PHARMACOKINETICS CONSIDERATION IN

CARDIOVASCULAR DISEASE PATIENTS:

A PK INSIGHT ON AMIODARONE

Dalia A. HamdyBPSc, MSc, PhD, RP (ACP), MRSC

Assistant professor, Faculty of PharmacyAlexandria University, Alexandria, Egypt

Member in the Egyptian Young academy of Sciences (EYAS)

dr.daliahamdy@gmail.com

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SESSION OUTLINE Guidelines on Use Amiodarone PK parameters Amiodarone PD Dosing Considerations Drug interactions and side effects Research insights

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REFERENCES Goldshlager N, Epstein A.E., Nacarelli G. et al. Practical

Guideline for clinicians who treat patients with amiodarone. ARCH INTERN MED.2000.160:1741-1748.

Giardina E.G. and Passman R. Clinical Uses of Amiodarone. Through Uptodate June 2016.

Siddoway L.A. Amiodarone guidelines for use and monitoring. Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright© 2003 American Academy of Family Physicians.

Schillinger, D. New Treatment Guidelines in Atrial Fibrillationand updates on NOACs. University of California. Through: http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schillinger.AtrialFibrillation.pdf

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CardioAlex-June-2016-DH2014 AHA/ACC/HRS Guideline for

the Management of Patients with Atrial Fibrillation

1. Initial clinical evaluation2. Preventing thromboembolism3. Rate control4. Rhythm control

Published in: Circulation. 2014; 129

http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schillinger.AtrialFibrillation.pdf

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http://www.ucsfcme.com/2016/MDM16M02/slides/15.Schillinger.AtrialFibrillation.pdf

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Should be used only if risks/side effects are considered and other agents are not suitable

Some knowledge of its PK, PD and electropharmacologic characteristics is essential for initiating therapy and dose adjustment

AMIODARONE(AM) IS

an iodinated class III antiarrhythmic benzofuran derivative drug.

a potassium channel blocker

a weak sodium channel blocker

non competitive α- and β- adrenergic receptors inhibitor

vagolytic and calcium-channel blocker.

2-butylbenzofuran-3-yl)- [4-(2-diethylaminoethoxy)- 3,5-diiodo-phenyl]- methanone (as the hydrochloride salt)

Podrid PJ. Ann Intern Med 1995;122:689—700. Connolly, S.J., 1999. Circulation 100, 2025–2034

AMIODARONE(AM) decreases heart rate prolongs PR and QTc intervals increases the duration of QRS complex in

electrocardiograms (ECG).

Human ECG

Mason JW et al. Circ Res. 1984 Sep;55(3):278-85

AMIODARONE(AM)

Shows extensive metabolism in hepatic and extrahepatic tissues

Grapefruit juice?!

Major metabolite is the N- desethylamiodarone (DEA), which possesses some of AM pharmacological and toxicological properties.

DEA has longer t1/2

DEA

Shayeganpour et al , Drug Metab. Dispos. 34:43-50 (2006).

AM highly lipophilic nature

peculiar PK parameters

large volume of distribution (Vd)~ 66 L/kg

long terminal half life (t1/2) 60 and 142 days

highly bound to plasma proteins (>95%)

erratic absorption (30%-70%) leading to low and unpredictable oral bioavailability . Effect of food?!

little correlation between the AM plasma concentration and drug efficacy or toxicity !!!!! Rats data?!

Wyss PA et al . J. Pharmacol. Exp. Ther. 254:502-507 (1990) & uptodate 2016

What

should we

expect?

An inhibitor to CYP3A4 enzyme Drug interactions?!

digoxin and warfarin

The dose of digoxin empirically reduced by 50% at the time of amiodarone initiation or the need for digoxin reevaluated altogether.

Digoxin levels should be measured within three days after amiodarone initiation.

A reduction in warfarin dose to prevent an elevation in the INR and potential bleeding complications. The INR level should be checked more frequently in the one to two weeks after amiodarone is initiated

Wyss PA et al . J. Pharmacol. Exp. Ther. 254:502-507 (1990) & uptodate 2016

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CardioAlex-June-2016-DH Shifting from IV to oral dose:The bioavailability 30-70%, Cmax ~5h Patients who have been on IV therapy for more than two weeks can be started on maintenance oral

amiodarone at a dose of 200 to 400 mg/day. Patients who have been on IV therapy for one to two weeks can be started on an intermediate

amiodarone dose of 400 to 800 mg/day. This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day.

