Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

Abstract

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intra-abdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra-abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 µg/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.

Application of Physiologically Based Absorption Modeling to Characterize the Pharmacokinetic Profiles of Oral Extended Release Methylphenidate Products in Adults

“…Predictions of pharmacokinetic parameters were considered successful if the fold error, i.e. difference between predicted and observed mean values, was less than a factor of two [ 49 , 51 – 55 ].…”

Evaluating a physiologically based pharmacokinetic model for predicting the pharmacokinetics of midazolam in Chinese after oral administration

“…It is well-recognized that PBPK modeling can assess ethnicity sensitivity in virtual populations, thereby informing the need for and design of real studies. Currently, PBPK models have been widely applied to the prediction of pharmacokinetics and drug-drug interactions in healthy subjects [11][12][13][14][15] and in specific populations (eg, cancer patients) in China [16][17][18] ; however, limited demographic and physiological knowledge (eg, liver weight, cardiac output, and enzyme abundance, etc) impede the development of the PBPK approach in the Chinese population. Presently, commercially available PBPK software (eg, SimCYP and Gastroplus) affords the opportunity to predict drug exposure and disposition in different ethnic groups.…”

Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice

“…The use of PBPK models developed in animals has aided in tissue distribution studies of various drugs. 27 , 28 , 29 For example, a PBPK model initially developed in mice was extrapolated to humans to successfully predict tissue concentrations of an anticancer agent and estimate its efficacy. 27 Similarly, PBPK modeling in rats has been instrumental for predicting antibiotic penetration in several human tissues and assessing the need for adverse drug reaction monitoring.…”

“… 27 Similarly, PBPK modeling in rats has been instrumental for predicting antibiotic penetration in several human tissues and assessing the need for adverse drug reaction monitoring. 28 , 29 By enabling predictions of drug availability in target organs, PBPK models may provide valuable insights regarding drug availability in target tissues that may correlate with efficacy and safety.…”