choice and monitoring of drug therapy - dr ashish bavdekar

Chairpersons: Aabha Nagral, Prashanth LK,SK YachhaTalk: Ashish Bavdekar  

Choice and Monitoring of Drug therapy

Wilson’s Disease – choice and monitoring of drug therapy

Dr. Ashish BavdekarAssociate Professor

Consultant Ped. GastroenterologistK.E.M. Hospital, Punebavdekar@vsnl.com

Wilson’s Disease - therapy

1) Reduce Cu to sub-toxic threshold - takes 6-12 months - DP, Trientine, TAM

2) Maintain slightly negative Cu balance - life long therapy - DP, Trientine, Zn

Zn + penicillamine

Zn + trientine

Zn sulfate

Zn acetate

trientine

penicillamine

transplanted

EuroWilson: initial treatment

Why?

“Available in our countryCheapTried and testedWhat we’ve always used

“Not available in our countryKept as second lineNot as effective?

“expensive”

Treatment depending on severity

acute liver failure with encephalopathy

acute liver failure without encephalopathy

intermediate severity

Asymptomatic transaminitis

Asymptomatic and normal LFTs

Neonate detected by screening

TxDP/Trientine + zinc‘bridge’

Modified Kings scoreTx if >11DP/Trientine + zinc

Score Bilirubinmol/Lɥ

INR ASTIU/L

WCCx 109/L

Albuming/L

0 0-100 0-1.29 0-100 0-6.7 >451 101-150 1.3-1.6 101-150 6.8-8.3 34-442 151-200 1.7-1.9 151-300 8.4-10.3 25-333 201-300 2.0-2.4 301-400 10.4-15.3 21-244 >301 >2.5 >401 >15.4 <20

Modified King’s score

A score > 11 = urgent need for transplantationValidated in other centres; better than PELD

Dhawan et al, 2005

acute liver failure with encephalopathy

acute liver failure without encephalopathy

intermediate severity

Asymptomatic transaminitis

Asymptomatic and normal LFTs

Neonate detected by screening

TxDP/Trientine + zinc‘bridge’

Modified Kings scoreTx if >11DP/Trientine + zinc

Zinc

Zinc – when to start?

Treatment depending on severity

acute liver failure with encephalopathy

acute liver failure without encephalopathy

intermediate severity

Asymptomatic transaminitis

Asymptomatic and normal LFTs

Neonate detected by screening

List for TxDP/Trientine + zinc‘bridge’

Modified Kings scoreTx if >11DP/Trientine + zinc

Zinc

Zinc – when to start?

Treatment depending on severity

DP Trientine ZincChelator Chelator Induces MT

Easy availability Patient named basis Easy availability

Reasonable costRs. 1500/month

V. ExpensiveRs. 30,000/month

CheapRs. 400/month

Side effects +++ Minimal SE Gastric discomfort

All except V. severe t-peniaDP intoleranceNeurological (?)

Initial co-RxPresympt. CasesMaintenance Rx

DP Trientine ZincChelator Chelator Induces MT

Easy availability Patient named basis Easy availability

Reasonable costRs. 1500/month

V. ExpensiveRs. 30,000/month

CheapRs. 400/month

Side effects +++ Minimal SE Gastric discomfort

All except V. severe t-peniaSignificant renal DDP intoleranceNeurological

Initial co-RxPresympt. CasesMaintenance Rx

Monitoring in WD ?

