Biomedical subjects

F Mentré

Publications and source records attributed to F Mentré.

At least 19 recordsLinked to original sources

PubMed2001

Development and implementation of the population Fisher information matrix for the evaluation of population pharmacokinetic designs.

In population pharmacokinetic studies, the precision of parameter estimates is dependent on the population design. Methods based on the Fisher information matrix have been developed and extended to population studies to evaluate and optimize designs. In this paper we propose simple programming tools to evaluate population pharmacokinetic designs. This involved the development of an expression for the Fisher information matrix for nonlinear mixed-effects models, including estimation of the variance of the residual error. We implemented this expression as a generic function for two software applications: S-PLUS and MATLAB. The evaluation of population designs based on two pharmacokinetic examples from the literature is shown to illustrate the efficiency and the simplicity of this theoretic approach. Although no optimization method of the design is provided, these functions can be used to select and compare population designs among a large set of possible designs, avoiding a lot of simulations.

Computer Simulation↗

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↗

PubMed2001

Optimal design of a population pharmacodynamic experiment for ivabradine.

PURPOSE: To design a parsimonious population pharmacodynamic experiment that has the same or greater efficiency than that provided by two phase I studies. METHODS: The design was based on optimization of the population Fisher information matrix. Options for optimization were (1) determination of the optimal sampling times for each group ("group" represents a group of subjects that have identical design characteristics), (2) determination of the optimal doses for each group, and (3) determination of the optimal group structure. RESULTS: (1) Optimizing the sampling times, while retaining only four unique times per group, provided a more parsimonious experiment with the same efficiency as the original "study" that involved on average 10 samples per subject. Splitting sampling times between the first dose and a steady-state dose gave the most informative design. (2) The optimal dose was the same in all groups and was the upper bound of the dose range. (3) The optimal population design consisted of only one group with four unique sampling times that are the same for all subjects. CONCLUSION: A population pharmacodynamic trial design is presented that is more parsimonious than the original study and would be appropriate for inclusion in a premarketing clinical study.

Benzazepines↗

PubMed2001

Population pharmacokinetic analysis and optimization of the experimental design for mizolastine solution in children.

Mizolastine is a second generation antihistamine agent approved in Europe for the treatment of allergic rhinitis and skin conditions for which Sanofi-Synthélabo is developing a pediatric solution. Our objective was to design the population pharmacokinetic (PK) study of mizolastine pediatric solution in children. A bioavailability study of this solution compared to the marketed tablet was performed in 18 young volunteers. These PK data were analyzed by nonlinear regression using a two-compartment open model with zero-order absorption. From the estimated parameters, we designed population PK studies in two groups of children: 6 to 12 years and 2 to 6 years, respectively. To compare several population designs and to derive the optimal ones, we used the determinant of the Fisher information matrix of the population characteristics using a first-order expansion of the model. We have evaluated a "reference" population design with 10 samples (from 0.25 to 36 hr after drug intake) per child in 6 children, which could not be implemented in practice for ethical reasons. We then derived optimal population designs with 1, 2, 3, 4, or 5 samples per child and a total of 60 samples. Finally, the designs that were implemented in the population PK study were "compromise" population designs with 60 samples; one defined for 20 children 6 to 12 years old, and one with 24 children 2 to 6 years. In the older group, the population design involved 8 children with a catheter from which 6 samples at time 0.25, 0.5, 0.75, 2, 3, and 6 hr after drug intake are collected, and 12 children with only one sample at time 8, 12, 24, or 36 hr. In the younger group, the population design involved 15 children with a catheter who are divided in three groups with four samples at different times from 0.25 to 6 hr after drug intake, and 12 children with only one sample at time 8, 12, 18, or 24 hr. The expected average increase of variances of these designs compared to the reference design were 1.6 and 1.8 for the older and younger group, respectively, which was decided to be acceptable. Better population designs would have involved three groups of children with five samples per child but could not be implemented in practice. The data of the PK study in children 6 to 12 years were available and were analyzed using NONMEM. A total of 53 concentrations were obtained in 18 children. The same two-compartment model with zero-order absorption was used. The interindividual variability in children was small. The estimated population parameters in children 6 to 12 years, were 0.28 L/kg for Vc/F, 0.10 L/hr per kg for CL/F, 0.53 hr-1 for lambda 1, 0.076 hr-1 for lambda 2, and 0.49 hr for Tabs. These values were close to the median values observed in young volunteers when standardized to 70 kg; notably, CL/F in L/hr per kg was similar, so that a dose of 0.15 mg/kg o.d. for mizolastine pediatric solution should give an equivalent area under the curve to a 10 mg o.d. tablet in adults.

