Transporter-Drive Interstitial Tissue Exposure and Pharmacodynamic Response of Meropenem in Sepsis: A Mechanistic PBPK Modeling Study.

A whole-body mechanistic PBPK model for meropenem (MPN) was developed in PK-Sim and validated using published plasma and tissue concentration-time data in healthy volunteers and critically ill patients. Renal elimination was implemented as glomerular filtration plus active tubular secretion (basolateral uptake via OAT3 with apical efflux), and non-renal clearance via DHP-mediated hydrolysis. The model was scaled to sepsis or septic shock by incorporating disease-specific physiological changes and optimizing OAT3 activity and tissue permeability to reproduce observed variability. Simulations in a virtual septic population assessed unbound interstitial concentrations in clinically relevant tissues under ILAS-recommended typical and maximum dosing MPN regimens. Antibacterial effect against Escherichia coli and Klebsiella pneumoniae was evaluated using a published PK/PD model driven by simulated unbound tissue concentrations. The PBPK model reproduced observed plasma profiles in healthy volunteers and captured plasma and subcutaneous interstitial exposure in sepsis. Simulations showed clear dissociation between plasma and interstitial exposure and marked tissue-specific heterogeneity. Predicted clearance increased in sepsis (augmented renal clearance) and decreased in septic shock (impaired renal function and secretion). Although maximum dosing increased plasma and tissue exposure, PD simulations indicated effects were already near the plateau with standard dosing, yielding minimal additional antibacterial benefit from routine dose escalation. Transporter-informed PBPK/PD modeling explains dynamic, severity-dependent changes in meropenem clearance and tissue exposure in sepsis, highlights limitations of plasma-only assessment, and supports individualized, mechanism-informed optimization rather than universal dose scaling.