On the unphysical hypotheses in pharmacokinetics and oral drug absorption: Time to utilize instantaneous rate coefficients instead of rate constants.

This work aims to explore the unphysical assumptions associated with i) the homogeneity of the well mixed compartments of pharmacokinetics and ii) the diffusion limited model of drug dissolution. To this end, we i) tested the homogeneity hypothesis using Monte Carlo simulations for a reaction and a diffusional process that take place in Euclidean and fractal media, ii) re-considered the flip-flop kinetics assuming that the absorption rate for a one-compartment model is governed by an instantaneous rate coefficient instead of a rate constant, and, iii) re-considered the extent of drug absorption as a function of dose using an in vivo reaction limited model of drug dissolution with integer and non-integer stoichiometry values. We found that drug diffusional processes and reactions are slowed down in heterogeneous media and the environmental heterogeneity leads to increased fluctuations of the measurable quantities. Highly variable experimental literature data with measurements in intrathecal space and gastrointestinal fluids were explained accordingly. Next, by applying power law and Weibull input functions to a one-compartment model of disposition we show that the shape of concentration-time curves is highly dependent on the time exponent of the input functions. Realistic examples based on PK data of three compounds known to exhibit flip-flop kinetics are analyzed. The need to use time dependent coefficients instead of rate constants in PBPK modeling and virtual bioequivalence is underlined. Finally, the shape of the fraction absorbed as a function of dose plots, using an in vivo reaction limited model of drug dissolution were found to be dependent on the stoichiometry value and the solubility of drug. Ascending and descending limbs were observed for the higher stoichiometries (2.0 and 1.5) with the low solubility drug. In contrast, for the more soluble drug, a continuous increase of fraction absorbed as a function of dose is observed when the higher stoichiometries are used (2.0 and 1.5). For both drugs, the fraction absorbed for the lower values of stoichiometry (0.7 and 1.0) exhibit a non-dependency on dose profile. Our results give an insight into the complex picture of in vivo drug dissolution since diffusion-limited and reaction-limited processes seem to operate under in vivo conditions concurrently.

Survival analysis: part II – applied clinical data analysis / 대한마취과학회지

As a follow-up to a previous article, this review provides several in-depth concepts regarding a survival analysis. Also, several codes for specific survival analysis are listed to enhance the understanding of such an analysis and to provide an applicable survival analysis method. A proportional hazard assumption is an important concept in survival analysis. Validation of this assumption is crucial for survival analysis. For this purpose, a graphical analysis method and a goodness-of-fit test are introduced along with detailed codes and examples. In the case of a violated proportional hazard assumption, the extended models of a Cox regression are required. Simplified concepts of a stratified Cox proportional hazard model and time-dependent Cox regression are also described. The source code for an actual analysis using an available statistical package with a detailed interpretation of the results can enable the realization of survival analysis with personal data. To enhance the statistical power of survival analysis, an evaluation of the basic assumptions and the interaction between variables and time is important. In doing so, survival analysis can provide reliable scientific results with a high level of confidence.