Adult↗

PubMed2001

Evaluation of tests based on individual versus population modeling to compare dissolution curves.

This study is aimed at comparing dissolution curves obtained for several batches of sustained release formulations of octreotide, a somatostatin analog used in acromegaly. We evaluated four tests to compare the parameters of two series of curves: a Mann-Whitney-Wilcoxon test comparing individual estimates; a likelihood ratio test after population analysis (NONMEM), and two Wald tests using population parameters estimated by two-stage methods. The four approaches were evaluated by simulations. The Mann-Whitney-Wilcoxon test and the population approach had adequate type-I error, and the latter provided the highest power under the alternatives simulated. The two-stage method including the uncertainty on individual estimates was disappointing.

Algorithms↗

PubMed2000

Modeling the kinetics of release of octreotide from long-acting formulations injected intramuscularly in rabbits.

Long-acting repeatable formulations (LAR) based on polymeric microspheres were manufactured to deliver octreotide, an octapeptide analogue used in acromegaly. We developed a model to describe the complex triphasic concentration versus time profile observed in rabbits after intramuscular (i.m.) injection of these LAR formulations. A 5-mg x kg(-1) dose of octreotide in a reference LAR formulation was given im to eight rabbits; two groups of four rabbits each received a different formulation. In each animal, 26 blood samples were taken over 49 days. Concentrations of octreotide were assayed by radioimmunoassay. A model describing the concentration profile was developed. Octreotide release was described using the succession of an exponential model, a semiempirical non-Fickian model, and a delayed Weibull model. Parameters were estimated using nonlinear regression, first for the eight rabbits that received the reference formulation and then for the other eight animals. The model provides an adequate description of the concentration versus time profile for the three formulations. For the reference phase, erosion accounted for 87% of total drug release. The formulation encapsulating an octreotide-acetate complex showed a prolonged diffusion phase.

Absorption↗

PubMed2000

Association between nasal carriage of Staphylococcus aureus and infection in liver transplant recipients.

We reviewed the records of 87 patients who underwent liver transplantation and who were screened by use of nasal swabs on the day before surgery. Twenty-four patients harbored methicillin-susceptible Staphylococcus aureus (MSSA), and 8 harbored methicillin-resistant S. aureus (MRSA). MSSA infection occurred in 3 (12.5%) of 24 MSSA carriers and in 2 (3.2%) of 63 noncarriers (nonsignificant). In contrast, MRSA infection occurred more frequently in MRSA carriers (7 [87.5%] of 8) than in MRSA noncarriers (8 [10.1%] of 79; P<.001). Nasal carriage of MRSA is associated with a very high risk of MRSA infection in liver transplant recipients.

Adolescent↗

PubMed2000

Prediction of fluindione maintenance dosage hampered by large intraindividual variability.

