The Need for Precise L-Thyroxine Dosing James V. Hennessey M.D. Associate Professor of Medicine...
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Transcript of The Need for Precise L-Thyroxine Dosing James V. Hennessey M.D. Associate Professor of Medicine...
![Page 1: The Need for Precise L-Thyroxine Dosing James V. Hennessey M.D. Associate Professor of Medicine Brown Medical School Current, pending and past affiliations:](https://reader036.fdocuments.in/reader036/viewer/2022062517/56649e7b5503460f94b7c93f/html5/thumbnails/1.jpg)
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 PharmaceuticalsResearch Support: Knoll, King Pharmaceuticals
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Indications for L-Thyroxine
• Primary Hypothyroidism (> 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- < 0.4 mIU/L
• Other experts recommend < 0.1 for high risk patients
Demers and Spencer NACB Guidelines 2003Demers and Spencer NACB Guidelines 2003 Mazzaferri 2000Mazzaferri 2000Singer et al. 1995Singer et al. 1995
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Individual TSH normal Range
• 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 87:1068-72Andersen et al. 2002 JCEM 87:1068-72
Mean +/- 2SD =1.27 (0.16 - 2.39)
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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 2000Brent & 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 2000Brent & 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
• Rx:LEVOTHROID (L), SYNTHROID (S)– 6 WEEK PERIOD THEN CROSSED OVER
• EVAL: TFT’s, TRH STIMULATION
Hennessey et al. 1985 Ann Intern Med 102:770-773
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Levothroid® or Synthroid® TT4 AND FTI
0
2
4
6
8
10
12
TT4 FTI
LevothroidSynthroid
g/d
L
Hennessey et al. 1985 Ann Intern Med 102:770-773
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Levothroid® or Synthroid®TT3 AND FT3I
0
20
40
60
80
100
120
140
160
180
TT3 FT3I
LevothroidSynthroid
Hennessey et al. 1985 Ann Intern Med 102:770-773
ng//
dL
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Levothroid® or Synthroid®TRH RESULTS
0123456789
10
TSH 0 TSH 15' TSH 30' TSHChange
LevothroidSynthroid
*
** * P<0.05 L>S
Hennessey et al. 1985 Ann Intern Med 102:770-773
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ASSESSMENT OF LT4 INTERCHANGEABILITY
• 31 PATIENTS (6 MEN, 25 WOMEN)– “LONG-STANDING 10 HYPOTHYROID”
• STABLE LT4 Rx > 6 WKS @ ENTRY
• 23/31 SYNTHROID (S) TO LEVOXINE
• 8/31 LEVOXINE (L) TO SYNTHROID
• TFT’s @ BASELINE AND FOUR MONTHS AFTER SWITCH
Escalante et al.1995Escalante 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.1995Escalante et al.1995
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L-T4 BIOEQUIVALENCE: NAME BRAND VS. GENERIC
• PATIENTS:– 24 HYPOTHYROID PATIENTS
• 16 HASHIMOTO’S THYROIDITIS
• 8 POST SURGICAL OR 131-I TREATMENT
– 22 IN FINAL ANALYSIS
• SETTING:– UCSF DEPT. CLINICAL PHARMACOLOGY
Dong et al 1997Dong 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 1997Dong et al 1997
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24 HOUR TFT PROFILES
Mayor et al 1995Mayor et al 1995
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TSH PROFILES
Dong et al 1997Dong et al 1997
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Data derived from Mayor et al. 1995, Dong et al. 1997Data 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; 87:1068-72.
• 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; 277:1205-1213 .
• Escalante et al.1995– Assessment of Interchangeability of Two Brands of Levothyroxine Preparations with a
Third-Generation TSH Assay. Am J Med. 1995; 98:374-378
• Hennessey et al. 1985– The equivalency of two L-thyroxine Preparations. Ann Intern Med. 1985; 102:770-773.
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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; 2:417-432.
• Singer et al. 1995
– Treatment Guidelines for Patients With Hyperthyroidism and Hypothyroidism JAMA 273:808-812.
• Singer et al. 1996
– Treatment Guidelines for Patients With Thyroid Nodules and Well-Differentiated Thyroid Cancer. Archives of Internal Medicine 156:2165-2172.