Abstract
The physiologically based pharmacokinetic (PBPK) approach facilitates the construction of novel drug–disease models by allowing incorporation of relevant pathophysiological changes. The aim of the present work was to explore and identify the differences in rifampicin pharmacokinetics (PK) after the application of its single dose in healthy and diseased populations by using PBPK drug–disease models. The Simcyp® simulator was used as a platform for modeling and simulation. The model development process was initiated by predicting rifampicin PK in healthy population after intravenous (i.v) and oral administration. Subsequent to successful evaluation in healthy population, the pathophysiological changes in tuberculosis and cirrhosis population were incorporated into the developed model for predicting rifampicin PK in these populations. The model evaluation was performed by using visual predictive checks and the comparison of mean observed/predicted ratios (ratio(Obs/pred)) of the PK parameters. The predicted PK parameters in the healthy population were in adequate harmony with the reported clinical data. The incorporation of pathophysiological changes in albumin concentration in the tuberculosis population revealed improved prediction of clearance. The developed PBPK drug–disease models have efficiently described rifampicin PK in tuberculosis and cirrhosis populations after administering single drug dose, as the ratio(Obs/pred) for all the PK parameters were within a two-fold error range. The mechanistic nature of the developed PBPK models may facilitate their extension to other diseases and drugs.
Highlights
Based pharmacokinetic (PBPK) approach has gained value in recent years as it provides novel opportunities for the prediction of systemic drug concentrations in both healthy and diseased populations [1,2,3]
By providing an opportunity to incorporate pathophysiological changes occurring in a disease, the Physiologically based pharmacokinetic (PBPK) approach facilitates the construction of drug–disease models [7,8,9,10,11]
The main objective of the study was to develop PBPK drug–disease models that incorporate the relevant pathophysiological changes occurring in tuberculosis and cirrhosis populations by using rifampicin as a model drug
Summary
Based pharmacokinetic (PBPK) approach has gained value in recent years as it provides novel opportunities for the prediction of systemic drug concentrations in both healthy and diseased populations [1,2,3]. By providing an opportunity to incorporate pathophysiological changes occurring in a disease, the PBPK approach facilitates the construction of drug–disease models [7,8,9,10,11]. In comparison with the classical top-down modeling approach, the PBPK models have the capacity to allow incorporation of disease-specific changes that can facilitate in construction of drug–disease models [14]. The PBPK approach can be very useful in predicting ADME of administered drugs in clinically important highly prevalent diseases (e.g., Tuberculosis)
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