In a previous study, the authors proposed a method to individualize fluindione dosage regimen, based on a pharmacokinetic/pharmacodynamic model describing the evolution of the International Normalized Ratio (INR). In this method, daily maintenance dosage for a target INR depends on the product of individual Cl and C50. The present work shows the results of a follow-up study in 50 patients for whom target INR was 2.5. INR measurements and dosage regimens were recorded both during hospital stay and during the 1st month of treatment. Patients were defined as equilibrated after 1 month if the last two INRs were in the range 1.5-3.5 under a stable dosage regimen. Actual maintenance dose was compared with the dose predicted using the three first INRs measured in the hospital. Intraindividual variability of Cl*C50 between hospital stay and after 1 month was evaluated. After 1 month, only 27 patients (54%) were equilibrated. Actual maintenance dose varied from 5 to 30 mg daily. There was no bias between predicted and actual maintenance dose (1.4 mg), but a large root mean squared error (8 mg) was found. The intraindividual variability in Cl*C50 between hospital and maintenance regimen was high (93%), which may explain the dispersion in the predicted maintenance dose.

Anticoagulants↗

PubMed1999

Nonparametric analysis of the absorption profile of octreotide in rabbits from long-acting release formulation OncoLAR.

Octreotide (octreotide-acetate, Sandostatin(R)) is a somatostatin analogue, used in long-term treatment of acromegaly. The present study describes the absorption profile in rabbits of octreotide after release from the long-acting formulation OncoLAR (denoted as octreotide-LAR). In a first experiment, the disposition kinetics of octreotide was studied for 24 h in six rabbits after intravenous (i. v.) injection of 0.025 mg of a solution of octreotide. In a second experiment, release kinetics was studied in eight rabbits for 49 days after an i.m. injection of 5 mg/kg of octreotide-LAR. Concentrations were determined by radioimmunoassay. After i.v. injection of octreotide, one- and two-compartment models were compared for each rabbit. A typical disposition profile was computed using the mean parameters. After i.m. injection of octreotide-LAR, deconvolution was performed using the point-area method. Individual absorption profiles were characterised using natural splines. The number of breakpoints was selected using the generalised cross-validation criterion. The two compartment model was selected based on the i.v. study. After i.m. administration, octreotide exhibited a triphasic absorption profile, with large interindividual variability. A transient peak followed the initial burst phase. The third phase covered 85% of total drug released. The approach allows a model-independent description of the in vivo absorption profile of octreotide-LAR.

Absorption↗

PubMed1999

Optimal sampling times for Bayesian estimation of the pharmacokinetic parameters of nortriptyline during therapeutic drug monitoring.

Sampling times for Bayesian estimation of the pharmacokinetic parameters of an antidepressant drug, nortriptyline, during its therapeutic drug monitoring were optimized. Our attention was focused on designs including a limited number of measurements: one, two, and three sample designs in which sampling times had to be chosen between 0 and 24 hr after the last intake of a test-dose study. The optimization was conducted in four groups of patients defined by their gender and the administration or not of concomitant drugs inhibiting the metabolism of nortriptyline. The Bayesian design criterion was defined as the expected information provided by an experiment. A stochastic approximation algorithm, the Kiefer-Wolfowitz algorithm, was used for the criterion maximization under experimental constraints. Results showed that optimal Bayesian sampling times differ between patients in monotherapy and polytherapy. For one-sample designs the measurements have to be performed either at the lower (0 hr) or at the upper (24 hr) bound of the admissible interval. Replications were often found for 2- and 3-point designs. Other sampling designs can lead to criterion close to the optimum and can therefore be performed without great loss of information. In contrast, we found that several designs lead to low values of the information criterion, which justifies the approach.

Absorption↗

PubMed1999

Constructing a prediction interval for time to reach a threshold concentration based on a population pharmacokinetic analysis: an application to basiliximab in renal transplantation.

