Clinical pharmacokinetics: Digoxin

YOUAN BI BENIET MARIUS

Pharm D, Master student in clinical Pharmacy

University of Nairobi

Outlines

INTRODUCTION

Part I : Pharmacokinetics of Digoxin

Part II : Determination of Digoxin dose regimen

CONCLUSION

Introduction

Digoxin: primary cardiac glycoside in clinical use

Main Clinical Indications:

Atrial Fibrillation

Therapeutic level of 0.5-1 mcg/L

Heart Failure

Increases cardiac output by (+) inotropic actions

Rate control by (-) chronotropic effects Therapeutic level of 0.5-2 mcg/L

Digoxin :naturally occurring drug (Digitalis spp.)

Introduction

Pediatric Injection – 100 mcg per 1 ml (1 ml ampule)

Tablets 62.5 ; 125 mcg ( yellow,) or 250 mcg ( white,)

Capsules (Lanoxicaps) – 50 mcg ( red,) , 100 mcg ( yellow,), and 200 mcg ( green,)

Pediatric Elixir – 50 mcg per 1 ml (10% alcohol)

Injection 250 mcg per 1 ml (1 ml ampule)

Introduction

Introduction

narrow therapeutic index

Most prominent features of the clinical use of digoxin

An endpoint of therapy which is difficult to

define and measure due to great variability in

serum digoxin concentrations in patients given

the same dose

Introduction

This condition has Led to the development of

monograms and equations designed to estimate

optimal digoxin dosage.

Equations Based on the most important

pharmacokinetic parameters

F & Vd loading dose (LD)

CL the maintenance dose & rate

(t½) time to steady state & the dosing interval

understanding the clinical pharmacokinetics of

Digoxin will help us to improve in the dosage

regimens design and ‘‘therapeutics drugs

monitoring’’.

Introduction

Incorrect dosage of digoxin occurs frequently

and is due in most cases to relative over- or

under dosage

Objective

To Describe the profile of digoxin concentration in

the body which depend of his absorption,

distribution, metabolism and elimination and to

give a digoxin dose regimen process through a

case study.

I-Pharmacokinetics of Digoxin

Absorption

80 % absorbed after oral administration of tablets

75-80 % absorbed after administration of elixir

75-80 % absorbed from liquid filled capsule

80 % absorbed IM but not recommended

I-Pharmacokinetics of Digoxin

Absorption: factors affecting bioavailability

40 % degraded by intestinal bacteria 1 in 10

FOOD: high fiber product

DRUGS: Antacids, cholestyramine, kaolin, sulfasalazine, metoclopramide and neomycin reduce bioavailability

1. serum digoxin concentration–time curve follows a two-compartment model

2. 8-12 hours tissues distribution phase.

DIGOXIN LEVELS after IV Dose

Distribution

I-Pharmacokinetics of Digoxin

DIGOXIN LEVELS after IV Dose

Distribution

3. During the distribution phase, digoxin in the serum is not in equilibrium with digoxin in the tissues

I-Pharmacokinetics of Digoxin

Distribution

Bound tightly to muscles tissues Vd Correlated well

with lean body Tissues , very large distribution volume

Vd = 7.3 L/kg x IBW , approximately 475 to 500L

25 % protein bound

Crosses the placenta and enter the breast milk –

Pregnancy category C

I-Pharmacokinetics of Digoxin

Less than 10 % undergoes hepatic metabolism

not dependent of the cytochrome P450 system

and it is not know to induce or inhibit it

metabolism via stepwise cleavage of the sugar moieties and lactone ring reduction

Metabolism

I-Pharmacokinetics of Digoxin

Digoxin Elimination follows first-order kinetics

50-70% is excreted almost entirely unchanged by the kidney

Affected by some drugs interactions & diseases conditions

Half life 36-48 hours and increase in case of renal impairment

Elimination

I-Pharmacokinetics of Digoxin

Determination of Digoxin dose regimen

Factors UnitsMinimum effective concentration, 0.5 ng/mL

Maximum safe concentration 2.0 (CHF*) >2.0 (atrial arrhythmias)

ng/mL

Bioavailability 0.7 (tablets) 0.80 (elixir) 0.95 (capsule)

