Digoxin Pharmacokinetic Dosing Information
Usage: Congestive heart failure with reduced ejection fraction
(HFrEF) class III and IV and atrial fibrillation/flutter.
Inhibits sodium-potassium ATPase pump causing calcium accumulation in myoctes
increasing contractile force. Inhibits AV nodal conduction and prolongation of
the effective refractory.
Onset of Action:
1-4 hours IV, 2-6 hours oral
Bioavailability (F): IV = 1, Tablet = 0.7, Elixir = 0.8,
Soft gelatin capsule = 1, Do not give IM as it is painful. Absorption is not
affected by CHF
Salt (S): Injection ; capsules, tablets, and elixir = 1
Molecular Weight:
~ 500 Daltons
Route of Administration:
IV, oral
Absorption:
Upper intestinal absorption, no first-pass effect. Decreased absorption
caused by antacids (separate doses by 2 hours), cholestyramine
(separate doses by 8 hours), kaolin-pectin (separate by 2 doses hours), and high
fiber meal. Reduced absorption in malabsorption syndromes, diarrhea, and
abdominal radiation.
Distribution: lean body weight,
skeletal muscle, does not distribute to fat
Peak concentrations:
oral ~
hours, IV immediate
Protein binding: 10%
Metabolism:
Excretion:
Renally filtered with tubular secretion, renal excretion linearly
correlated with creatinine clearance, fecal excretion with enterohepatic
cycling, 30-50% nonrenal, 50-70% renal
Vd(L/kg): Numerous equations have been derived to calculate
volume of distribution (Jusko, Paulson and Welling, Reuning, Sheiner, Williams).
Similar results are obtained with Jusko, Paulson and Reuning's equations. As
loading doses are calculated using Vd Paulson's or Jusko's equation
is recommended as they are more conservative with high creatinine clearances
values. A graphic comparison is displayed below.
Vd ranges from ~ 7.3 L/kg of lean body weight to 4.8 L/kg when creatinine
clearance is < 10 ml/min. The Volume of distribution is decreased with
renal dysfunction.
Reuining Equation: Vd(L) = [3.8 L/kg * Lean Body Weight(kg) + 3.1 * (Creatinine Clearance in ml/min)]
* Multiplier
Jusko Equation: Vd(L) = [226
L/1.73m2 + ((298 L/1.73m2 * Clcr ml/min/1.73m2) / (29.1 ml/min/1.73m2 + Clcr ml/min/1.73m2))
]*(Patient Surface Area/1.73) * Multiplier
Paulson
and Welling Equation: Vd(L) = (4.5 +0.028 * Clcr ml/min/1.73m2) * Lean Body Weight
(kg) * Multiplier
Quinidine (multiplier) = 0.7, rapid rise in level, hold one digoxin dose after
quinidine is started
Hypothyroid
(multiplier) = 0.7
Hyperthyroid (multiplier)
= 1.3
Cl (L/hour): Digoxin has both a metabolic and renal component to
clearance. Several equation have been derived to calculate clearance in
patient with and without CHF. The calculated clearance values are lower in
Sheiner's equations and they are recommended as
the maintenance dose is determined by clearance and a more conservative dose
will be calculated. See graphic below.
Sheiner Equation: Non CHF Patient: Clearance (L/hour) = [(0.8 ml/kg/min *Lean Body Weight(kg) + Creatinine Clearance(ml/min))* 60/1000]
* Multiplication Factor
Sheiner Equation: CHF Patient:
Clearance (L/hour) = [(0.33 ml/kg/min *Lean Body Weight(kg) + 0.9*
Creatinine Clearance(ml/min)) )*60/1000] * Multiplication Factor
Koup
Non CHF(L/hour): [(1.303 * Clcr ml/min +41 ml/min)*60/1000 ] * Multiplication
Factor
Koup CHF(L/hour):
[(1.303 * Clcr ml/min + 20 ml/min)*60/1000] * Multiplication Factor
Multiplication Factors for Drug
and Disease State Interactions:
Amiodarone = 0.5
Canaglifozin = 0.8
Carvedilol = 0.75
Dronedarone = 0.5
Ketoconazole
& Itraconazole = 0.5
Propafenone = 0.75
Quinidine =
0.5
Ranolazine = 0.67
Verapamil = 0.75
Hypothyroid = 0.7
Hyperthyroid = 1.3
Low and high flux hemodialysis:
Due to digoxin's very large volume of distribution little is removed
K (1/hours): volume of distribution and clearance dependent
Half-life (hours): Half-life is dependent of volume of distribution and clearance.
Normal renal function 2 days, ESRD 4-6 days
Dosage Forms:
Injection, tablets, capsules, and elixir
Usual Interval:
Adults once daily usually in the morning. Children divided dose twice daily.
Divided doses are used if a loading dose is
administered (50%, 25%, and 25% of the total dose is administered 6 hours apart).
Loading doses may be given IV or orally.
Usual Loading and Maintenance Dose: A loading dose is not recommended in CHF
but is commonly used in atrial fibrillation/flutter.
