Physiologically based pharmacokinetic modeling of levetiracetam to predict the exposure in hepatic and renal impairment and elderly populations

Abstract

Levetiracetam (LEV) is an anti-epileptic drug approved for use in various populations. The pharmacokinetic (PK) behavior of LEV may be altered in the elderly and patients with renal and hepatic impairment. Thus, dosage adjustment is required. This study was conducted to investigate how the physiologically-based PK (PBPK) model describes the PKs of LEV in adult and elderly populations, as well as to predict the PKs of LEV in patients with renal and hepatic impairment in both populations. The whole-body PBPK models were developed using the reported physicochemical properties of LEV and clinical data. The models were validated using data from clinical studies with different dose ranges and different routes and intervals of administration. The fit performance of the models was assessed by comparing predicted and observed blood concentration data and PK parameters. It is recommended that the doses be reduced to ~70%, 60%, and 45% of the adult dose for the mild, moderate, and severe renal impairment populations and ~95%, 80%, and 57% of the adult dose for the Child Pugh-A (CP-A), Child Pugh-B (CP-B), and Child Pugh-C (CP-C) hepatic impairment populations, respectively. No dose adjustment is required for the healthy elderly population, but dose reduction is required for the elderly with organ dysfunction accordingly, on a scale similar to that of adults. A PBPK model of LEV was successfully developed to optimize dosing regimens for special populations. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The role of multiple physiological factors contributing to the large variability in levetiracetam (LEV) pharmacokinetics (PKs) has not been systematically characterized, and the functional status of the major drug elimination organs may influence the behavior of LEV exposure in vivo, which may confound information

Zn(II)–curcumin prevents cadmium-aggravated diabetic nephropathy by regulating gut microbiota and zinc homeostasis

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