In vitro to human in vivo translation – pharmacokinetics and pharmacodynamics of quinidine

Abstract

SummaryThe translational sciences aim to transfer results from basic research to the treatment of animals or patients. One of the approaches that could be utilized to achieve this goal is the in vitro-in vivo extrapolation (IVIVE) concepts of PK and PD mechanistic modeling and simulation to highlight the importance of assessing drug effect and safety in the preliminary phases of the drug development process. the IVIVe application approach necessitates the provision of three data sets: 1) drug related (ADMe processes and activity), 2) system data (describing population and variability of the chosen parameters), and 3) simulated trial design (Rostami-Hodjegan and tucker, 2007). the IVIVe methodology is a robust evaluation tool that assesses inter-individual variability based on the virtual population characteristics in the population study group.to assess the application value of the described approach, quinidine was selected as the model drug in the virtual study described here. the study endpoints covered plasma concentration of the parent compound and its main metabolite, 3-OH quinidine, from the pharmacokinetic side. either Qtc interval or the drug triggered change as compared to the baseline (ΔQT/ ΔQTc) were used as the pharmacodynamic effect descriptors. this pharmacodynamic effect dictates that drug cardiac safety should be regarded as a pivotal focal point of this study. Preclinical studies routinely use in vitro approaches to assess cardiac safety; however, non-rodent species (e.g., dogs, monkeys) are commonly used in the assessment procedure. this study proposes a novel concept based on a combination of mechanistic PBPK/PD modeling and simulation to predict the cardiac effects of drugs and thus help to incorporate the 3Rs concept

The inhibition of Pseudomonas aeruginosa biofilm formation by micafungin and the enhancement of antimicrobial agent effectiveness in BALB/c mice

“…The inconsistencies between the in vitro and in vivo results may be explained by the notion that different conditions can trigger different mechanisms in bacteria (Davies et al 1988). Furthermore, the host immune system may account for some of these discrepancies (Chen et al 2011;Polak 2013).…”

Application of a systems pharmacology model for translational prediction of hERG ‐mediated QT c prolongation

“…), in which different drug concentrations are extracellularly added. For translational predictions from in vitro data, both the use of C u (Polak ; Mirams et al. ) and tissue concentration (Chetty et al.…”

Interaction Between Domperidone and Ketoconazole: Toward Prediction of Consequent QTc Prolongation Using Purely In Vitro Information

“…The Cardiac Safety Simulator system was used to simulate the drugs triggered ECG modification. The platform combines a physiologically based electrophysiological model of the human left ventricular cardiomyocytes (TNNP ‐ ten Tusscher‐Noble‐Noble‐Panfilov) and a database of human physiological, genotypic, and demographical data enabling prediction of the QT prolongation in humans based on the in vitro data 10 . To account for the heterogeneities in ionic currents between endocardial, midmyocardial, and epicardial cells, a 1D fiber model paced at the endocardial side was used.…”

“…These models consist of the mechanism‐based nodes, describing the physiology of single cardiac cells and they require information on the interaction of a drug candidate with each component of the pathway 7 . Alternative minimal models may be used to answer specific questions, which require less detailed information and are therefore potentially more practical in the early drug development stage 8 , 9 , 10 . Demonstrating applicability and limitations of such models is highly desirable for expansion of the systems pharmacology approach in the area of assessing cardiotoxicity to overcome the limited conditions under which the clinical TQT (thorough QT/QTc) studies are performed (where many permutations of real‐life scenarios cannot be tested despite the use of some arbitrary supratherapeutic concentrations as a conservative safety margin).…”

“…7 Alternative minimal models may be used to answer specific questions, which require less detailed information and are therefore potentially more practical in the early drug development stage. [8][9][10] Demonstrating applicability and limitations of such models is highly desirable for expansion of the systems pharmacology approach in the area of assessing cardiotoxicity to overcome the limited conditions under which the clinical TQT (thorough QT/QTc) studies are performed (where many permutations of real-life scenarios cannot be tested despite the use of some arbitrary supratherapeutic concentrations as a conservative safety margin). The current study provides such a case for the cardiotoxicity output expected from a combined administration of domperidone (DOM) and KETO where there are potential pharmacokinetics (PK) and pharmacodynamics (PD) interaction combinations.…”