Basiliximab is an immunosuppressant chimeric monoclonal antibody directed to the human interleukin-2 receptor alpha-chain used for prevention of acute rejection episodes in organ transplantation. The minimally effective serum concentration necessary to saturate receptor epitopes in kidney transplant patients is 0.2 microgram/ml. To guide dose selection for Phase 3 efficacy trials, a population pharmacostatistical model was fitted to intensively sampled Phase 2 pharmacokinetic data. This served as a basis from which to examine candidate dose regimens with respect to the duration over which receptor-saturating concentrations would be achieved posttransplant. Three prediction methods were assessed: one based on simulations, and two others based on first-order approximation using either inverse regression or inversion of confidence intervals. An 80% prediction interval was generated by each method to evaluate its predictive performance against prospectively collected Phase 3 data in 39 renal transplant patients who received two injections of 20 mg basiliximab, one prior to surgery and one on Day 4 posttransplant. All methods provided correct prediction of the duration of receptor-saturating concentration. As anticipated, the best performance was obtained from the simulation method which predicted 30 values in the 80% prediction interval, 19.7-52.7 days. The actually observed 80% interval from the Phase 3 data was 23.7-58.3 days.

Algorithms↗

PubMed1998

Relationships between low red blood cell count and clinical response to fluoxetine in depressed elderly patients.

Biological variables specifically linked with serotonin deficiency were assessed in geriatric depression. Sixteen depressed patients, all > or = 60 years of age and with scores on the Montgomery-Asberg Depression Rating Scale (MADRS) > or = 20, were treated with fluoxetine (20 mg/day) for 42 days. Biological variables measured on days 1 and 42 included whole blood and plasma serotonin, plasma total and free tryptophan, and platelet paroxetine and ketanserin binding. Seven of the 16 patients showed a positive clinical response (i.e. MADRS score < or = 12 at day 42). The pre-treatment red blood cell count was the variable most related to clinical response; low levels were found in almost all responders. To a lesser extent, plasma free tryptophan before treatment was also correlated to therapeutic response, with lower values being found in responders. During treatment, plasma free tryptophan was increased in responders and decreased in non-responders. The finding that elderly depressed patients with low pre-treatment red blood cell counts subsequently responded to fluoxetine treatment is consistent with the view that tryptophan, the precursor of serotonin in brain, is taken up by red blood cells.

Aged↗

PubMed1998

Rapid and simple micromethod for the quantification of fluindione in human plasma using high-performance liquid chromatography.

A new high-performance liquid chromatographic (HPLC) assay without any extraction procedure was developed for the quantification of fluindione in plasma using a 100-microl sample volume and coumarin as the internal standard. A deproteinization procedure was coupled with a reversed-phase HPLC separation using a 250x4.6 mm I.D. C18 column and a UV detector set at 280 nm. Peak height ratios were linear over the range 0.05 to 10 microg/ml (correlation coefficient >0.998). The method was found to be highly reproducible, as indicated by the low value obtained for the coefficient of variation: C.V. < or = 6.1% (n = 10). The limit of quantification, estimated under the described conditions at a signal-to-noise ratio of three and with a C.V. lower than 20% for precision and accuracy, was 0.025 microg/ml. The total turnaround time was 25 min. After storage of blood samples at concentrations of 0.1, 0.5 and 2.5 microg/ml at room temperature and exposition to light for 120 h, no degradation of fluindione occurred. This micromethod is simple (no extraction step), fast and currently is being used for drug monitoring.

Anticoagulants↗

PubMed1998

Population pharmacokinetic-pharmacodynamic analysis of fluindione in patients.