Disease FactorsEuthyroid = 1.0 Hypothyroid = 0.7 Hyperthyroid=1.25

Concurrent Therapy FactorsNone = 1.0 Quinidine = 0.6 Verapamil = 0.6

CHF FactorNone = 1.0 CHF = 0.9 More than one disease or concurrent therapy factor: Use Factor =1.0

Factor

Digoxin Equation

w/ renal dysfunction: Vd = (3.12 x CLcr* + 3.84) CT* x IBW

IBW = 50 (or 45.5) + 2.3 x (inches over 60)

CLdig (L/h)= (0.06 x CHF x CLcr + 0.02) x Factor x IBW

CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females)

Vd = 7.3 L/kg x IBW

Determination of Digoxin dose regimen

Digoxin Case

WB is a 75-year-old female with PMH including atrial

fibrillation, type II diabetes, hypertension, and renal

insufficiency. She is 5’4’’tall and weighs 75 kg. Her SCr

is 3.4 mg/dL. Calculate a loading and maintenance dose

for Lanoxin tablets for Mrs. B.

– Target Cpss = 1.0 mcg/L for atrial fibrillation

II- Determination of Digoxin dose regimen

CALCULATE LOADING DOSE (1/3)

LD = Vd x Cp/F 

where Vd = Volume of distribution (liters)Cp = target serum level (mcg/l)F = bioavailability factor

• IV push = 1

• capsules= 0.95

• elixir = 0.8

• tablets = 0.75

WB w/ Renal Dysfunction

Vd = (3.12 x CLcr + 3.84) CT x IBW

CLcr = ((140 - Age) x IBW) / (72 x SCr) ( x 0.85 for females)

CT = Concurrent Therapy Factors =1

IBW = 45.5 kg + 2.3 (4 in) = 54.7 kg

= ((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min

Vd = (3.8 L/kg x 54.7 kg) + 3.1 (12.35 mL/min) = 246.15 L

CALCULATE LOADING DOSE (2/3)

WB w/ Atrial fibrillation

Target Cpss = 1.0 mcg/L

Lanoxin tablets Dose regimen for

F = bioavailability factor = 0.75

LD = Vd x Cp/F 

LD = (246.15 L x 1 mcg) / (0.7) = 351.64 mcg

CALCULATE LOADING DOSE (3/3)

Use 375 mcg tabs once

CALCULATE MAINTENANCE DOSE (1/3)

MD = (Cldig x Cp x tau) / F

where Cldig = Digoxin clearance (l/hr)

Cp = target serum level (mcg/l)

tau = dosing interval (hours)

F = bioavailability factor

CALCULATE OF MAINTENANCE DOSE (2/3)

Cldig = Digoxin clearance

((140-75) x 54.7 kg (.85)) / (3.4 x 72) = 12.35 mL/min CLcr =

IBW = 54.7 kg

3.37 L/hr

Cldig=

Cldig = (0.8 ml/min/kg x IBW) + CLcr

(0.8 mL/min/kg x 54.7 kg) + 12.35 mL/min = 56.11 mL/min

Cldig= 56.11 mL/min x 0.06 =

Cldig 3.37 L/hr

Target Cpss = 1.0 mcg/L

tau = 24hours

F tablets = 0.7

=

MD = (3.37 L/h x 1 mcg/L x 24h ) / 0.7 =115.54 mcg

Then Use 125 mcg tabs qday

CALCULATE OF MAINTENANCE DOSE (3/3)

Conclusion

Digoxin is a very cheap and effective drug and

therefore useful clinically in heart failure

equations designed to estimate optimal digoxin

dosage are very useful to avoid under or over dosage

NTI : understanding of the clinical pharmacokinetics useful to prevent digoxin toxicity

References

20th edition top 200 pharmacy drug cards. SFI Medical Publishing. 2004.

Tharp, R. (2006) Digoxin Dosing. : http://www.rxkinetics.com/dig.html

Medicinal Plants. (2006) Digoxin Image. Updated Aug 12, 2005. :http://www.science.siu.edu/plant biology/PLB117/Nickrent.Lecs/Medicine.html

Digoxin Structure. Retrieved March 8, 2006 from world wide web: http://medpharm.chunma.ac.kr/Aldja/CVS/cardiac_glycoside/img/digoxin_structure.GIF

Thank you very much

For your attention!!!