Population pharmacokinetics of digoxin in japanese patients: A 2-compartment pharmacokinetic model

Objective: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. Design: Retrospective analysis of clinical pharmacokinetic data. Patients and participants: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). Methods: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. Results: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 · TBW + 0.112 · CL_CR) · 0.77^SPI· 0.784^CCB, V₁ = 1.83 L/kg, V₂ = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V₁ and V₂ are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL_CR is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. Conclusions: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.