OBJECTIVE: Fluindione is a vitamin K antagonist with a long half-life. This study was designed to investigate the pharmacokinetics and pharmacodynamics of multiple doses of fluindione in patients. METHODS: In a learning group of 49 patients who began fluindione treatment, blood samples were taken 12, 18, or 24 hours after one, three, and five doses. Concentration of fluindione, activity of clotting factors II, VII, IX and X, prothrombin complex activity (PCA), and international normalized ratio (INR) were measured. An indirect-response pharmacodynamic model was used for each effect. A comprehensive analysis was performed with a nonparametric population approach. The model was evaluated in 24 other patients: blood samples were taken 24 hours after two, three, four, and six doses; and PCA and INR were observed. RESULTS: Analysis of concentrations and clotting factor activities showed notably that (1) fluindione has a long half-life (median, 69 hours), and (2) concentration that inhibits the synthesis of the clotting factors by 50% varied for each factor, with a median ranging from 0.25 to 2.05 mg.L-1 for factors VII and II, respectively. The results obtained for INR and PCA were validated in the 24 subsequent patients. CONCLUSION: The population approach allowed the comparison of several pharmacodynamic submodels. This first application of the indirect-response model to multiple oral anticoagulant doses in patients confirmed that both the pharmacokinetics and the pharmacodynamics of fluindione show substantial interindividual variability.

Anticoagulants↗

PubMed1998

Assessment of the global two-stage method to EC50 determination.

Preclinical studies of a new drug supply sets of concentration-effect observations. For each experiment, EC50 is estimated through fitting of the Emax model. Naive pooling of these individual estimates, also called the Standard Two-Stage method (STS), is usually performed. A better combination is obtained by the Global Two-Stage method (GTS) which takes into account the variability of the nonlinear regression estimation errors. The performances of STS and GTS are compared on real and simulated data. The results show that GTS performs better than STS in terms of bias or RMSE, especially in case of poorly designed experiments. Degradation of the quality of STS results in simulations appears to be mainly due to some experiments that are usually rejected by experimenters. Such rejections are avoided when using GTS, which hence is particularly suitable for systematic treatment of this kind of data.

Chemistry, Pharmaceutical↗

PubMed1998

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.

Benzimidazoles↗

PubMed1998

Robust optimal design for the estimation of hyperparameters in population pharmacokinetics.

The expectation of the determinant of the inverse of the population Fisher information matrix is proposed as a criterion to evaluate and optimize designs for the estimation of population pharmacokinetic (PK) parameters. Given a PK model, a measurement error model, a parametric distribution of the parameters and a prior distribution representing the belief about the hyperparameters to be estimated, the EID criterion is minimized in order to find the optimal population design. In this approach, a group is defined as a number of subjects to whom the same sampling schedule (i.e., the number of samples and their timing) is applied. The constraints, which are defined a priori, are the number of groups, the size of each group and the number of samples per subject in each group. The goal of the optimization is to determine the optimal sampling times in each group. This criterion is applied to a one-compartment open model with first-order absorption. The error model is either homoscedastic or heteroscedastic with constant coefficient of variation. Individual parameters are assumed to arise from a lognormal distribution with mean vector M and covariance matrix C. Uncertainties about the M and C are accounted for by a prior distribution which is normal for M and Wishart for C. Sampling times are optimized by using a stochastic gradient algorithm. Influence of the number of different sampling schemes, the number of subjects per sampling schedule, the number of samples per subject in each sampling scheme, the uncertainties on M and C and the assumption about the error model and the dose have been investigated.

Humans↗

PubMed1998

Modeling INR data to predict maintenance fluindione dosage.

This study was designed to construct a pharmacokinetic/pharmacodynamic model describing the evolution of International Normalized Ratio (INR) under oral anticoagulation treatment by fluindione in patients and to develop a method for individualization of fluindione dosage. Three indirect response models describing the concentration-INR relationship were tested using a nonparametric estimation method. INR was modelled as a quantity being produced and eliminated. According to a log-likelihood ratio test, the evolution of INR was best modelled as an inhibition of its elimination by fluindione. The selected model was evaluated in 24 additional patients with INR measurements (after 2, 3, 4, 6, and 10 doses). Using a Bayesian method with data until day 4, INR was correctly predicted for days 6 and 10. The population characteristics of fluindione were estimated, pooling the two groups of patients. A Bayesian method for individualization of dosage regimen was developed, based on a risk function for INR at steady state. Prescription rules for fluindione were derived using this method retrospectively on the 73 patients in this study.

Anticoagulants↗