Patients who have been on IV therapy for one week or less should probably receive the usual oral amiodarone loading dose of 400 to 1200 mg/day (typically in two divided doses). This should be continued until a total loading dose of 10 grams has been received, then the dose should be reduced to the usual maintenance dose of 200 to 400 mg/day.

Both oral and IV therapy can be given concurrently for a few days if there is a concern about gastrointestinal tract function.

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CardioAlex-June-2016-DHAMIODARONE DOSING IN SPECIAL POPULATIONLiver and Kidney Impairment Metabolized in the liver. (DEA, active

metabolite) Thus: Dose reduction is probably necessary in patients with significant hepatic disease.

In comparison, there is minimal elimination of both amiodarone and desethylamiodarone by the kidneys Why?

Dialysis?Thus no dose adjustment of amiodarone in renal disease or dialysis.

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CardioAlex-June-2016-DHAMIODARONE DOSING IN SPECIAL POPULATION

Pregnant and Nursing MothersAmiodarone complications during pregnancy include:●Hypothyroidism or hyperthyroidism in the mother or fetus because of the iodine in amiodarone●Fetal bradycardia●Fetal QT interval prolongation●Premature labor●Low birth weight

Amiodarone was found in fetal tissue and breast milk.

For these reasons, 1. Use of amiodarone in pregnancy should be reserved for maternal and

fetal arrhythmias not responding to agents with known safety. 2. Concomitant beta blocker therapy should be avoided. 3. Breast feeding is not recommended when the mother is taking

amiodarone

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CardioAlex-June-2016-DHAMIODARONE DOSING IN SPECIAL POPULATIONChildren the overall safety and efficacy of amiodarone

in children has not been fully established.

Optimal dosing is less well established in children

For oral therapy, dosing is based upon body weight or, in children less than one year of age, upon body surface area.

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CardioAlex-June-2016-DHAMIODARONE DOSING IN SPECIAL POPULATIONChildren The loading dose, which can be given in one or

two divided doses per day, is 10 to 15 mg/kg per day or 600 to 800 mg/1.73 m2 per day for 4 to 14 days or until adequate control of the arrhythmia is attained

The dose should then be reduced to 5 mg/kg per day or 200 to 400 mg/1.73 m2 per day once daily for several weeks. If the arrhythmia does not recur, the lowest effective dose should be used for maintenance. The usual minimal dose is 2.5 mg/kg per day.

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CardioAlex-June-2016-DH For IV therapy in critically ill children with

tachyarrhythmias who have not responded to standard therapy, two dosing regimens have been reported:

1. A loading dose of 5 mg/kg divided into five 1 mg/kg aliquots, with each aliquot given over five to 10 minutes.

If necessary, additional 1 to 5 mg/kg doses can be given 30 minutes later on a similar schedule. The average loading dose is 6.3 mg/kg.

Among those requiring a continuous infusion, the amiodarone infusion rate is typically 7 to 10 mcg/kg per min (10 to 15 mg/kg per day).

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CardioAlex-June-2016-DH For IV therapy in critically ill children with

tachyarrhythmias who have not responded to standard therapy, two dosing regimens have been reported:

2. A loading dose of 5 mg/kg infused over one hour, then a maintenance infusion rate starting at 5 mcg/kg per min.

The mean effective maintenance dose is 9.5 mcg/kg per min (13.7 mg/kg per day).

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RESEARCH PK INSIGHTS

A study in 2008 on rats

Journal of Cardiovascular Pharmacology

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EFFECT OF HL ON AM HEART AND PLASMA CONCENTRATIONS IN RAT

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EFFECT OF HL ON EKG

Volts

0 0.04 0.08 0.12 0.16 0.2 0.24 sec

QT

QT

RR

RR

12h after last dose

EFFECT OF HL ON EKG

QTC calculated using Fridericia's formula (QTc=QT/ (RR) 1/3 )

Bazett’s formula (QTc=QT/RR1/2)

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AM CONCENTRATION EFFECT RELATIONSHIP IN RAT

Hamdy DA and Brocks DR.J Cardiovasc. Pharmacol. 2009. 53(1):

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