# Presentation: 391008

## 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

## 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 2003**

**Mazzaferri 2000**

**Singer 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 87:1068-72**

- 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 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 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

- g/dL

- Hennessey et al. 1985 Ann Intern Med 102:770-773

## Levothroid® or Synthroid®TT3 AND FT3I

- Hennessey et al. 1985 Ann Intern Med 102:770-773

- ng//dL

## Levothroid® or Synthroid®TRH RESULTS

- *

- *

- *

- * 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.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.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 1997**

## L-T4 BIOEQUIVALENCE

- _TREATMENT RAMDOMIZATION:_
- PREV.  _EU_THYROID 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**

## 24 HOUR TFT PROFILES

**Mayor et al 1995**

## TSH PROFILES

**Dong et al 1997**

## Data derived from Mayor et al. 1995, Dong et al. 1997

**Data 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.