Digoxin PKs

What are the different formulas and doses of digoxin?

• parenteral

  • 0.25mg/mL, 0.05mg/mL

  • usually IV for loading doses

• oral liquid

  • 0.05mg/mL

• tablet

  • 0.0625mg, 0.125mg, 0.25mg

What is the oral bioavailability of digoxin?

• tablets → 0.7-0.75

• Elixir → 0.8

Why is there less than complete bioavailability?

P-glycoprotein (PGP) is involved in limiting digoxin absorption and enhancing elimination.

What is the interaction between PGP and digoxin?

• digoxin is a substrate for PGP

• PGP is a transmembrane protein involved in efflux of drugs from cells

  • found in liver, kidney and small intestine

• limits drug bioavailability

  • 45-80% reach portal circulation

• can differ through drug interactions that induce or limit PGP in the enterocyte

What is the interaction between digoxin and lapatinib?

• lapatinib inhibits PGP activity

• significantly increases digoxin absorption

What is the distribution of digoxin?

• volume of distribution is ~ 7L/kg (5-9 L/kg)

  • decreased in renal disease/failure

• significant binding to muscle tissue

  • little distribution into adipose tissue → so no increase in obesity

• minimal plasma protein binding

• use ideal body weight for dosing calculations

What do you see in terms of concentration changes due to distribution?

• biphasic decline in concentrations

  • initial rapid decrease due to distribution to tissues

  • slower terminal elimination phase → 6-12h

What does elimination look like for digoxin?

• mostly renally cleared, unchanged → 75%

  • filtration and tubular secretion

  • renal clearance slightly above ClCr

  • PGP involved with secretion

• non-renal clearance

  • healthy patients → 40mL/min

  • HF patients → 20mL/min

  • not due to metabolism, but PGP secretion into bile (which is decreased into HF patients)

What is the half-life of digoxin?

• long half-life 36-48 hours good renal function

• increased to 4-6 days in poor renal function

• can be dosed infrequently

  • hard for adherence, so dose once daily

• can take several weeks to reach steady state

What are pharmacokinetic drug interactions with digoxin?

• Inhibitors of PGP → increase plasma conc and toxicity (increase F and decrease Cl)

  • clarithromycin - 10x more likely to cause toxicity

  • azole antifungals

  • verapamil

  • amiodarone

  • ritonavir - longer elimination and half-life

• Inducers of PGP → lower digoxin concentration

  • phenytoin

  • rifampin - no effect in IV b/c PGP in enterocyte

  • St. Johns Wort

What are pharmacodynamic drug interactions with digoxin?

• occurs with drugs that have similar effects on inotropic or AV conduction

  • BBs, amiodarone, verapamil, diltiazem

• diuretics may increase the risk of hypokalemia resulting in digoxin toxicity

What are symptoms of digoxin toxicity?

Are concentration related and can occur when concentrations reach > 2mcg/L .

What are the digoxin dosing guidelines for CKD patients?

• standard dose was historically 0.25mg once daily

  • doses should be reduced based on renal function

  • doses should be reduced for 65y+

  • only larger patients with CrCl > 70-80mL/min should be on this dose

  • patients with reduced renal function that got > 0.125mg increase risk of toxicity 6x

• *be cautious if see older, smaller or CKD patient started on this dose

What is the therapeutic range for Afib with reduced ejection fraction?

• reduce AV nodal conduction

• rage: 0.8-2mcg/L

  • target → 1.2-1.5 mcg/L

What is the therapeutic range for heart failure?

• range: 0.5-1 mcg/L

  • target → 0.8 mcg/L

When do you want to take measured concentrations?

• samples should be collected at:

  • steady-state → 4-5 half-lives = 1-2 weeks

  • post-distribution phase → ideally a trough

• concentration over dosing interval tend not to fluctuate since half-life is longer than dosing interval

How is the loading dose given?

• need to know indication so know what to target

  • loading mainly for AF patients

• separated into 3 divided doses

  • 50% initially, 25% at 6h and 25% at 12h

How to change dosing based on digoxin’s kinetics?

• exhibits first-order kinetics

  • dose changes produce proportional changes in steady state concentrations

  • 50% reduction in dose → decreases steady state plasma conc by 50%

What is DigiFab?

• digoxin-specific antibodies that bind to digoxin and prevent the drug from binding to tissues

• each vial contains 40mg → that can bind 0.5mg digoxin