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.