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F Mentré

Publications and source records attributed to F Mentré.

6 recordsLinked to original sources
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↗
PubMed1990

Flecainide acetate dose-concentration relationship in cardiac arrhythmias: influence of heart failure and amiodarone.

The trough concentration-dose (C/D) ratio of flecainide was prospectively studied in 78 patients with various cardiac arrhythmias. After the removal of two outlier values, no influence of body weight on C/D ratio was evidenced. Coadministration of amiodarone, and, moreover, the presence of heart failure increase the C/D ratio, from 2.01 +/- 0.78 to 2.55 +/- 0.37 and 2.9 +/- 1.19 ng/ml/mg, respectively (p less than 0.001 by two-factor analysis of variance). The presence of both heart failure and amiodarone therapy increases the C/D ratio to 3.88 +/- 1.07 ng/ml/mg. A single loading oral dose (30 mg/kg) of amiodarone increased C/D measured at the sixth hour in nine patients from 2.27 +/- 0.50 to 2.57 +/- 0.73 ng/ml/mg (p less than 0.05). The trough C/D ratio increased more during chronic treatment from 2.03 +/- 0.86 to 2.92 +/- 1.32 ng/ml/mg (p less than 0.05). Thus, a dosage reduction of flecainide (of 50% in some cases) is mandatory, in case of heart failure or the combination with amiodarone therapy, to obtain a plasma level of the drug that is similar to those observed in patients with a normal heart and without amiodarone therapy. The flecainide-amiodarone interaction seems time dependent.

Adult↗
PubMed1988

Nonparametric maximum likelihood estimation for population pharmacokinetics, with application to cyclosporine.

A new method, nonparametric maximum likelihood (NPML), for statistical analysis of population kinetic data is proposed. NPML provides a discrete estimate of the whole probability density function of the pharmacokinetic parameters. This permits a straightforward derivation of usual population characteristics. To illustrate the application of the NPML method, a population analysis of cyclosporine RIA measured plasma levels in 188 bone marrow transplant patients after intravenous infusion, is presented. The capability of NPML to extract population information from sparse individual data is also outlined.

Biometry↗
PubMed1988

Hyperparameter estimation using stochastic approximation with application to population pharmacokinetics.

A stochastic approximation algorithm is proposed for recursive estimation of the hyperparameters characterizing, in a population, the probability density function of the parameters of a statistical model. For a given population model defined by a parametric model of a biological process, an error model, and a class of densities on the set of the individual parameters, this algorithm provides a sequence of estimates from a sequence of individuals' observation vectors. Convergence conditions are verified for a class of population models including usual pharmacokinetic applications. This method is implemented for estimation of pharmacokinetic population parameters from drug multiple-dosing data. Its estimation capabilities are evaluated and compared to a classical method in population pharmacokinetics, the first-order method (NONMEM), on simulated data.

Algorithms↗