Digoxin : Clinical pharmacokinetics Pharmacokinetics (ADME) and Digoxin case study

1. Clinical pharmacokinetics: Digoxin
YOUAN BI BENIET MARIUS
Pharm D, Master student in clinical Pharmacy
University of Nairobi

2. Outlines
INTRODUCTION
Part I : Pharmacokinetics of Digoxin
Part II : Determination of Digoxin dose regimen
CONCLUSION

3. 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.)

4. Introduction

5.  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

6. 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

7. 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

8.  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

9. 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.

11. 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

12. 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

13. 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

14. 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

15. 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

16.  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

17.  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

19. Determination of Digoxin dose
regimen
Factors Units
Minimum 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 Factors
Euthyroid = 1.0 Hypothyroid = 0.7
Hyperthyroid=1.25
Concurrent Therapy Factors
None = 1.0 Quinidine = 0.6 Verapamil = 0.6
CHF Factor
None = 1.0 CHF = 0.9
More than one disease or concurrent therapy
factor: Use Factor =1.0
Facto
r

20. 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

21. 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

22. 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

23.  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)

24.  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

25. 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

26. 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/mi
Cldig= 56.11 mL/min x 0.06 =

27. 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)

28. 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

29. 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_st
ructure.GIF

30. Thank you very much
For your attention!!!