{Purpose. Better dosing is needed for antibiotics, including teicoplanin (TEI), to prevent emergence of resistant bacterial strains. Here, we assess the TEI pharmacokinetics (PK) related to a 10 mg/l minimum inhibitory concentration (MIC) target in ICU children (4 to 120 months; n=20) with gram+infections. Methods. Standard administration of TEI was with three 10 mg/kg Q12h, loading infusions, and maintainance with 10 mg/kg or 15 mg/kg Q24h. During maintenance, 9 samples (3/day) were collected per patient and the PK analyzed with Nonlinear Mixed Effects Model (NONMEM). Results. Thirty-five percent of concentrations in older children (greater than or equal to2 months) vs. 8% in younger infants (<12 months) were below the target MIC. The global bicompartmental population PK parameters were {[}mean (interindividual CV%)] CL=0.23 l/h {[}72%]

Purpose. i) To develop novel approaches for the construction of bio-equivalence ( BE) limits incorporating both the intrasubject variability and the geometric mean ratio (GMR), and ii) to assess the performance of the novel approaches in comparison to several scaled BE procedures and the classic unscaled average BE. Methods. Plots of the BE limits or the extreme GMR values accepted as a function of the coefficient of variation ( CV) were constructed for published and the developed scaled procedures. Two-period crossover BE investigations with 12, 24, or 36 subjects were simulated with assumptions of a CV 10%, 20%, 30%, or 40%. The decline in the percentage of accepted studies was recorded as the true GMR for the two formulations was raised from 1.00 to 1.50. Acceptance of BE was evaluated by published and the developed scaled procedures, and, for comparison, by the unscaled average BE. Results. Two GMR-dependent BE limits are proposed for the evaluation of average BE: i) BELscG1 with Ln(Upper, Lower BE limit) = +/-{[}(5-4GMR)0.496s + Ln(1.25)], and ii) BELscG2 with Ln(Upper, Lower BE limit) = +/-{[}(3-2GMR)(0.496s + Ln(1.25))], where s is the square root of the intrasubject variance. The range of BE limits becomes narrower as GMR values deviate from unity, and increases with variability. The two new approaches exhibit the highest statistical power at low CV values. At high levels of variability, BELscG1 and BELscG2 show high statistical power, as well as the lowest percentages of acceptance among the scaled methods when GMR = 1.25. The latter becomes more obvious when a large number of subjects is incorporated in the studies. Conclusions. The GMR and CV estimates of the BE study can be used in conjunction with the GMR vs. CV plot for the assessment of average BE. The new approaches, BELscG1 and BELscG2, appear to be highly effective at all levels of variation investigated.

Two different approaches were used to study the kinetics of the enzymatic reaction under heterogeneous conditions to interpret the unusual nonlinear pharmacokinetics of mibefradil. Firstly, a detailed model based on the kinetic differential equations is proposed to study the enzymatic reaction under spatial constraints and in vivo conditions. Secondly, Monte Carlo simulations of the enzyme reaction in a two-dimensional square lattice, placing special emphasis on the input and output of the substrate were applied to mimic in vivo conditions. Both the mathematical model and the Monte Carlo simulations for the enzymatic reaction reproduced the classical Michaelis-Menten ( MM) kinetics in homogeneous media and unusual kinetics in fractal media. Based on these findings, a time-dependent version of the classic MM equation was developed for the rate of change of the substrate concentration in disordered media and was successfully used to describe the experimental plasma concentration-time data of mibefradil and derive estimates for the model parameters. The unusual nonlinear pharmacokinetics of mibefradil originates from the heterogeneous conditions in the reaction space of the enzymatic reaction. The modified MM equation can describe the pharmacokinetics of mibefradil as it is able to capture the heterogeneity of the enzymatic reaction in disordered media.

Purpose. To set up a theoretical basis for identifying biowaivers among Class II drugs and apply the methodology developed to nonsteroidal anti-inflammatory drugs ( NSAIDs). Methods. The dynamics of the two consecutive drug processes dissolution and wall permeation are considered in the time domain of the physiologic transit time using a tube model of the intestinal lumen. The model considers constant permeability along the intestines, a plug flow fluid with the suspended particles moving with the fluid, and dissolution in the small particle limit. The fundamental differential equation of drug dissolution-uptake in the intestines is expressed in terms of the fraction of dose dissolved. Results. The fundamental parameters, which define oral drug absorption in humans resulting from this analysis, are i) the formulation-related factors, dose, particle radius size, and ii) the drug-related properties, dimensionless solubility/dose ratio (1/q), and effective permeability. Plots of dose as a function of (1/q) for various particle sizes unveil the specific values of these meaningful parameters, which ensure complete absorption for Class II drugs {[}(1/q) < 1]. A set of NSAIDs were used to illustrate the application of the approach in identifying biowaivers among the NSAIDs. Conclusions. The underlying reason for a region of fully absorbed drugs in Class II originates from the dynamic character of the dissolution-uptake processes. The dynamic character of the approach developed allows identification of biowaivers among Class II drugs. Several biowaivers among the NSAIDs were identified using solubility data at pH 5.0 and in fed-state-simulated intestinal fluid at pH 5.0. The relationships of formulation parameters, dose, particle radius, and the drug properties, dimensionless solubility/dose ratio (1/q), and permeability with the fraction of dose absorbed for drugs with low 1/q values {[}(1/q) < 1] can be used as guidance for the formulation scientist in the development phase.

Advances in mathematics and physics that deal with fractal geometry, fractal kinetics and chaotic dynamics have offered new insights for complex, kinetic and dynamical phenomena. These concepts can be applied to describe the heterogeneous nature of drug processes in the human body. Using these concepts, all processes related to gastrointestinal drug absorption (i.e. dissolution or release, transit and uptake) are considered to take place in non-homogeneous, disordered media. In pharmacokinetic modeling, fractal spaces and branching transport networks, or stochastic models, replace the classical compartmental models. Classical pharmacodynamics relies on the suppression or amplification of a steady-state baseline; however, the underlying physiological systems are often much more complex. Therefore, tools of nonlinear dynamics are used to analyze the drug effect.

Indicator dilution studies are used to provide estimates for several physiological parameters such as cardiac output as well as intra- and extravascular volumes. This study introduces a novel technique for the estimation of recirculatory parameters. A mathematical model based on a dispersion-convection partial differential equation (PDE), derived from the fractal geometry of the vascular tree and the hydrodynamics of the blood flow, is used to describe the spatiotemporal profile of tracers in the circulatory system. Initially, the equation is fitted to concentration-time (C, t) data of a tracer to derive the parameter estimates of the model equation; in a subsequent step, these estimates along with appropriate changes of the parameters of the PDE are used to generate the early concentration-time profile of a hypothetical appropriate tracer without recirculation. Thus, the area under the concentration-time curve of the first passage of the tracer is calculated and used for the estimation of various physiological parameters, including cardiac output, miscellaneous partial blood volumes, and the corresponding mean transit times. The procedure was applied successfully to literature data of various tracers from humans and dogs.