<p>The Effect of Liver and Kidney Disease on the Pharmacokinetics of Clozapine and Sildenafil: A Physiologically Based Pharmacokinetic Modeling</p>

Abstract

Background and Objectives: Physiologically based pharmacokinetic (PBPK) modeling permits clinical scientists to reduce practical constraints for clinical trials on patients with special diseases. In this study, simulations were carried out to validate the pharmacokinetic parameters of clozapine and sildenafil using Simcyp ® simulator in young male adults and compare the effect of renal or hepatic impairment on the pharmacokinetic parameters of clozapine and sildenafil. Also, the effect of age on pharmacokinetic parameters of both drugs was investigated in healthy population and in patients with renal and hepatic impairment. Methods: A full PBPK model was built in the simulator for clozapine and sildenafil based on physicochemical properties and observed clinical results. The model used was Advanced, Dissolution, Absorption and Metabolism (ADAM) for both drugs. Results: The PBPK model adequately predicted the pharmacokinetic parameters of clozapine and sildenafil for the healthy adult population. In the simulation results, the bioavailability of both drugs was remarkably raised in both renal and hepatic impairment in young and elderly populations. Conclusion: PBPK modeling could be helpful in the investigation and comparison of the pharmacokinetics in populations with specific disease conditions.

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

“…In comparison to the ADAM model, the first-order absorption model improves simulation performance. In the Ghoneim et al [ 20 ], observed data was from patient with renal impairment or hepatic impairment whereas patients in the current clinical study did not have renal impairment or hepatic impairment. Difference of physiological characteristics might have contributed to determination of the model structure.…”

“…It is believed that only one published study exists constructing the PBPK modeling of the clozapine in patients [ 20 ]. The first-order absorption model for clozapine produced the best fit in this study.…”

“…In the Ghoneim et al [ 20 ] reported that the ADAM model produced the best fit in young male adults with renal and hepatic impairments. The simulation performance of the ADAM model was superior to the first-order absorption by applying physiological factors that significantly affect absorption.…”

“…It was found to be statistically significant with clozapine concentrations being higher in patients aged between 41 and 60 years than in patients aged between 20 and 40 years. In addition, Ghoneim et al [ 20 ] reported that aging is accompanied by decreased in renal and hepatic functions and changes in plasma protein concentrations. These results are in agreement with those of other studies [ 25 26 27 28 29 ].…”

Preparation of solid dispersion systems for enhanced dissolution of poorly water soluble diacerein: In-vitro evaluation, optimization and physiologically based pharmacokinetic modeling

“…Recently, PBPK modeling has received great attention for the prediction of systemic drug concentrations in healthy and special populations [ 19 ]. Also, prediction of inter-individual variabilities accompanied by absorption, distribution, metabolism and excretion (ADME) of administered drugs has been achieved by PBPK modeling [ 20 , 21 ]. In addition, it can promote development of drug-disease model via incorporation of pathophysiological variabilities occurring within a certain disease [ 22 ].…”