Population pharmacokinetics of unbound and total drug concentrations following intravenously administered carbamazepine in elderly and younger adult patients with epilepsy

Abstract

The objective of the study was to investigate the pharmacokinetics (PK) of unbound and total plasma carbamazepine (CBZ) concentrations following simultaneous administration of intravenous and oral formulations. We tested the hypothesis that age-related alterations in physiology and patient characteristics influence CBZ disposition and protein binding. Patients (n = 113) on maintenance therapy received a 100 mg dose of a novel, intravenous, stable-labeled (SL) CBZ formulation as partial replacement of their morning CBZ dose. A two-compartment model described unbound and total SL-CBZ data. The stable-labeled intravenous dosing methodology enabled the estimation of the CBZ clearance (CL) and volumes of distribution. The CL of CBZ was dependent on race through the model equation unbound CL (L/hour) = 11.2 × (1.30)(Race); where Race = 1 for Caucasian, 0 for African American. Total body weight explained 57% and 70% of the interindividual variability in the central and peripheral volumes of distribution, respectively. Age, sex, smoking, plasma albumin, and alpha 1-acid glycoprotein concentrations had no effect on CL, binding or volumes of distribution. The model was evaluated via bootstrap and predictive check. Results may support race specific dosing for CBZ where an average African-American individual would receive 70% of the standard dose prescribed for the Caucasian person.

Figure 1

(A) Scatter plot of observed unbound SL-carbamazepine concentration versus time after dose. (B) Scatter plot of observed total SL-carbamazepine concentration versus time after dose. The line through the data represents a Locally Weighted Scatterplot Smoother (LOESS) fit to the data.

Figure 2

Goodness of fit plots for the final population pharmacokinetic model. (A) Identity plot of observed versus population predicted unbound concentration. (B) Identity plot of observed versus individual predicted unbound concentration. (C) Identity plot of observed versus population predicted total concentration. (D) Identity plot of observed versus individual predicted total concentration. (E) Scatter plot of conditional weighted residuals (CWRES) versus population predicted unbound concentration. (F) Scatter plot for CWRES versus time after dose for unbound concentration fit. (G) Scatter plot for CWRES versus population predicted total concentration and (H) Scatter plot for CWRES versus time after dose for total concentration fit.

Figure 3

Visual predictive check plots of observed unbound (A) and total (B) SL-CBZ concentrations (open circles), median (solid line), and 5th and 95th quantiles (dashed lines) of 1 000 simulated data sets.