Treatment of Hypothyroidism

There are three major goals in the treatment of hypothyroidism: replace the missing hormones, relieve symptoms, and achieve a stable biochemical euthyroid state. While these goals should not be difficult to achieve, 20% to 40% of treated patients are not receiving optimal pharmacotherapy.

Thyroid Hormone Products

A number of thyroid hormone products are marketed in the United States (Table 44-3). These products include synthetic LT4 and T3, combinations of synthetic LT4

and T3, and animal-derived products. Despite the availability of a wide array of thyroid hormone products, it is clear that synthetic LT4 is the treatment of choice for almost all patients with hypothyroidism.11 12 Using LT4 mimics the normal physiology of the thyroid gland, which secretes mostly T4 as a prohormone. Peripheral tissues convert T4 to T3 as needed, based on metabolic demands. If T3 is used to treat hy-pothyroidism, the peripheral tissues lose their ability to control local metabolic rates. LT4 also has distinct pharmacokinetic advantages over T3. With a 7 to 10 day half-life, LT4 provides a very smooth dose-response curve with little peak and trough effect. In a small number of patients who have impairment of conversion of T4 to T3, addition of T3 may be warranted. T3, with a 24-hour half-life, provides a significant peak and trough effect, and many patients will have symptoms of thyrotoxicosis after each dose is administered. For patients who have difficulty adhering to a once-daily regimen, a once-weekly LT4 regimen is safe and effective. 1

Animal-derived products such as desiccated thyroid and thyroglobulin are obtained from cow and pig thyroid and have various degrees of purity. These products contain both LT4 and T3, but the amount of T3 is much higher (T4:T3 = 4:1) than what would be found in the human thyroid gland (T4:T3 = 14:1). With the desiccated thyroid products, there are concerns about standardizing the amount of hormone and lot-to-lot variability. While some patients want to use these agents because they are "natural," they are not natural for humans. With the strong evidence supporting the safety and efficacy of LT4 in the treatment of hypothyroidism, there is no rationale for the use of these animal-derived products. Patients who are being treated with these agents should be strongly encouraged to switch to synthetic LT4. Also, patients should be encouraged not to purchase thyroid hormone- or iodine-containing products from health food stores or from questionable Internet sites.

Several studies have been published that evaluate the use of LT4 and T3 combinations in ratios that mimic human physiology. A meta-analysis of 11 randomized, controlled clinical trials comparing LT4 and T3 combinations with LT4 monotherapy show no outcome benefit with combination therapy.16 Except in rare circumstances (such as patients with impaired T4-to-T3 conversion), there is no rationale for using combinations of LT4 and T3 to treat hypothyroidism.

Bioequivalence and LT4 Product Selection

LT4 products have a long history of bioavailability problems. Over the years, LT4 bioavailability has increased, so maintenance doses today are significantly lower than those seen in the 1970s and early 1980s. Currently, the average bioavailability of LT4 products is about 80%. Because of longstanding concerns about LT4 bioequivalence, and because LT4 products had never undergone formal approval by the FDA under the 1938 Food, Drug, and Cosmetics Act, the FDA mandated that all manufacturers of LT4 products submit an Abbreviated New Drug Application (ANDA) to keep their products on the U.S. market after 2001.18 Products approved under this process would have to comply with FDA manufacturing and bioequivalence standards. This FDA action has resulted in many changes in the U.S. LT4 market, as well as renewed interest in LT4 bioequivalence. By 2009, a variety of brand and generic products had been approved by the FDA. Some of the generic products carry AB ratings (bioequivalence) to certain brand products.19

Table 44-3 Thyroid Preparations

Content

Relative Dase

Cmmenu

IT, (Synthroid, Leworyl. Unithrotdlofll*1« Ujrvfc, and gene lies

Ifcuhyronine (CytomcO

Synthelic LT; 25,501 75,68, 104 11?. iJS, 137. 150, ITS, 700, and 300 mcq lablelv 503 Fig vial lor inietlion

Synthetic T,; 5,25, and 50 <mcg uWfli

60 meg

15 meg

Thyioid OieytxalMj) U5P Destcjfod pork o beef

lhyiogfcibdlln (Pnolold)

lhynuid gUnitytmfljint T and TjiClK.S.l, I. 1.4, i, J, 4, ,i"<t i grit'i CatAti I'jnullf puiifled pork llvyioylobuliif 3?r45, 100. tiaanJ M0 ring laUeti 5yiHln1it tr 11 in 1i*r_*d 4:1 latto:'/,. /. 1,1, J Hienqifi Ut*SS

