RESUMEN
In preclinical and clinical experiments, pharmacokinetic (PK) studies are designed to analyse the evolution of drug concentration in plasma over time i.e. the PK profile. Some PK parameters are estimated in order to summarize the complete drug's kinetic profile: area under the curve (AUC), maximal concentration (C(max)), time at which the maximal concentration occurs (t(max)) and half-life time (t(1/2)).Several methods have been proposed to estimate these PK parameters. A first method relies on interpolating between observed concentrations. The interpolation method is often chosen linear. This method is simple and fast. Another method relies on compartmental modelling. In this case, nonlinear methods are used to estimate parameters of a chosen compartmental model. This method provides generally good results. However, if the data are sparse and noisy, two difficulties can arise with this method. The first one is related to the choice of the suitable compartmental model given the small number of data available in preclinical experiment for instance. Second, nonlinear methods can fail to converge. Much work has been done recently to circumvent these problems (J. Pharmacokinet. Pharmacodyn. 2007; 34:229-249, Stat. Comput., to appear, Biometrical J., to appear, ESAIM P&S 2004; 8:115-131).In this paper, we propose a Bayesian nonparametric model based on P-splines. This method provides good PK parameters estimation, whatever be the number of available observations and the level of noise in the data. Simulations show that the proposed method provides better PK parameters estimations than the interpolation method, both in terms of bias and precision. The Bayesian nonparametric method provides also better AUC and t(1/2) estimations than a correctly specified compartmental model, whereas this last method performs better in t(max) and C(max) estimations.We extend the basic model to a hierarchical one that treats the case where we have concentrations from different subjects. We are then able to get individual PK parameter estimations. Finally, with Bayesian methods, we can get easily some uncertainty measures by obtaining credibility sets for each PK parameter.
Asunto(s)
Teorema de Bayes , Simulación por Computador , Modelos Estadísticos , Farmacocinética , Animales , RatasRESUMEN
One of the main factors defining intestinal drug absorption is the solubility of the compound in the gastrointestinal environment. This study reports the solubility of a series of 27 commonly used acidic, neutral and basic drugs in human intestinal fluid samples collected from the duodenum or jejunum of healthy volunteers under fasted state conditions. The interindividual variability as well as the impact of factors such as pH, sampling site and bile salts on the solubility in human intestinal fluids was investigated. The solubility measurements were evaluated using a statistical experimental design. Variability in solubility across volunteers and sampling sites was highly compound-specific and appeared to be substantial for weak acids and bases and for lipophilic drugs. Both pH of the samples and the abundance of amphiphilic components were responsible for the variability observed in the solubility values obtained. The results confirm strong interindividual differences in intraluminal solubility, especially for compounds with high lipophilicity and/or compounds with a pKa value within the physiological pH range. It is important to recognize this variability in intestinal drug solubility as it may considerably influence the therapeutic outcome among patients.
Asunto(s)
Líquidos Corporales , Duodeno , Absorción Intestinal , Yeyuno , Preparaciones Farmacéuticas/química , Variación Biológica Individual , Ayuno , Humanos , Concentración de Iones de Hidrógeno , SolubilidadRESUMEN
The apparent permeability index is widely used as part of a general screening process to study drug absorption, and is routinely obtained from in vitro or ex vivo experiments. A classical example, widely used in the pharmaceutical industry, is the in vitro Caco-2 cell culture model. The index is defined as the initial flux of compound through the membrane (normalized by membrane surface area and donor concentration) and is typically computed by adapting a straight line to the initial portion of the recorded amounts in the receiver compartment, possibly disregarding the first few points when lagging of the transfer process through the membrane is evident. Modeling the transfer process via a two-compartmental system yields an immediate analogue of the common Papp as the initial slope of the receiver quantity, but the two-compartment model often does not match observations well. A three-compartment model, describing the cellular layer as well as donor and receiver compartments, typically better represents the kinetics, but has the disadvantage of always having zero initial flow rate to the receiver compartment: in these circumstances the direct analogue of the Papp index is not informative since it is always zero. In the present work an alternative definition of an apparent permeability index is proposed for three-compartment models, and is shown to reduce to the classical formulation as the cellular layer's volume tends towards zero. This new index characterizes the intrinsic permeability of the membrane to the compound under investigation, can be directly computed in a completely observer-independent fashion, and reduces to the usual Papp when the linear two-compartment representation is sufficient to accurately describe compound kinetics.
Asunto(s)
Permeabilidad , Farmacocinética , Algoritmos , Células CACO-2 , Membrana Celular/metabolismo , Humanos , Absorción Intestinal , Modelos Lineales , Modelos Estadísticos , Preparaciones Farmacéuticas/metabolismoRESUMEN
Few attempts have been made to model mathematically the progression of type 2 diabetes. A realistic representation of the long-term physiological adaptation to developing insulin resistance is necessary for effectively designing clinical trials and evaluating diabetes prevention or disease modification therapies. Writing a good model for diabetes progression is difficult because the long time span of the disease makes experimental verification of modeling hypotheses extremely awkward. In this context, it is of primary importance that the assumptions underlying the model equations properly reflect established physiology and that the mathematical formulation of the model give rise only to physically plausible behavior of the solutions. In the present work, a model of the pancreatic islet compensation is formulated, its physiological assumptions are presented, some fundamental qualitative characteristics of its solutions are established, the numerical values assigned to its parameters are extensively discussed (also with reference to available cross-sectional epidemiologic data), and its performance over the span of a lifetime is simulated under various conditions, including worsening insulin resistance and primary replication defects. The differences with respect to two previously proposed models of diabetes progression are highlighted, and therefore, the model is proposed as a realistic, robust description of the evolution of the compensation of the glucose-insulin system in healthy and diabetic individuals. Model simulations can be run from the authors' web page.
Asunto(s)
Complicaciones de la Diabetes/etiología , Diabetes Mellitus Tipo 2/complicaciones , Modelos Teóricos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Simulación por Computador , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/diagnóstico , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/metabolismo , Progresión de la Enfermedad , Humanos , Insulina/sangre , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Adulto JovenRESUMEN
Combinatorial chemistry is widely used in drug discovery. Once a lead compound has been identified, a series of R-groups and reagents can be selected and combined to generate new potential drugs. The combinatorial nature of this problem leads to chemical libraries containing usually a very large number of virtual compounds, far too large to permit their chemical synthesis. Therefore, one often wants to select a subset of "good" reagents for each R-group of reagents and synthesize all their possible combinations. In this research, one encounters some difficulties. First, the selection of reagents has to be done such that the compounds of the resulting sublibrary simultaneously optimize a series of chemical properties. For each compound, a desirability index, a concept proposed by Harrington,(20) is used to summarize those properties in one fitness value. Then a loss function is used as objective criteria to globally quantify the quality of a sublibrary. Second, there are a huge number of possible sublibraries, and the solutions space has to be explored as fast as possible. The WEALD algorithm proposed in this paper starts with a random solution and iterates by applying exchanges, a simple method proposed by Fedorov(13) and often used in the generation of optimal designs. Those exchanges are guided by a weighting of the reagents adapted recursively as the solutions space is explored. The algorithm is applied on a real database and reveals to converge rapidly. It is compared to results given by two other algorithms presented in the combinatorial chemistry literature: the Ultrafast algorithm of D. Agrafiotis and V. Lobanov and the Piccolo algorithm of W. Zheng et al.