Abstract
This study was aimed at determining the population pharmacokinetics of digoxin and identifying factors that explain pharmacokinetic variability in elderly patients. The data of 142 elderly patients and 448 samples were collected after repetitive oral digoxin. Blood samples were drawn at various times after administration. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling program (NONMEM). A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices as well as other commonly used co-medications were explored. The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 8.9 L h−1 (43.2 %) and 420 L (65.8 %), respectively. The residual variability was 31.6 %. CL/F decreased significantly with renal function, total body weight, calcium channel blockers or spironolactone co-therapy and symptom with congestive heart failure. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM. These results provide important information for clinicians to optimize digoxin regimens in elderly patients.
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References
Bauer LA, Horn JR, Pettit H (1996) Mixed-effect modeling for detection and evaluation of drug interactions: digoxin-quinidine and digoxin-verapamil combinations. Ther Drug Monit 18:46–52
Chan AL, Wang MT, Su CY, Tsai FH (2009) Risk of digoxin intoxication caused by clarithromycin-digoxin interactions in heart failure patients: a population-based study. Eur J Clin Pharmacol 65:1237–1243
DeVore KJ, Hobbs RA (2007) Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration. Pharmacotherapy 27:472–475
EL Desoky ES, Nagaraja NV, Derendorf H (2002) Population pharmacokinetics of digoxin in Egyptian pediatric patients: impact of one data point utilization. Am J Ther 9:492–498
Elliott WJ, Ram CV (2011) Calcium channel blockers. J Clin Hypertens (Greenwich) 13:687–689
Hines LE, Murphy JE (2011) Potentially harmful drug–drug interactions in the elderly: a review. Am J Geriatr Pharmacother 9:364–377
Hornestam B, Jerling M, Karlsson MO, Held P, D.A.T. Group (2003) Intravenously administered digoxin in patients with acute atrial fibrillation: a population pharmacokinetic/pharmacodynamic analysis based on the digitalis in acute atrial fibrillation trial. Eur J Clin Pharmacol 58:747–755
Karlsson MO, Sheiner LB (1993) The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 21:735–750
Keller F, Rietbrock N (1977) Bioavailability of digoxin: some pitfalls and problems. Int J Clin Pharmacol Biopharm 15:549–556
Krusteva E (1992) Changes in the plasma levels and basic pharmacokinetic parameters of digoxin used in combination with gentamicin, amiodarone and spironolactone. Folia Med (Plovdiv) 34:24–28
Kurzawski M, Bartnicka L, Florczak M, Gornik W, Drozdzik M (2007) Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients. Pharmacol Rep 59:107–111
Miura T, Kojima R, Sugiura Y, Mizutani M, Takatsu F, Suzuki Y (2000) Effect of aging on the incidence of digoxin toxicity. Ann Pharmacother 34:427–432
Morris SA, Hatcher HF, Reddy DK (2006) Digoxin therapy for heart failure: an update. Am Fam Physician 74:613–618
Nagaraja NV, Park YJ, Jeon S, Sands CD, Derendorf H (2000) Population pharmacokinetics of digoxin in Korean patients. Int J Clin Pharmacol Ther 38:291–297
Parke J, Holford NH, Charles BG (1999) A procedure for generating bootstrap samples for the validation of nonlinear mixed-effects population models. Comput Methods Programs Biomed 59:19–29
Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9:503–512
Shlipak MG (2003) Pharmacotherapy for heart failure in patients with renal insufficiency. Ann Intern Med 138:917–924
Takara K, Kakumoto M, Tanigawara Y, Funakoshi J, Sakaeda T, Okumura K (2002) Interaction of digoxin with antihypertensive drugs via MDR1. Life Sci 70:1491–1500
Tanigawara Y, Okamura N, Hirai M, Yasuhara M, Ueda K, Kioka N, Komano T, Hori R (1992) Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 263:840–845
Wade JR, Kelman AW, Howie CA, Whiting B (1993) Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J Pharmacokinet Biopharm 21:209–222
Yukawa E, Suematu F, Yukawa M, Minemoto M, Ohdo S, Higuchi S, Goto Y, Aoyama T (2001) Population pharmacokinetics of digoxin in Japanese patients: a 2-compartment pharmacokinetic model. Clin Pharmacokinet 40:773–781
Yukawa M, Yukawa E, Suematsu F, Takiguchi T, Ikeda H, Aki H, Mimemoto M (2011a) Population pharmacokinetic investigation of digoxin in Japanese infants and young children. J Clin Pharmacol 51:857–863
Yukawa M, Yukawa E, Suematsu F, Takiguchi T, Ikeda H, Aki H, Mimemoto M (2011b) Determination of digoxin clearance in Japanese elderly patients for optimization of drug therapy: a population pharmacokinetics analysis using nonlinear mixed-effects modelling. Drugs Aging 28:831–841
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Chen, R., Zou, Sl., Wang, Ml. et al. Population pharmacokinetics of digoxin in elderly patients. Eur J Drug Metab Pharmacokinet 38, 115–121 (2013). https://doi.org/10.1007/s13318-012-0107-8
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DOI: https://doi.org/10.1007/s13318-012-0107-8