Age
Loading Dose
Intravenous (mcg/kg):
Divided in 3 doses of 50, 25%, and 25% of
the total dose every 6 hours Maintenance Dose
Intravenous
(mcg/kg/day)
Premature Neonates less than 4 weeks
15-25
4-6 divided into 2 dose
Full Term Neonates
20-30
5-8 divided into 2 doses
1 year < 2 years
30-50
9-15 divided into 2 doses
Children 2 - 5 years
25-35
6-9 divided into 2 doses
Children 5 - 10 years
15-30
4-8 divided into 2 dose
Children > 10 years
8-12
2-3
Adults years
10-15 mcg/kg
62.5-250 per day
Initiation of therapy: .
Therapeutic Levels:
Narrow therapeutic window
CHF: 0.5-0.8 mcg/L
Atrial
Fibrillation: 0.5-2 mcg/L, higher levels may be required to control
ventricular rate
Serum Sampling Times and Recommended Monitoring:
Trough levels are recommended for routine monitoring daily or every other
day. Due to the long-half life steady state achievement is delayed and serum
levels will slowly rise without a loading dose. Post-dose levels are recommended no sooner
than 6 hours for an IV dose and
12 hours for an oral dose. In dialysis patients drawn
pre-dialysis sample or wait at least 6 hours post-dialysis for re-distribution to
be complete. Note: a wide variation in the minimal time post-dose for sampling
may be found in texts a conservative approach is recommended. Renal
status and serum electrolytes (Potassium, Magnesium, Calcium) should be monitored prior to and
periodically during therapy.
Pharmacokinetic Model: Digoxin displays two-compartment
model kinetics, with high serum levels during the distribution phase
as the central compartment is 1/10 the size of the tissue
compartment. The half-life of
distribution is ~ 35 minutes. The heart is in the peripheral tissue compartment and the
pharmacological effect is seen in a couple of hours. Tissue and central
compartment levels are at equilibrium in 4-6 hours. A linear one-compartment
open model is adequate for dosage predictions when levels are drawn after an
oral dose when absorption and distribution are complete. Blood levels > =12
hours after a dose are recommended to ensure absorption and distribution are
complete When levels are at steady state doses can be adjusted proportional to the desired concentration. Equations used to calculated Vd and Clearance
note above
show a large degree of variation. Conservative dosing is recommended with serum
level monitoring to individualize the patient's dose.
Caution: Avoid in
hypertrophic cardiomyopathy, sinus node disease, 2nd & 3rd AV block, cardiac
amyloidosis, and Wolff-Parkinson-Whit syndrome.
Side Effects (Non-concentration-dependent):
Toxicity: Decreased heart rate, EKG changes, arrhythmias,
nausea, vomiting diarrhea, visual color changes, headache, fatigue, malaise,
neurologic pain, and confusion. Hypokalemia increases the cardiac effects and risk
of digoxin toxicity. Digoxin is contraindicated in patients with significant sinus or
VA block unless permanent pacemaker in place.
Common Drug interactions:
Decrease clearance: See clearance above
Increased clearance:
See clearance above
Disease state or physiologic condition interactions:
Decrease
clearance: CHF, Hypothyroidism
Increase clearance: Hyperthyroidism
Dosage Calculations:
BMI: Actual Body Weight
/ (Height in meters)^2
Body Weight Calculations:
Ideal Body Weight
IBW(kg) (Devine Formula)
Adult Males (18 years and older) in kg: 50 kg + 2.3*(Height in inches greater
than 60 inches)
IBW(kg) (Devine Formula) Adult Female (18 years and older): 45.5 + 2.3*(Height in
inches greater than 60 inches)
Fat Free Mass (Janmahasatian Formula):
FFM(kg) Adult Males = 9270 * Actual Body Weight(kg) / (668 + (216* BMI))
FFM(kg) Adult Females = 9270 * Actual Body Weight(kg) / (8780 / (244*(BMI))
Body Surface Area in Meters Squared = ((Weight in kg)^0.425)*((Height
in centimeters)^0.725)*(71.84/10000)
Dosing Weight(kg) =
Lean Body Weight
Creatinine Clearance (ml/min)
Males: (140-age(years))*(IBW) /(serum creatinine(mg/dl)*72)
Females: 0.85 * Creatinine Clearance
for male
Clearance(L/hr) = see Cl above
Vd(L) = see Vd above
K(1/hours) = Clearance
/ Vd
Loading Dose(mcg) = Cp desired(mcg/L) * Vd(L)
/ (Salt*Fraction), usually divided into 3 doses of 50%, 25%, and
25% of the total dose given every 6-h hours.