• To determine clinical and biochemical

improvement/deterioration

• Determine effective decoppering

• Ensure compliance

• To identify adverse effects of medications

• To review diagnosis if necessary

Monitoring plan (chelators)

• Clinical– Liver status, neuro-psychiatric worsening– KF ring annually

• Biochemical (USG)– CBC, Urine, LFTs– Initially 5, 10, 15, 30 days initially– Later 3 mo, 6mo,

• Urinary Cu, Serum free copper (Serum Cu & Cp)– Initially after a month, 4 times per year– Later 1-2 times per year

Monitoring plan (chelators)

• Clinical– Liver status, look for side effects– KF ring annually

• Biochemical (USG)– CBC, Urine, LFTs– Initially 5, 10, 15, 30 days initially– Later 3 mo, 6mo,

• Urinary Cu, Serum free copper (Serum Cu & Cp)– Initially after a month, 4 times per year– Later 1-2 times per year

DP Trientine ZincEarly (1-3wks)Fever, RashNeutropenia, Thrombo, Proteinuria, LnpathyNeurolog deterioration

Avoid iron + TRashesHaem. GastritisSideroblastic ALoss of taste

GastritisLeucopeniaIncreased lipase and amylase

LateNephrotoxicityLupus like SSkin – EPS, pemphigus, lichen planus, V LateMyasthenia, PolymyositisRetinitis

Monitoring plan (chelators)

• Clinical– Liver status, neuro-psychiatric worsening– KF ring annually

• Biochemical (USG)– CBC, Urine, LFTs– Initially 5, 10, 15, 30 days initially– Later 3 mo, 6mo,

• Urinary Cu, Serum free copper (Serum Cu & Cp)– Initially after a month, 4 times per year– Later 1-2 times per year

Biochemical improvement

• Children on long-term chelation

– 20/32 children normalised at variable times

– INR - median of 1.8 yrs (0-12.2)

– AST – median of 0.97 yrs (0-9)

– Bilirubin – median of 0. yrs (0-2.3)

• Asymptomatic sibs

– 15/17 normalised LFTs

– Median 283 days (35days-6.7yrs)Dhawan et al, 2005

Monitoring plan (chelators)• Clinical

– Liver status, neuro-psychiatric worsening– KF ring annually

• Biochemical (USG)– CBC, Urine, LFTs– Initially 5, 10, 15, 30 days initially– Later 3 mo, 6mo,

• Urinary Cu, S. free copper (Serum Cu & Cp)– Initially after a month, 4 times per year– Later 1-2 times per year

Zinc DP / Trientine

Initial Rx U Cu 100-500 ug/dS free Cu > 25 ug/dL

U Cu > 500ug/dS free Cu > 25 ug/dL

Good control U Cu < 75ug/dS free Cu 10-15 ug/dL

U Cu 200-500 ug/dU Cu < 100 ug/d 48hrs after stopping DPS free Cu 10-15ug/dL

Non-compliance/Inadequate dose

U Zn < 2mg/d U Cu < 200 ug/dU Cu > 500 ug/dS free Cu > 15ug/dL

Over-treatment U Cu < 25 ug/d S. free Cu < 5 ug/dLAnemia, leucopeniaIncreased ferritin

U Cu < 200 ug/dS. free Cu < 5 ug/dLAnemia, leucopeniaIncreased ferritin

Urinary copper in Wilson’s disease

Zinc DP / Trientine

Initial Rx U Cu 100-500 ug/dS free Cu > 25 ug/dL

U Cu > 500ug/dS free Cu > 25 ug/dL

Good control U Cu < 75ug/d

S free Cu 10-15 ug/dL

U Cu 200-500 ug/dU Cu < 100 ug/d 48hrs after stopping DPS free Cu 10-15ug/dL

Non-compliance/Inadequate dose

U Zn < 2mg/d

S free Cu > 15ug/dL

U Cu < 200 ug/dU Cu > 500 ug/dS free Cu > 15ug/dL

Over-treatment U Cu < 25 ug/d S. free Cu < 5 ug/dLAnemia, leucopeniaIncreased ferritin

U Cu < 200 ug/dS. free Cu < 5 ug/dLAnemia, leucopeniaIncreased ferritin

Urinary copper / serum ‘free’ copper

Summary

• Chelators - mainstay of treatment (hepatic)

• Zinc has role in long-term Rx, neurological, co-Rx

• Monitoring is crucial

– Clinical and improvement in LFTs slow

• Monitoring for Cu balance important

– Interpretation important

– Compliance