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.

FIGURE 1

Observed and predicted LEV and the metabolite ucb L057 plasma concentration profiles in adults included in the model development after single (a, c, e, g, i) and multiple doses (k, m) orally of LEV (actual values and semilogarithmic). Fraction of the dose excreted in the urine (f _e) for each dose group (b, d, f, h, j). The goodness‐of‐fit plot of plasma drug concentrations following oral LEV in adults (n). Symbols represent individual or mean observed data digitized from different literature. The solid, colored areas represent the predicted mean and 5th to 95th range of the current physiologically‐based pharmacokinetic model at respective doses in adults. FDA, US Food and Drug Administration; EMA, European Medicines Agency; LEV, levetiracetam.

FIGURE 2

Observed and predicted LEV plasma concentration profiles in adults included in the model development after single (a–h) and multiple doses (i‐k) intravenous infusions of LEV (actual values and semi‐logarithmic). The goodness‐of‐fit plot of plasma drug concentrations following intravenous infusions LEV in adults (l). LEV, levetiracetam.

FIGURE 3

Observed and predicted LEV plasma concentration profiles in renal impairment populations included in the model development after single (a–d) 500 mg or 250 mg orally of LEV (actual values and semilogarithmic). Fraction of the dose excreted in the urine (f _e) for each dose group (e–h). Box‐whisker plots of populations at different disease stages after oral LEV to compare AUC (i–k). The goodness‐of‐fit plot of plasma drug concentrations following oral LEV in renal impairment populations (l). AUC, area under the curve; LEV, levetiracetam.

FIGURE 4

Observed and predicted LEV and the metabolite ucb L057 plasma concentration profiles in hepatic impairment populations included in the model development after single (a–d) 1000 mg orally of LEV (actual values and semi‐logarithmic). Fraction of the dose excreted in the urine (f _e) for each dose group (e–h). Box‐whisker plots of populations at different disease stages after oral LEV to compare AUC (i–j). LEV and ucb L057 goodness‐of‐fit plot of plasma drug concentrations following oral administration in hepatic impairment populations (k–l). AUC, area under the curve; CP, Child‐Pugh; LEV, levetiracetam.

FIGURE 5

Comparison of oral 500 mg LEV plasma drug concentration time profiles (a), f _e curves (b), and AUC box plots (c) in adult and elderly populations. Box‐whisker plots of elderly populations at different disease stages after oral LEV to compare AUC (renal impairment: d and e, hepatic impairment: f and g). AUC, area under the curve; f _e, fraction of the dose excreted in the urine; LEV, levetiracetam.