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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 PharmaceuticalsResearch Support: Knoll, King Pharmaceuticals
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
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)
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
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
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
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
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
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
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
INTERCHANGEABILITY RESULTS
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
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
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
24 HOUR TFT PROFILES
Mayor et al 1995Mayor et al 1995
TSH PROFILES
Dong et al 1997Dong et al 1997
Data derived from Mayor et al. 1995, Dong et al. 1997Data derived from Mayor et al. 1995, Dong et al. 1997
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.
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.