Pharmacokinetic Strategies in Deciphering Atypical Drug Absorption Profiles

Abstract

Drug absorption is a very complex process that manifests itself through potential interaction with a host of physicochemical and physiological variables. Some factors that may affect the absorption processes include presystemic metabolism/efflux, the "absorption window" along the gastrointestinal tract, disease states, demographics (gender, age, ethnicity), and biopharmaceutical classification of solid dosage forms. Despite the complexity of the absorption processes, the analysis of the absorption kinetic data is mostly empirical, and the assumption of first-order absorption is axiomatic. Nevertheless, we often encounter irregular drug absorption profiles (such as double-peak, absorption window-type absorption profiles, etc.) that cannot be satisfactorily described by a simple first-order absorption process. The selection of an inappropriate absorption model would result in the misspecification of the pharmacokinetic model and subsequent erroneous prediction of the dosing regimen. This article presents several pharmacokinetic strategies in analyzing typical and atypical absorption profiles. The atypical absorption profiles discussed in this article include parallel first-order absorption, mixed zero-order and first-order absorption, Weibull-type absorption, absorption window with or without Michaelis-Menton absorption, time-dependent absorption, and inverse Gaussian density absorption. In any event, intravenous drug concentration-time data are generally needed to avoid the ambiguousness in the absorption analyses.

Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube

“…While an exact explanation for this profile is not known, there are several potential factors that may have contributed to this result: (1) upon crushing the tablet and suspending it in water, the fine drug particles may have dissolved quickly, leading to a more rapid initial phase of absorption; (2) after administering the NG suspension, initial, rapid gastric emptying may have been quickly followed by a slowing of emptying and transit time associated with ingestion of the liquid meal; and/or (3) despite auscultatory confirmation of gastric placement of the NG tube, the distal end of NG tube may have been in close proximity to the pyloric sphincter, such that some of the suspension may have flowed directly into the duodenum, essentially bypassing the stomach, and leading to rapid initial onset of absorption. [17][18][19] Some potential limitations of this study include the fact that, for practical reasons, only a select number of beverages or foods were tested in vitro. All NG tube placements were intragastric, thus the results from this study are not directly applicable to individuals who have a more distal placement of feeding tubes (e.g., proximal or distal small intestine, or ascending colon).…”

Slow drug delivery decreased total body clearance and altered bioavailability of immediate‐ and controlled‐release oxycodone formulations

“…The success of Weibull functions in describing drug release from oral formulations have been shown to capture concentration gradients near the releasing boundaries of the Euclidian matrix (Kosmidis and Argyrakis 2003), as well as adequately describe the fractal kinetics behavior associated with the fractal geometry of the dissolution environment. In addition, due to its versatile and flexible forms, Weibull function has been used numerically to describe complex plasma concentration–time profiles of oral absorption of drugs (Vk 1987; Zhou 2003). To describe the convex ascending oxycodone plasma concentration–time profile prior to C max , a time‐varying Weibull function was introduced to describe time‐varying absorption rate constant as follows:$ffalse(x;\mathrm{italic\lambda },kfalse)=\left\{\begin{array}{cc}\frac{k}{\mathrm{italic\lambda }}{\left(\frac{x}{\mathrm{italic\lambda }}\right)}^{k-1}{e}^{-{(x/\mathit{\lambda })}^k}& x\ge 0,\\ 0& x<0,\end{array}\right.$ …”

A New Model for Prediction of Drug Distribution in Tumor and Normal Tissues: Pharmacokinetics of Temozolomide in Glioma Patients

“…Linear system analysis has been used for various pharmacokinetic applications, such as depicting drug absorption, and is viewed as an alternative to and more general than classic compartmental modeling (see review in ref. 18). In this regard, system analysis does not discern a compartmental structure for drug disposition as in classic compartmental modeling but rather relies on the convolution integral, which has the general form as follows;…”