Nomogram for Estimating Plasma Unbound Disopyramide Concentrations in Patients with Varying Plasma alpha;1hyphen;Acid Glycoprotein Concentrations

摘要

Since plasma protein binding of disopyramide (DP)mdash;a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmiasmdash;is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotalof the drug and plasma concentration of alpha;1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14ndash;1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p 0.001) with the Bmaxvalue over the range 0.09ndash;2.28 g/L. For this reason, we substituted Bmaxcalculated by the regression equation as a function of AAG and the overall mean kaand nonspecific binding parameter values for the respective individual variables of the binding model, so that Cuof each plasma sample was estimated from the corresponding data on Ctotaland plasma AAG levels. Accuracy of the retrospectively established nomogram was evaluated in a prospective manner by comparing Cudata of DP estimated by the nomogram with those actually measured by a conventional ultrafiltration method in 51 plasma samples obtained on separate occasions from 16 different cardiac patients receiving chronic DP therapy. Good agreement (r = 0.91, p 0.001) existed between Cuvalues obtained from the two different methods. Thus, the proposed nomogram appears to be a useful means to interpret Ctotalof DP under a routine TDM, particularly in patients with pathophysiological factor(s) associated with AAG concentration changes.