A TWO-COMPARTMENT PHARMACOKINETICS BASED DECISION RULE FOR PREDICTION OF INDIVIDUALIZED AMIODARONE MAINTENANCE DOSES USING RESPONSE TO A STANDARD LOADING DOSE

Abstract

Personalized Medicine is not a one-dose-fits-all undertaking. Adjusting amiodarone (AM) dose is challenging because a 55 d half-life means time to steady state is > 6 mo. Linear personal pharmacokinetics (PK), means that AM maintenance dose will be proportional to accumulated AM concentration at the first point that good clinical effect is observed. At that point, just enough drug to produce efficacy is present for the first time, a time that could be labelled as the Goldilocks Moment (GM). Since measuring AM concentration is not always available, we studied if AM dosing history prior to GM (e.g. first sinus rhythm) could predict optimum individual dosing. A decision rule was developed using population-PK information from a 77 pt study (Clin Pharmacol Ther 2000;67:642-52). Because the population data followed a 2-compartment model for AM PK, this gave a superior prediction of best maintenance dose compared to a simpler 1-compartment (whole body) model. Initiating amiodarone with a standard loading dose of 400 mg TID for 2 wk, 400 mg BID for 2 wk, 400 mg OD for 2 wk and then a 200 mg/d maintenance allows the compilation of a table that predicts individualized maintenance dose based on number of day required to reach GM. The ability of a PK rule-based prediction of optimal dosing to achieve therapeutic steady-state AM concentration (range of 0.5 - 1.5 mg/L) was compared to standard dosing using fixed 200 mg/d maintenance. The ideal result (i.e. dose-rule-determined-steady-state concentration = target) was contained within 95% confidence interval for the predictive dosing-rule, but not for fixed dose (Figure 1 showing black line for ideal relationship is contained in confidence interval for doses calculated using time to “Initial-Goldilocks” observation, e.g. first occurrence of sustained sinus rhythm). The fixed loading dose produces the amiodarone, desethylamiodarone (DEA) and effect-site DEA concentrations over time seen in Figure 2. The proposed decision rule provides for a simple initial dose estimation in individual patients with atrial fibrillation, without requiring precise knowledge of their PK profile. Replacing an arbitrary, standard maintenance-dosing regimen with an individually calculated maintenance dose moves closer to Personalized Medicine for amiodarone patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)