THERAPEUTIC DRUG MONITORING FORANTIEPILEPTIC DRUGS & LITHIUM

SAMARINA MUSAAD

samarina.musaad@Labtests.co.nzsamarinam@adhb.govt.nz

Overview…

Introduction: Old versus newA few groups of AEDs

Why TDM?Common themes & examplesPitfalls in AED TDMOCPs & pregnancyAssaysThe role of the pathology laboratory in monitoring AEDsScenariosSummary & “golden rules”Lithium

Resources: Lexi-interact (uptodate), ILAE guidelines (provided), BPAC statementwww.bpac.org.nz “Prescribing issues associated with anticonvulsant medication forepilepsy”.

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Introduction

New versus old

Newer AEDs (e.g. vigabatrin, lamotrigine, topiramate) have wider therapeutic indices,fewer side effects, and simpler kinetics compared to older drugs(e.g. phenytoin, carbamazepine, valproate)

Group & example Mechanism of action Comment

Barbiturates-phenobarbital CNS suppressant Its sedative effect limits its use

Benzodiazepines*-clonazepam CNS suppressant Long term use is discouragedbecause they cause tolerance anddependency

Carboxamides-carbamazepine,oxcarbazine

Inactivates Na channels Carbamazepine’s activemetabolite (epoxide) is equallypotent and is responsible for 10-40% activityOxcarbazine is better toleratedthan carbamazepine

Fatty acids-Na valproate,vigabatrin

Multiple mechanisms (selectivelyinactivates Na channels, ↑brain GABA,against Ca currents)

Assays for vigabatrin are notreadily available

Hydantoins-phenytoin,fosphenytoin

Inactivates Na channels TDM is most usefulFosphenytoin is an injectableprodrug for phenytoin

Triazines-lamotrigine Not fully understood# Newer drug

Introduction A few groups…

• *Diazepam is used for status epiplepticus, rarely paraldehyde• # probably selectively inactivates Na channels

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ILAE guidelines Patsolas et al2008

Why TDM?

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Why TDM?

Common reasons to check blood levels

I. Assessing complianceII. There is a change in pharmacokinetics e.g. pregnancy, adding another

drug, uraemia, changing a drug formulationIII. Clinical suspicion of toxicityIV. Need to re-adjust the dose

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Louis 2009

Why TDM?

& establish an individual’stherapeutic baseline

or an unexpected changein response

or dose increases

Common themes to remember:

Peak levels for assessing toxicity & trough levels for assessing compliance

Start monitoring after steady state is expected to have been achieved

Most are metabolised by the liver (with some exceptions e.g. exceptions vigabatrin)

Doses need adjustment in hepatic impairment and severe renal impairment (the latter decreasesprotein binding)

T1/2 changes with concomitant use of a CYP inducer or inhibitor

Consider organ specific function tests/monitoring based on potential side effects

Many are highly protein bound in plasma so drugs often compete for protein binding e.g.valproate displaces phenytoin increasing its free fraction

High loading doses can cause paradoxical intoxication in which seizures worsen

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Drug Absorption/elimination and

metabolism

Side effects Symptoms oftoxicity

Specialconsiderations

Carbamazepine(Tegretol)

Slow & erratic/hepatic

Gastrointestinal(vomiting, diarrhoea),skin (rash),

neurological,neutropenia, &hyponatraemia

Visual (blurred vision,

diplopia, nystagmus) &neurological(drowsiness, ataxia)

-Potent CYP inducer-Active metabolite canaccumulate causingtoxicity even in thepresence of“therapeutic” levels ofthe parent drug-Monitor every 2 monthsuntil levels are stable-Decreases FT4 levels(unknown clinicalsignificance)- Causes SIADH #

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Examples…

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Patsalos et al 2008

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Drug Absorption/elimination

andmetabolism

Side effects Symptoms oftoxicity

Specialconsideration

s

Phenytoin(dilantin)Fosphenytoin is aninjectable solubleprodrug

Slow andoftenincomplete/Hepaticglucuronidation; 25%unchanged inurine

Cosmetic(gingivalhyperplasia,hirsutism), folatedeficiency#, &low BMD*

Visual (double

vision) &neurological(confusion, ataxia)

-Potent inducer-Clearancefollows 1st orderkinetics before itreverts to 0order kinetics-Fosphenytoin(cerebyx) to betested at least 2hrs after IV and4 hrs after IMadministration

• *Reduction in bone mineral density is partly due to induction of CYP 450 causing ↑ Vit D catabolism• #By inhibiting intestinal absorption

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Silverman et al 1988

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Drug Absorption/elimination

andmetabolism

Side effects Symptoms oftoxicity

Specialconsiderations

Na Valproate(epilim, valproicacid)

Rapid andnear completeabsorption/hepatic

Gastrointestinal(nausea, vomiting,diarrhoea),neurological(headache,dizziness), rash, &depression

Hepatictoxicity &acute toxicencephalopathy

-Broadspectruminhibitor ofCYP and UGT-glucuronidation-Can bemeasured atleast 8 hrs postdose to trough

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Drug Absorption/elimination

andmetabolism

Side effects Symptoms oftoxicity

Specialconsideration

s

Phenobarbital Slow butcomplete/hepatic; 25%excretedrenallyunchanged

Sedation,tolerance

Confusion,delirium,somnolence

-Potentinducer

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Drug Absorption/elimination

andmetabolism

Side effects Symptoms oftoxicity

Specialconsideration

s

clonazepam Wellabsorbed/Hepatic andrenallyexcreted

CNSsuppression,paradoxicaleffects(anxiety,sweating),amnesia

Coma, ataxia,somnolence

-long acting

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Drug Absorption/elimination

andmetabolism

Side effects Symptoms oftoxicity

Specialconsideration

s

Lamotrigine Quick efficientoralabsorption/hepaticglucuronidationfollowed byrenal excretion

