Biomedical subjects

E Comets

Publications and source records attributed to E Comets.

8 recordsLinked to original sources

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

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↗

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

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↗

PubMedDate not supplied

An in vivo pharmacokinetic/pharmacodynamic model for antiretroviral combination.

PURPOSE: The objective of this study was to investigate the pharmacokinetic/pharmacodynamic properties of an antiretroviral therapy in HIV-infected patients. METHOD: Eight HIV-infected patients received zidovudine, lamivudine, and indinavir as their first antiretroviral treatment. Pharmacokinetic data were analyzed separately using a one-compartmental model with first-order absorption, and the individual estimates were used to simulate drug concentrations. To determine the relationship between drug concentrations and the antiviral effect, an in vitro E(max) model was tested. Alternatively, a dynamic model was built describing the viral and cellular pathophysiology, including the turnover of viral replication in infected cells and the production of virus under treatment. RESULT: The E(max) model fit poorly the experimental data. The complex model was not identifiable with the data available in this study, however a simplified model allowed us to estimate the pharmacodynamic parameters reflecting the decrease of both infected cells and viral load under antiretroviral treatment. CONCLUSION: Using potent highly active antiretroviral therapy, the treatment was so effective that it was not possible to estimate the parameters of the relationship between drug concentrations and the reduction of viral load. Even if the relationship does exist, the direct response model of antiretroviral agents cannot be demonstrated, however the simplified model provides an understanding of the synergy of such a combination and offers suggestions as how to prevent the emergence of viral resistant strains.

Adult↗