Go4d standard for I reading hyrcuhynoidism, products not thsrjpetit* jSy equti'jlenc; fill itpbnneni Jtw t-l.t mrg/tg/djyjwtiMi lynching from jriimjl pr>duc t fewer cakulaksJ daily dra: by 25-50- meg IV foiir> ijnoty nc«J«J Hjicly riopdnt in (rwnmefn 01 hypothyioidivn npid

■ib/n*|rtkyi.uiil iitLniTi.Kdt H |k: J^IIM; InoKiSdJ

toxicity imius LTjj no outcome benefll 1o combining milli U

horphyiiologt for humans unpredictable hormone cortWtl and vijbllify; T, ienflirt! may tjuv: tonicity

Nonphyiiologic T: T, raid T,content maycause Iimcity; remmcd from U5. nvirkl

Hmiphyvokxik tr-1. r,o)( T i tiHitL-m maytduw.L1twfc.ity

LT,levo1lvio«ine, T„Hiiodothyronine;TJ, IfyioM«*.

For many years, there have been concerns regarding the FDA bioequivalence methodology for LT4 products. FDA bioequivalence standards allow a -20% to +25%

variance in pharmacokinetic parameters between the test and reference products.

Many people feel that this degree of allowed variance is not appropriate for a narrow-

therapeutic-index (NTI) drug such as LT4. Also, there are unique challenges to performing bioequivalence studies with an endogenous hormone such as LT4. Because these single-dose pharmacokinetic studies are done in healthy volunteers, the pharma-

cokinetic data are a combination of endogenous and exogenous LT4. Seventy percent of the area under the curve (AUC) in these studies consists of the subjects' endogenous T4. Thus, it is doubtful that bioavailability differences among products could be

detected. Blakesley and colleagues showed that the standard FDA bioequivalence methodology would rate 600, 450, and 400 mcg LT4 doses as bio equivalent. This study also showed that mathematically removing the subjects' endogenous T4 level (baseline correction) improves the sensitivity of the analysis, allowing a distinction between 33% and 25% but not 12.5% dose differences. Based on these data, the FDA, since 2003, has required that LT4 bioequivalence data undergo baseline correction. While this method has improved the ability to identify large differences in LT4 bio-equivalence, small but clinically significant differences will not be identified.

More important than bioequivalence is the therapeutic equivalence of LT4

products. Will patients have the same outcomes if bioequivalent products are used?

The study by Dong and colleagues helps to answer this question. Twenty-two well-controlled hypothyroid women were randomly switched to the same dose of four different products every 6 weeks. Nonbaseline corrected bioequivalence data showed these products to be bioequivalent. However, as each product switch occurred, more

of the subjects had an abnormal TSH level. By the end of the third product switch, 52% had an abnormal TSH level. This is strong evidence that LT4 products are not therapeutically equivalent even if they are rated as bioequivalent by the FDA.

Evidence does exist that small differences in the LT4 dose can result in large changes in TSH. The impact on TSH of small changes in LT4 dose was assessed in

21 adult therapeutically optimized hypothyroid patients. When the daily dose was reduced by 25 mcg, 78% had an elevated TSH level. When the daily dose was increased by 25 mcg, 55% had a low TSH level. Clearly, differences in the LT4 dose or bioavailability within the FDA-allowed variance for bioequivalent products can cause significant changes in TSH.

O There is no evidence that one LT4product is better than another. However, given the evidence that these products do have different bioavailabilities, patients should be maintained on the same LT4product. Given the generic substitution regulations of most states, this is best accomplished by prescribing a brand-name product or otherwise assuring that the product remains constant, and not allowing substitution in the way mandated by state regulations. While practitioners are pressured by managed-care organizations and employers to substitute LT4 products as a cost-saving measure, such switching is not in the best interest of the patient and should not be allowed. If patients are switched to a different product, a TSH determination should be done in 6 to 8 weeks to allow retitration. The economic impact of retitration must be considered when formularies are changed to reduce the drug acquisition cost.

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