reduced in both populations in a dose-dependent fashion. CONCLUSIONS: Tolcapone effectively inhibited the formation of 3-O-methyldopa and resulted in a decrease in levodopa CL. The consequent increase in levodopa bioavailability was mostly offset by reductions in levodopa dose. It is possible that decreased fluctuations in plasma levodopa concentrations rather than increased levodopa exposure may explain the clinical benefits obtained with tolcapone.

Adult↗
PubMed2000

Pharmacokinetic/pharmacodynamic modeling in drug development.

We propose a framework for considering the role of pharmacokinetic/pharmacodynamic modeling in drug development and an appraisal of its current and potential impact on that activity. After some introduction, definitions, and background information on drug development, we discuss subject-matter models that underlie pharmacokinetic/pharmacodynamic modeling and show how they determine appropriate statistical models. We discuss the broad role modeling can play in drug development, enhancing primarily the "learning" steps, i.e. acquiring the information needed for the label and for planning efficient confirmatory clinical trials. Examples of past applications of modeling to drug development are presented in tabular form, followed by a discussion of some practical issues in application. Modeling will not reach its potential utility until it is manifest as a visible and separate work unit within a drug development program. We suggest that that work unit is the "in numero" study: a protocol-driven exercise designed to extract additional information, and/or answer a specific drug-development question, through an integrated model-based (meta-) analysis of existent raw data, often pooled across separate (clinical) studies.

Animals↗
PubMed1999

Relationships between exposure to saquinavir monotherapy and antiviral response in HIV-positive patients.

OBJECTIVE: The aim of this study was to confirm the most appropriate dosage of a new soft gelatin capsule (SGC) formulation of the HIV protease inhibitor saquinavir by investigating the relationships between systemic (plasma) exposure to saquinavir and plasma HIV RNA and CD4+ cell counts using empirical mathematical modelling. DESIGN AND SETTING: A randomised, non-blind, multicentre, dose-ranging 8-week study of monotherapy with 400, 800 or 1200 mg of saquinavir-SGC or 600 mg of the hard gelatin capsule (HGC) formulation, both administered 3 times daily, was carried out in protease inhibitor-naive, HIV-positive adults. Two surrogate markers of response, plasma HIV RNA level and CD4+ cell count, were fitted to 2 measures of systemic drug exposure, the area under the plasma concentration-time curve (AUC) and trough plasma concentration (Cmin), using 6 exposure-response models of progressively increasing complexity. Akaike and Schwarz model selection criteria were applied to determine the most effective pharmacokinetic-pharmacodynamic relationship. RESULTS: A total of 88 patients were randomised; pharmacokinetic and pharmacodynamic data were available for 84 patients. In terms of plasma HIV RNA, pharmacokinetic-pharmacodynamic relationships were best described by a 2-parameter maximum effect (Emax) model, which predicted a typical maximum reduction in viral load of 1.94 log10 copies/ml [coefficient of variation (CV) 12%], with a half-maximal antiviral response occurring at a Cmin of 50 micrograms/L (CV 40%). Saquinavir-SGC 1200 mg administered 3 times daily produced a median AUC to 24 hours (AUC24) of approximately 20,000 micrograms/L.h, corresponding to 85% of the maximum achievable antiviral effect as defined by the model. None of the models yielded a satisfactory fit for CD4+ cell count. CONCLUSION: Empirical mathematical modelling confirmed that, when administered 3 times daily, the optimum dose of saquinavir-SGC is 1200 mg, corresponding to 3600 mg/day.

Adult↗
PubMed1997

An evaluation of the integration of pharmacokinetic and pharmacodynamic principles in clinical drug development. Experience within Hoffmann La Roche.

