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.


METHODS
Retrospective analysis of clinical pharmacokinetic data.


METHODS
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 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, 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.
Yukawa
E
E
Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. yukawa@shunsan.phar.kyushu-u.ac.jp
Suematu
F
F
Yukawa
M
M
Minemoto
M
M
Ohdo
S
S
Higuchi
S
S
Goto
Y
Y
Aoyama
T
T
D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003201:Computers; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies; D014018:Tissue Distribution
D002316:Cardiotonic Agents; D004077:Digoxin