The Need for Precise LThyroxine Dosing

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The Need for Precise L-Thyroxine Dosing

• James V. Hennessey M.D.
• Associate Professor of Medicine
• Brown Medical School

Current, pending and past affiliations Speakers
Bureau Abbott, Forest Pharmaceuticals Research
Support Knoll, King Pharmaceuticals
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Indications for L-Thyroxine

• Primary Hypothyroidism (gt 95 of cases)
• Principle dose titration parameter TSH
• Recommended target range 0.5 - 2.0 mIU/L
• Suppression therapy for Thyroid Cancer
• Principle dose titration parameter TSH
• Recommended target range 0.1- lt 0.4 mIU/L
• Other experts recommend lt 0.1 for high risk
  patients

Demers and Spencer NACB Guidelines 2003
Mazzaferri 2000
Singer et al. 1995
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Individual TSH normal Range
Mean /- 2SD 1.27 (0.16 - 2.39)

• 16 caucasian men
• 24-52 yrs (median 38)
• 15 no Hx Thyroid Dz, goiter nor medication
• Blood samples
• monthly (0900-1200)
• stored frozen
• analyzed random order in same assay run

Participants
Andersen et al. 2002 JCEM 871068-72
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Subclinical Thyroid Disease

• Definition High or low TSH while T4 and T3
  remain within laboratory reference range
• Both Subclinical Hypo and Hyperthyroidism are
  associated with physiologic and biochemical
  abnormalities as well as increased risk of
  certain diseases.

Brent Larsen 2000
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Adverse Effects of Thyroxine Rx

• Excess Overt (symptomatic) Thyrotoxicosis
• Subclinical Thyrotoxicosis
• Excess bone loss
• Postmenopausal women
• Cardiac arrhythmias or dysfunction
• increased pulse rates
• increased cardiac wall thickness
• increased cardiac contractility
• increased risk of atrial fibrillation

Brent Larsen 2000
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EQUIVALENCY OF TWO THYROXINE PREPARATIONS

• PATIENTS ON LT4
• 34 CLINICALLY EUTHYROID PATIENTS
• 25 WITH 1º HYPOTHYROIDISM
• 9 - GOITER SUPPRESSION INDICATION
• RxLEVOTHROID (L), SYNTHROID (S)
• 6 WEEK PERIOD THEN CROSSED OVER
• EVAL TFTs, TRH STIMULATION

Hennessey et al. 1985 Ann Intern Med 102770-773
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Levothroid or Synthroid TT4 AND FTI
?g/dL
Hennessey et al. 1985 Ann Intern Med 102770-773
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Levothroid or SynthroidTT3 AND FT3I
ng//dL
Hennessey et al. 1985 Ann Intern Med 102770-773
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Levothroid or SynthroidTRH RESULTS


Plt0.05 LgtS

Hennessey et al. 1985 Ann Intern Med 102770-773
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ASSESSMENT OF LT4 INTERCHANGEABILITY

• 31 PATIENTS (6 MEN, 25 WOMEN)
• LONG-STANDING 10 HYPOTHYROID
• STABLE LT4 Rx gt 6 WKS _at_ ENTRY
• 23/31 SYNTHROID (S) TO LEVOXINE
• 8/31 LEVOXINE (L) TO SYNTHROID
• TFTs _at_ BASELINE AND FOUR MONTHS AFTER SWITCH

Escalante et al.1995
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INTERCHANGEABILITY RESULTS
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ASSESSMENT OF LT4 INTERCHANGEABILITY

• RESULTS
• 6/24 (24) EUTHROID ON Synthroid WERE THYROTOXIC
  ON Levoxine
• 2/21 (9.5) EUTHYROID ON Levoxine WERE THYROTOXIC
  ON Synthroid
• 8/31 (26) HAD CHANGE IN BASAL TSH CLASSIFICATION

Escalante et al.1995
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L-T4 BIOEQUIVALENCE NAME BRAND VS. GENERIC

• PATIENTS
• 24 HYPOTHYROID PATIENTS
• 16 HASHIMOTOS THYROIDITIS
• 8 POST SURGICAL OR 131-I TREATMENT
• 22 IN FINAL ANALYSIS
• SETTING
• UCSF DEPT. CLINICAL PHARMACOLOGY

Dong et al 1997
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L-T4 BIOEQUIVALENCE

• TREATMENT RAMDOMIZATION
• PREV. EUTHYROID ON 0.1 OR 0.15 mg/d
• Rx for min 6 weeks prior to study entry
• BLOCK ASSIGNMENT
• 4 CROSSOVER SCHEMES (6 weeks each)
• A Levoxyl?
• B Pharm. Basics (Geneva)
• C Pharm. Basics (Rugby)
• D Synthroid?

Dong et al 1997
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24 HOUR TFT PROFILES
Mayor et al 1995
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TSH PROFILES
Dong et al 1997
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Data derived from Mayor et al. 1995, Dong et al.
1997
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References

• Andersen et al. 2002
• Narrow Individual Variations in Serum T4 and T3
  in Normal Subjects A Clue to the Understanding
  of Subclinical Thyroid Disease. JCEM 2002
  871068-72.
• Brent and Larsen 2000
• Treatment of Hypothyroidism The Thyroid, Eighth
  Edition, 2000. Braverman Utiger eds.
  pp.853-860.
• Dong et al. 1997
• Bioequivalence of generic and brand levothyroxine
  products in the treatment of hypothyroidism. JAMA
  1997 2771205-1213 .
• Escalante et al.1995
• Assessment of Interchangeability of Two Brands
  of Levothyroxine Preparations with a
  Third-Generation TSH Assay. Am J Med. 1995
  98374-378
• Hennessey et al. 1985
• The equivalency of two L-thyroxine Preparations.
  Ann Intern Med. 1985 102770-773.

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References

• Mazzaferri 2000
• Carcinoma of Follicular Epithelium Radioiodine
  and Other Treatment and Outcomes The Thyroid,
  Eighth Edition . Braverman Utiger eds.
  pp.904-929.
• Mayor et al. 1995
• Limitations of Levothyroxine Bioequivalence
  Evaluation Analysis of an attempted Study. Am J
  Therapeutics 1995 2417-432.
• Singer et al. 1995
• Treatment Guidelines for Patients With
  Hyperthyroidism and Hypothyroidism JAMA
  273808-812.
• Singer et al. 1996
• Treatment Guidelines for Patients With Thyroid
  Nodules and Well-Differentiated Thyroid Cancer.
  Archives of Internal Medicine 1562165-2172.