Maintenance Dose(mcg) =
Cpaverage(mcg/L) * Tau(Hours) * Clearance(L/hr) / (Fraction*Salt)
Cpssaverage(mcg/L)
= Salt * Fraction * Dose(mcg) / (Clearance(L/hr) * Tau)
Cpssmaximum(mcg/L) =
Salt * Fraction *
Dose(mcg) / (Vd(L) * (1-exp(-K*Tau)))
Cpssminimum(mcg/L) =
Cpmaximum(mcg/L) * exp(-K*Tau)
Time to Level from start of dosing (days) =
- Ln(1
- (level / Css average)) / (K(1/hours)*24)
Time to
Fraction of Steady State (days) = Ln (1- (Fraction of Steady State
to Achieve)) / (K(1/hours) * 24)
Time(days) from Known
Level to Fraction of Steady State to Achieve =
Ln[ (1-(Fraction of Steady State to Achieve)) / ( 1-
(Current Level / Steady State Level))] / (K*24)
Cp(mcg/L)
= (S*F*Dose(mcg)* (1-Exp(-KNTau))*Exp(-KT))
/ (Vd(L)*(1*Exp(-KTau))), where N equals number of doses given
Digoxin Dosing Calculator Using Population
Dosing or Levels Under Steady State or Non-Steady State Conditions,
Download
The Solver Add-in must be available for
the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in
Click Go, Check Solver Add-in, and select OK.
Digoxin Excel downloadable Bayesian Digoxin dosing Calculator, open compartment open model, for steady state or Non-Steady State dosing using the method of superposition.
This is a more versatile tool than the one above. The tool creates a data file of data fittings that maybe used to perform MUEs. The Solver Add-in must be available for the file to run. In Excel do the following: Click File, Click Options, Click Add-ins, Manage Excel Add-in Click Go, Check Solver Add-in, and select OK.
References:
Bauman JL, DiDomenico RJ, Viana M, Fitch M. A method of determining the dose of digoxin for heart failure in the modern era. Arch Intern Med. 2006 Dec 11-25;166(22):2539-45. doi: 10.1001/archinte.166.22.2539. Erratum in: Arch Intern Med. 2007 Mar 12;167(5):496. Dosage error in article text. PMID: 17159022.
DiDomenico RJ, Bress AP, Na-Thalang K, Tsao YY, Groo VL, Deyo KL, Patel SR, Bishop JR, Bauman JL. Use of a simplified nomogram to individualize digoxin dosing versus standard dosing practices in patients with heart failure. Pharmacotherapy. 2014 Nov;34(11):1121-31. doi: 10.1002/phar.1480. Epub 2014 Aug 28. PMID: 25164709; PMCID: PMC4227958.
Jusko WJ, Szefler SJ, Goldfarb AL. Pharmacokinetic design of digoxin dosage regimens in relation to renal function. J Clin Pharmacol. 1974 Oct;14(10):525-35. doi: 10.1002/j.1552-4604.1974.tb01367.x. PMID: 4430731.
Konishi H, Shimizu S, Chiba M, Minouchi T, Koida M, Yamaji A. Predictive performance of serum digoxin concentration in patients with congestive heart failure by a hyperbolic model based on creatinine clearance. J Clin Pharm Ther. 2002 Aug;27(4):257-65. doi: 10.1046/j.1365-2710.2002.00418.x. PMID: 12174027.
Koup JR, Greenblatt DJ, Jusko WJ, Smith TW, Koch-Weser J. Pharmacokinetics of digoxin in normal subjects after intravenous bolus and infusion doses. J Pharmacokinet Biopharm. 1975 Jun;3(3):181-92. doi: 10.1007/BF01067907. PMID: 1159622.
Marcus FI. Pharmacokinetic interactions between digoxin and other drugs. J Am Coll Cardiol. 1985 May;5(5 Suppl A):82A-90A. doi: 10.1016/s0735-1097(85)80466-6. PMID: 2985676.
Sheiner LB, Beal SL. Bayesian individualization of pharmacokinetics: simple implementation and comparison with non-Bayesian methods. J Pharm Sci. 1982 Dec;71(12):1344-8. doi: 10.1002/jps.2600711209. PMID: 7153881.
Sheiner LB, Rosenberg B, Marathe VV. Estimation of population characteristics of pharmacokinetic parameters from routine clinical data. J Pharmacokinet Biopharm. 1977 Oct;5(5):445-79. doi: 10.1007/BF01061728. PMID: 925881.
Tsujimoto G, Sasaki T, Ishizaki T, Suganuma T, Hirayama H. Re-examination of digoxin dosage regimen: comparison of the proposed nomograms or formulae in elderly patients. Br J Clin Pharmacol. 1982 Apr;13(4):493-500. doi: 10.1111/j.1365-2125.1982.tb01410.x. PMID: 7066164; PMCID: PMC1402043.
Williams PJ, Lane JR, Capparelli EV, Kim YH, Coleman R. Direct comparison of three methods for predicting digoxin concentrations. Pharmacotherapy. 1996 Nov-Dec;16(6):1085-92. PMID: 8947982.
This site is developed and maintained for educational use. No warranties are expressed or implied.
If you have questions or suggestions concerning the dosing tools please contact Marshall Pierce PharmD.
Please help support the development and maintenance of this educational site. Donate at PayPal
© 2020 Marshall Pierce