Pharmacometrics for Organ Dysfunction and Rapidly Changing Physiology

Organ dysfunction is often translated into dosing through categorical renal or hepatic impairment, yet critical illness and organ support can change clearance and distribution faster than those categories update. To map how pharmacometric studies represent organ dysfunction and rapidly changing physiology, emphasizing temporal covariates, dynamic clearance, model transportability, therapeutic drug monitoring, and model-informed precision dosing. Evidence from 2017–2025 was sought using structured pharmacokinetic/pharmacometric searches combined with renal, hepatic, critical-illness, extracorporeal-support, and dynamic-physiology terms. The operational ledger identified 87 records; 19 duplicates were removed, 68 records were screened, 37 full texts were assessed, and 23 eligible evidence reports entered the synthesis. Renal dysfunction can affect filtration, secretion, and drug clearance; hepatic dysfunction can alter transport, metabolism, flow-related determinants, and exposure in mechanism-dependent ways. Critical illness and organ support add changing distribution, intrinsic clearance, and extracorporeal clearance. External evaluation and concentration-informed Bayesian updating can improve prediction, but performance remains model- and context-specific.Pharmacometric interpretation is strongest when organ dysfunction is treated as a time-indexed exposure-generating state rather than a diagnosis alone. A proposed state–trajectory–decision-horizon framework separates observed physiology, model assumptions, forecast uncertainty, and dose action without assuming that dynamic models are universally superior.