Rash, nausea Dizziness,ataxia,blurred vision,vomiting, &statusepilepticus

-blood levelsare linear todose-welltolerated-valproatesignificantlyincreaseslevels

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Louis 2009

Common pitfalls in AED blood monitoring and dosing

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Adjustments in context of blood level and clinical picture

(removal of the temporal lobe;VNS- vagas nerve stimulation)

Oral contraception and pregnancy

What AEDs can do to OCPs: Inducers decrease the effect of oral contraception

What OCPs can do to the AEDs: Oestrogen induces glucuronidation → so with combinedOCPs, HRT & in pregnancy renal excretion of some drugs would be increasede.g. lamotrigine

Therefore…→ a better option for contraception when taking AEDs is IUDs

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What pregnancy can do to AEDs: In pregnancy there is generally reduced drug proteinbinding and increased metabolism and clearance due to changes in body weight,hormonal effects, and the contribution of the fetoplacental unit to drug distribution

Therefore …→ total levels of highly protein bound drugs drop significantly

→ clearance of lamotrigine and valproate is significantly increased

→ monitoring at least once every trimester is recommended

Assays and relevant testsDrug Assay Other organ specific tests

Carbamazepine Immunoassay FBC & LFTs at commencement,then on regular basis*

Phenytoin Immunoassay Consider measuring albuminlevels

Na valproate Immunoassay LFTs

Phenobarbitone Immunoassay LFTs & renal function

Clonazepam LCMS Consider LFTs and FBC

Lamotrigine Immunoassay

Vigabatrin HPLC Visual field testing before andsix monthly after starting

Gel tubes are not suitable for many of these drugs*It may be more practical to monitor neutropenia by symptoms

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Role of the pathology laboratory is to provide accurate, reproducible, clinicallyrelevant results, & to be available for consultation

• Right patient at the right time

• Clinical details on request forms

• Suitable collection tubes

• Proficiency testing

• TAT

• Therapeutic ranges

• Units

• Interpretive comments

• Critical phone limits

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Pre-analytical

Analytical

Post-analytical

Practical scenarios…

• The level is “critical” but there is no specified time for the last dose, what do I do?

• Na valproate is added to “the mix”

• A paediatric neurologist calls and expresses concern over the high numberof “elevated” lamotrigine levels his patients are having

• Your laboratory has a significant flyer in your EQA program. Upon closerinspection you see that the entire method group shifted!

• Certain drug levels from the community laboratory are always low!

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In summary

• “Routine” monitoring is not recommended• AEDs have numerous and complex pharmacokinetic interactions• Educate requestors on need for relevant details on the request form• Always ask the questions: what change has there been to the patient’s

clinical/physiological state? why test? is the patient well at this level?• Levels below the upper “reference range” do not exclude toxicity or

paradoxical intoxication i.e. can still be too high for the individual

• Elevated levels do not imply toxicity

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12/02/2018s musaad 30Patsalos et al 2008

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Lithium

Naturally occurring ion; oral preparation is in the form of a lithium salt (carbonate, sulphate, chloride, or citrate)

Soluble and well absorbed in the stomach

Does not bind to plasma proteins and does not undergo hepatic metabolism

Excreted unchanged by the kidneys- clearance can increase by 50% in pregnancy

Used to treat bipolar disorder

Increases the risk of hypothyroidism in bipolar disorder

Decreases renal response to ADH

Lithium induced hyperparathyroidism (LIH) with long term treatment, mechanism unclear

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Malhi et al 2012

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• Polyuria may exacerbate hypercalcaemia in long term lithium usersMalhi et al 2012

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Side effects with long term treatment

• Renal diabetes insipidus- through resistance to ADHmay be irreversible with chronic use

Treatment- stop lithium if possible, or Rx amiloride (a K sparing diuretic that inhibits Na & lithiumreabsorption)

• Lithium induced hyperparathyroidism (LIHP)- probably changes the set point for PTH secretionincidence of hypercalcaemia in patients taking lithiumcan be 7x higher than the general populationcomparable to familial hypo-calciuric hypercalcaemiaworsened in case of concomitant diabetes insipidus

Treatment- calcimimetics, surgical removal of one or multiple adenomas, bilateral parathyroidectomy

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• Hypothyroidism- inhibits iodine uptake, iodotyrosine coupling and T4 release.8-19% of patients on lithium compared to 0.5-1% ofthe general population

Treatment- thyroxine

• Weight gain – due to polyphagia, depressive episodes (bipolar disorder),hypothyroidism

Treatment – dietary and lifestyle measures

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Malhi et al 2012

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Golden rule number 11

Be nice to the clinical pharmacist!

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Theodore Roosevelt: Courage is not having thestrength to go on it is going on when you don’thave the strength

Danny Glover

Prince

Little girl next door

FACES OF EPILEPSY

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References

Silverman AK, Fairly J, Wong R et al. Cutaneous and immunologic reactions to phenytoin. J AM ACAD DERMATOL1988;18:721-41

Malhi GS, Tanious M, Das P et al. The science and practice of lithium Therapy (Review article) ANZJP 2012;46:192-211

St.Louis EK. Monitoring Antiepileptic Drugs: A Level- Headed Approach Current Neuropharmacology 2009;7:115-119