Effect of Protein Binding of Pilsicainide on the Pharmacokinetics

Abstract

To evaluate the effect of protein binding of pilsicainide on its clearance and the contribution of protein binding to optimized pilsicainide therapy, clinical laboratory and pharmacokinetic data were studied in 160 Japanese inpatients (Study 1) and 18 Japanese inpatients (Study 2). To determine the relation between protein concentration and the protein binding ratio of pilsicainide in vitro, the effect of human alpha1-acid glycoprotein (AAG) and human albumin on the binding ratio was studied. The mean ratio of serum pilsicainide concentration to dose per body weight (C/D) increased with increases in the C-reactive protein (CRP) concentration in Study 1. The AAG level increased with increases in the CRP concentration and the binding ratio increases in the AAG concentration in the Study 2. The binding ratios increased with increased AAG and albumin concentrations; the AAG concentration relative to the ratio was particularly large in vitro study. These results suggest C/D is increased in patients with high CRP levels because of binding of pilsicainide to protein, resulting decreased clearance.

Guidelines for Therapeutic Drug Monitoring of Cardiovascular Drugs Clinical Use of Blood Drug Concentration Monitoring (JCS 2015) ― Digest Version ―

“…A nomogram for calculating the initial dose of pilsicainide has been developed on the basis of a population pharmacokinetics analysis, and should be used to set the initial dose for elderly patients (Figure 8). 109,110 HTU28 How should blood drug concentration monitoring of digoxin be conducted for elderly patients?…”

Quantitation of pilsicainide in microscale samples of human biological fluids using liquid chromatography–tandem mass spectrometry

“…1, and ions at 273 → 110 and 325 → 79, respectively, were selected for subsequent quantitative analysis. The calibration curve for PLC ranged from 5 to 2000 ng/mL in human plasma, from 5 to 500 ng/mL in ultrafiltered plasma solution, and from 25 to 2000 ng/mL in urine, which were the concentration ranges of PLC in biological fluids in previous reports [7][8][9][10]. In addition, a LLOQ was obtained by simple extraction procedure using diethylether.…”

“…To the best of our knowledge, only five previous reports described the determination of PLC plasma and/or urine concentrations in humans [4,5,7,8,12]. The limit of detection (LOD) of PLC using solid-phase extraction was reported to be 50 ng/mL in 1-mL sample of both human plasma and urine [4,5], and that using the liquid-liquid extraction method was 10 ng/mL [8] and 50 ng/mL [7] in 0.5-mL sample, respectively. However, while assay methods using a solid-phase extraction column are convenient, they are not economical.…”

Plasma Protein Binding and Volume of Distribution: Determination, Prediction and Use in Early Drug Discovery

“…The inter-individual variability in imatinib clearance was significantly reduced when normalized for the plasma AAG concentration [6]. Comparable clinical findings have been presented on the anti-arrhythmic agent, pilsicainide, where patients with increased levels of C-reactive protein and AAG exhibited lower clearance and increased total plasma concentrations of pilsicainide [9].…”

“…And, of course, a value of 99.9% bound versus a value of 99% bound represents a 10-fold difference, but measuring a value of >99% with confidence is generally problematic. 9.2 Impact of Plasma Protein Binding on PK, Exposure, Safety Margins, Potency Screens and Drug-Drug Interaction representation of the partition phenomena between plasma and target as well as nontarget tissues is shown in Figure 9.1. In either case, assessing drug exposure as the area under the plasma concentration-time curve (AUC) or maximal plasma concentration (C max ), expressed in their free forms (i.e., unbound AUC, unbound C max ) can be paramount.…”