The integration of pharmacokinetic and pharmacodynamic principles into drug development has been proposed as a way of making it more rational and efficient. The use of these principles in drug development to make scientific and strategic decisions is defined as the 'pharmacokinetic-pharmacodynamic guided approach to drug development'. The objectives of this survey were: (i) to assess the extent the pharmacokinetic-pharmacodynamic guided approach to drug development has been used in a large multinational pharmaceutical company: (ii) to evaluate the impact of pharmacokinetic and/or pharmacodynamic results on clinical drug development; and (iii) to identify factors which prevented the full application of the pharmacokinetic-pharmacodynamic guided approach. This was done by looking at 18 projects in the current development portfolio at Hoffman La Roche and evaluating the use of this approach by interviewing the responsible clinical pharmacologist using a standardised questionnaire. (i) Benefits from using the pharmacokinetic-pharmacodynamic guided approach were reported in every project, independent of development phase and therapeutic area. This approach was more extensively used in the recent projects. The selection of dosages in clinical studies was found to be the most important application of pharmacokinetic-pharmacodynamic results in terms of an impact on drug development. (ii) Time savings, up to several months, could be quantified in 8 projects during the entry-into-man studies and in 6 projects during the phase II or III studies. In 4 projects, 1 clinical study was avoided. (iii) The most important scientific factor preventing the full application of the approach was the lack of knowledge on the predictive value of the pharmacodynamic or surrogate marker for effect (6 projects). The results of the survey have shown that the use of the pharmacokinetic-pharmacodynamic guided approach has contributed to making clinical drug development more rational and more efficient. Opportunities to apply the pharmacokinetic-pharmacodynamic approach should be identified in each project and a project specific strategy for the pharmacokinetic-pharmacodynamic guided approach should be defined during phase 0 of drug development.

Cost-Benefit Analysis↗
PubMed1997

Exploring clinical study design by computer simulation based on pharmacokinetic/pharmacodynamic modelling.

Computer simulations have been successfully applied in various industries (e.g. automobile, aerospace) to make product development more efficient. Just recently, it was suggested to use simulations in support of clinical drug development for predicting clinical outcomes of planned trials. The methodological basis for this approach is provided by pharmacokinetic and pharmacodynamic mathematical models together with Monte Carlo techniques. In the present paper, the basic notions of clinical trial simulation are introduced and illustrated with the example of an oral anticancer drug. It is shown that computer simulation helps to evaluate consequences of design features on safety and efficacy assessment of the drug which are not easily obtained otherwise. An overview of existing simulation resources with respect to training and software is provided.

Administration, Oral↗
PubMed1996

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.

Belgium↗
PubMed1996

The use of population pharmacokinetics in drug development.

Currently, there is an increasing focus on the implementation of pharmacokinetic-pharmacodynamic (PK-PD) studies and modelling as essential tools for drug development. Strategies involving specifically the population approach, which are based on relatively recent statistical methodology (e.g. nonlinear mixed effects modelling, NONMEM) have been advocated for investigating pharmacokinetic and pharmacodynamic variability as well as dose-concentration-effect relationships. The present article outlines this approach, and discusses how it can be implemented within the framework of the studies currently performed as part of the clinical phases of new drug development. It also considers study design and performance, based on real-life experiences. Population approaches, if designed carefully and early, as part of the planning of the drug development programme, are expected to play a significant role at every phase of the programme and to contribute to providing information that is valuable for registration purposes. Statistical methodology and software are now widely available. However, practical issues such as integration of the population approach within existing protocols, quality control of the data, timing of laboratory and statistical analyses, as well as resource allocation, remain legitimate concerns to be considered in prospective studies.

Clinical Trials, Phase I as Topic↗
PubMed1994

Population approaches in drug development. Report on an expert meeting to discuss population pharmacokinetic/pharmacodynamic software.

An expert meeting to discuss population pharmacokinetic/pharmacodynamic software was held in Brussels in November 1993 under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. Recently developed statistical methods offer the possibility of gaining integrated information on pharmacokinetics and response from relatively sparse observational data obtained directly in patients who are being treated with the drug under development. These methods can minimize the need to exclude patient groups and also allow analysis of a variety of unbalanced designs that frequently arise in the evaluation of the relationships between dose or concentration on the one hand and efficacy or safety on the other relationships that do not readily lend themselves to other forms of statistical analysis. The purpose of the Brussels meeting was to evaluate the state of both existing software and software under development, and to specify the needs and wishes of potential users of such software. It was apparent from the meeting that software development for population data analysis is currently a very active area of investigation and that several very good packages are already available, with more in development. The general consensus of the meeting was that well validated, easy to use software was essential to the implementation of the population approach to drug development.

