Physiologically based pharmacokinetic modeling to predict OAT3-mediated drug-drug interactions of meropenem in varying stages of chronic kidney disease

[Yuri05]

https://pubmed.ncbi.nlm.nih.gov/36716979/ Jing Dong, Jinyao Liu, Yanhui Liu, Jiachen Yao, Yan Lu, Zheng Jiao, Wenyan Li
Eur J Pharm Sci. 2023 Jan 27;106395. doi: 10.1016/j.ejps.2023.106395

Highlights

• Whole-body physiologically based pharmacokinetic (PBPK) models of meropenem and piperacillin were built and evaluated in healthy adults and in adults with varying stages of CKD, providing useful tools to support the investigation of OAT3-mediated DDI in adults with varying stages of CKD.
• PBPK DDI model simulations showed that the inhibitory effect of probenecid and piperacillin on OAT3 increased the AUC of meropenem in healthy adults, while acyclovir could not influence the pharmacokinetics of meropenem.
• All predicted probenecid-meropenem, piperacillin-meropenem and acyclovir-meropenem DDI AUC ratios were decreased with degree of renal impairment.
• Our presented meropenem DDI model demonstrated that patients with CKD may be less vulnerable to OAT3-mediated DDIs compared with healthy adults.

Keywords: Chronic kidney disease; Drug-drug interactions (DDIs); Meropenem; Organic anion transporter 3; Physiologically based pharmacokinetic model.