Development and Evaluation of Physiologically Based Pharmacokinetic Drug–Disease Models for Predicting Rifampicin Exposure in Tuberculosis and Cirrhosis Populations

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.

Development of physiologically‐based pharmacokinetic models for standard of care and newer tuberculosis drugs

“…For nine of the compounds (bedaquiline, clofazimine, ethambutol, ethionamide, isoniazid, linezolid, pyrazinamide, rifampicin, and rifapentine), the constructed models provide additional performance verification or the ability to account for additional mechanistic functionality (e.g., to describe DDIs or to simulate lung concentrations). 7 , 28 , 29 , 30 , 31 , 32 , 33 , 34 For the other two compounds (cycloserine and kanamycin), the constructed PBPK models are the first to be published in the literature.…”

Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients

“…13,14,23,43 The average fold error (AFE) and root mean square error (RMSE) were calculated for further verification of the developed PBPK model. 14,44 The box-whisker plots were used to express the drug dosing recommendations in cirrhosis patients (CP-A-C). For this purpose, AUC unbound and AUC total of the propranolol in healthy and diseased populations (CP-A-C) were determined.…”

“…10 The pathophysiological changes occurring in chronic conditions (liver cirrhosis) can be incorporated into a physiologically based pharmacokinetic (PBPK) model to predict and optimize administered drug doses. [11][12][13][14][15] There is a need to develop a generic whole-body PBPK model of propranolol for a wide range of intravenous (IV) and oral (PO) doses among healthy and diseased populations as it is still one of the most recommended drugs for a variety of CVD and NCVD. 16 The availability of published clinical PK data, after IV and oral administration of propranolol in healthy populations, can assist the development of the wholebody PBPK model of propranolol by using a systematic model-building approach.…”

A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications

“…Since diazepam is administered through different routes of administration (IV, oral, intranasal, and rectal), if a PBPK model that can predict its PK after application of different dosage forms is developed, it may have many clinical applications. Keeping this in mind, a PBPK diazepam model was developed using a systematic model-building approach [ 37 , 38 ] that was capable of predicting its ADME through different routes of drug administration. This study aims to develop a PBPK model in a healthy population for the prediction and evaluation of diazepam pharmacokinetics after the administration of the drug through different routes, i.e., IV, oral, intranasal, and rectal.…”