Humans↗
PubMed1994

Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125.

The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio = 8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membrane-limited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (KP) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady state in vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances; in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration and AUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.

Adult↗
PubMed1993

A mathematical model for dynamics of cardiovascular drug action: application to intravenous dihydropyridines in healthy volunteers.

A physiologically based mathematical model was built to describe the pharmacodynamic effects in response to the administration of intravenous (iv) dihydropyridine drugs in healthy volunteers. This model incorporates a limited number of hemodynamic variables, namely, mean arterial blood pressure (MAP), cardiac output (CO) or heart rate (HR), stroke volume (SV), and total peripheral resistance (TPR), into a closed-loop system supposed to represent essential features of the cardiovascular regulation. We also defined an additional auxiliary control variable (U) which is thought to represent primarily the role of the baroreceptor reflex. It was assumed that the variable U was related to MAP changes through both deviation- and rate-sensitive mechanisms. Other model parameters are the baseline levels for MAP, CO (or HR), and TPR, as well as time constants to account for further temporal aspects of the regulation. Finally, TPR was assumed to be linked to the plasma concentrations of dihydropyridine drugs via a conventional pharmacokinetic/pharmacodynamic (PK/PD) model, relying upon an effect compartment and a linear, hyperbolic, or sigmoidal relationship between the reduction in TPR and the drug concentrations at the effect site. The model characteristics were explored by studying the influence of various parameters, including baseline levels and deviation- and rate-sensitive control parameters, on the hemodynamic responses to a fictive constant rate i.v. infusion of a vasodilator drug. Attempts were also made to mimic literature data with nifedipine, following i.v. administration under both constant and exponentially decreasing infusion rates. The applicability of the model was demonstrated by fitting hemodynamic data following i.v. infusion of nicardipine to healthy volunteers, under experimental conditions similar to those described above for nifedipine. The effect model for the action of nicardipine on TPR, combined with the physiological model including a feedback control loop, allowed an adequate quantitative description of time profiles for both cardiac output and mean arterial pressure. The suggested model is a useful tool for integrated data analysis of hemodynamic responses to vasodilator drugs in healthy volunteers. Computer simulations suggest that a graded variation of a few model parameters--including baseline levels of TPR and MAP and the deviation-sensitive parameter of the arterial pressure control--would also be able to account for the pattern of hemodynamic response observed in hypertensive patients, which is qualitatively different to that seen in normotensive subjects. Extrapolation of drug response from the healthy volunteer to the hypertensive patient is allowed by our model. Its usefulness for an early evaluation of drug efficacy during drug development is under current investigation.

Adult↗
PubMed1991

Simultaneous pharmacokinetic modeling of a drug and two metabolites: application to albendazole in sheep.

Albendazole pharmacokinetic parameters were determined in lambs after iv, oral, and intraruminal single administrations. The parent drug and two metabolites, albendazole sulfoxide and albendazole sulfone, were simultaneously determined in whole blood, plasma, and urine using an HPLC method. The parent drug was only recovered in plasma when injected intravenously. For other routes, only the two metabolites were detectable; they were present in red blood cells and plasma at equal concentrations. The pharmacokinetic parameters were determined by using compartmental models which simultaneously described the two oxidative steps and the urinary excretion of the sulfoxide derivative. Dose-dependent pharmacokinetics was studied in the dose range 0.95-3.8 mg/kg. The results showed that clearance remained constant within the tested dose range since the area under the curve normalized to the dose was similar in the cases of sulfoxide and sulfone metabolites, whatever the route of administration. The drug appeared to be extensively metabolized in the body regardless of the route of administration. Sulfoxidation probably took place in liver, but other tissues seemed to be responsible for the formation of the sulfoxide which has been described as the major anthelmintic derivative of albendazole.

Administration, Oral↗
PubMed1991

A mathematical model of the kinetics of 5-fluorouracil and its metabolites in cancer patients.

A compartmental model of the kinetics of 5-fluorouracil (5-FU) and its catabolites in humans is proposed. This model was developed using data from a previous study in which plasma levels and urinary amounts of unchanged drug and metabolites were quantitated after i.v. bolus injection of 500 mg/m2 5-FU in ten patients. Biliary excretion was also quantified in two subjects. The different processes, biochemical transformations, and urinary and biliary excretion were adequately described by first-order kinetics. The technique of multiresponse modelling was used for global fitting of all data for each patient. Satisfactory agreement was achieved between measured and predicted values. This model enabled accurate evaluation of pharmacokinetic parameters that could not be adequately calculated using a model-free analysis. The total clearance and elimination half-life of 5-FU and its catabolites are reported for all subjects. The estimated mean half-life was 6.9 +/- 3.9 min for unchanged 5-FU and 225 +/- 352, 7.6 +/- 4, and 9.6 +/- 7.7 min, respectively, for the three measured catabolites dihydrofluorouracil (FUH2), alpha-fluoro-beta-ureidopropionic acid (FUPA), and alpha-fluoro-beta-alanine (FBAL). The percentage of anabolic, catabolic, urinary, and biliary elimination in total clearance was also quantitated. Anabolic clearance accounted for 39% +/- 14% of total 5-FU clearance, with substantial variation occurring among patients. Urinary clearance represented 6.5% +/- 3.2%, 0.8% +/- 0.9%, 13.2% +/- 4.7%, and 98.2% +/- 2.5% of total clearance for 5-FU, FUH2, FUPA, and FBAL, respectively. The model was also satisfactorily fitted to the data of a patient deficient in dihydropyrimidine dehydrogenase, an enzyme previously thought to be the rate-limiting step for 5-FU catabolism. In this case, catabolism was highly reduced and urinary excretion of 5-FU increased up to 64% of total drug clearance. This first global model of the kinetics of 5-FU and all of its catabolites in patients given an i.v. bolus infusion of 500 mg/m2 5-FU represents a further step toward detailed comprehensive modeling of the kinetics of this drug.

Fluorouracil↗
PubMed1991

Mathematical model for in vivo pharmacodynamics integrating fluctuation of the response: application to the prolactin suppressant effect of the dopaminomimetic drug DCN 203-922.

We propose a general pharmacokinetic-pharmacodynamic model that integrates the rhythmic fluctuation of hormone secretion for the description of the hormone-lowering effect of a drug. The mathematical model takes into account the variation in response observed after administration of a placebo and the drug. It is assumed that the change with time in the physiological response during the placebo period results from fluctuations in the concentration of hypothetical endogenous molecules. The mathematical formulation for predicting the response after drug intake is derived assuming competitive interaction of these "molecules" with the active species for binding to receptors. The suggested "fluctuation model" was implemented in order to describe the time course of the prolactin (PRL) plasma level after administration of two oral doses (2.5 and 5.0 mg) of the dopaminomimetic compound DCN 203-922 (DCN) to 9 healthy male subjects. Its performance was compared with that of conventional modeling approaches, in which the circadian changes after placebo are neglected and the hormone baseline is assumed to be constant. The new model provided a better description of the time course of PRL in most subjects. It was used for prediction of the amplitude and duration of the PRL suppressant effect after single and chronic administration of DCN at various dosage regimens as well as after changes in drug absorption.

Adult↗
PubMed1991

Exploratory analysis of population pharmacokinetic data from clinical trials with application to isradipine.

Drug level monitoring during routine clinical visits in the course of phase III trials provides a means to document pharmacokinetic variability in a patient population. Such a pharmacokinetic screen was performed for the new calcium antagonist isradipine. A total of 697 blood samples were collected at any time after the morning dose from 252 patients who had received oral doses of isradipine. Three approaches of data analysis based on exploratory (graphical and statistical) techniques were used to relate plasma level to patient demographic data and laboratory parameters. The pharamacokinetics of isradipine seemed to be influenced by the demographic variables of age (already detected in conventional studies) and weight, as well as by the blood serum levels of inorganic phosphorous, uric acid, alkaline phosphatase, and bilirubin, but only to a small, clinically irrelevant extent. The findings from the three approaches were complementary. They suggest that a pharmacokinetic screening in clinical trials is feasible at reasonable experimental cost and effort and provides useful data on interindividual and intraindividual pharmacokinetic variability in patients.

Adult↗