A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism

Abstract

Thyroxine hormone has been recognised since the early part of the nineteenth century and levothyroxine has been available since the mid-nineteenth century as a replacement for deficient thyroid hormones. While levothyroxine remains the staple treatment for hypothyroidism even to this day, its optimal use can be challenging. As is often the case with older drugs, the pharmacokinetics of levothyroxine is often under-appreciated or misunderstood and many factors influence the optimal dosing of levothyroxine. This article will review the pharmacokinetics of levothyroxine in the treatment of hypothyroidism and highlight major concepts that should aid both clinicians and researchers.

Role of the Thyroid Hormones

Thyroid hormones play a vital role in the human body and, as such, the absence of such hormones requires treatment. Generally, levothyroxine is used to treat thyroid hormone deficiency, and after a brief review of thyroid hormone physiology, this article will highlight what is known about the pharmacokinetics (PKs) of levothyroxine, as well as describe factors that can influence its PKs. The thyroid gland is responsible for the synthesis, storage and release of metabolic hormones including iodine-containing thyroxine (T₄) and triiodothyroxine (T₃). These hormones are crucial in the regulation of many metabolic processes and are vital for normal growth and development.¹ They are also involved in calorigenic, cardiovascular and metabolic effects. The hormones exert their effects presumably by activating gene transcription of messenger RNA and proteins. To do so, they enter the cell nucleus and bind to DNA-bound thyroid receptors, which regulate gene transcription.^1,2

T₄ and T₃ Production and Feedback Loop Mechanism

Normally, the hormones secreted by the thyroid are regulated by the hypothalamic–pituitary–thyroid (HPT) axis through a negative feedback system. Low levels of circulating T₄ and T₃ initiate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormones (TSH) from the pituitary. On interaction with its specific receptor, TSH stimulates the thyroid follicular cells to synthesise T₄ and T₃ and release them into the bloodstream. When circulating levels of T₄ and T₃ increase, they inhibit the release of TRH and TSH (i.e. negative feedback mechanism) thereby decreasing their own production.^1–4 The predominant hormone produced by the thyroid gland is T₄, with approximately 70–90 mcg of T₄ and 15–30 mcg of T₃ produced daily.^1,5 The production of the T₃ hormone by the thyroid gland is insufficient to meet the daily requirements of the organs in the body. Therefore, approximately 80 % of the body’s required T₃ comes from peripheral conversion of T₄ to T₃.^4,6 Although both T₄ and T₃ are active, T₃ is more active as thyroid receptors within the cell nucleus have a 10-fold greater affinity for T₃.^2,4

Indication and Dosage

Levothyroxine is a synthetic T₄ hormone that is biochemically and physiologically indistinguishable from the natural one, and it is administered when the body is deficient in the natural hormone.⁷ Oral administration of levothyroxine is thus indicated for acquired primary (thyroidal), secondary (pituitary) and tertiary (hypothalamic) hypothyroidism.⁸ It is also used to treat euthyroid goiters including thyroid nodules, subacute or chronic lymphocytic thyroiditis, multinodular goiter or for thyroid cancer patients who have undergone thyroidectomy, and as an adjunct to surgery and radioiodine therapy.¹

For an average adult under the age of 50, the typical levothyroxine sodium dose is approximately 1.7 mcg/kg/day, which is equivalent to approximately 100–125 mcg/day. Older patients or patients with cardiac disease may require less levothyroxine and doses should be titrated at intervals of 4–6 weeks. Newborns, infants and adolescents require doses greater than 1.7 mcg/kg/day.The guidelines that were recently released by the American Association of Clinical Endocrinologists and American Thyroid Association task force on hypothyroidism in adults, in addition to diagnosis, include suggestions of therapy.⁹

Literature Search Method

A literature review was conducted in PubMed, Embase (1974 to week 47 of 2012) and Medline (1946 to third week of November 2012) using the terms ‘levothyroxine’ and ‘pharmacokinetics’. The searches in Pubmed and Embase/Medline returned 1217 and 147 publications, respectively.

Pharmacokinetic Properties

Major characteristics of levothyroxine PKs are summarised in Table 1 and are described in more detail below.

Table 1: Summary of Levothyroxine PK.

Pharmacokinetic Characteristic	Description
Main site of absorption	Small intestine (jejunum and ileum)
Bioavailability	70–80 % in euthyroid person; may be slightly higher in hyperthyroid patients
Tmax	2–3 hours
Vd	11–15 L
Protein binding	T4 >99.9 % T3 = 99.8 %
T1/2	T4 = 6.2 and 7.5 days in euthyroid and hypothyroid patients, respectively T3 = 1.0 and 1.4 days in euthyroid and hypothyroid patients, respectively
CL	T4 = 0.055 and 0.038 L/h in euthyroid and hypothyroid patients, respectively

Vd = Volume of distribution; L = Litres; CL = Clearance

Absorption and Bioavailability

Levothyroxine is mainly absorbed in the small intestine, more specifically through the duodenum, jejunum and ileum.^10,11 Very little is absorbed in the stomach. Consequently, patients with shorter small intestines (bowel resection) have reduced absorption and require higher levothyroxine doses.¹² The time to maximum concentration (Tmax) occurs at approximately 2 hours in euthyroid volunteers while it is delayed to approximately 3 hours in hypothyroid patients.¹³ Food also delays Tmax.^13,14

The bioavailability of levothyroxine is approximately 60–80 % in euthyroid volunteers.^14–16 It may be slightly higher in hypothyroid and hyperthyroid patients,^15,16 and is decreased in the presence of food from 79 % under fasted conditions to 64 % under fed conditions for a 100 mcg dose.¹⁴

The absorption of levothyroxine appears to be influenced by gastric pH.^17,18 Centanni et al. demonstrated that in euthyroid patients suffering from nontoxic multinodular goiter, impaired gastric acid secretion or the use of omeprazole was associated with increased dosing requirements in order to adequately suppress TSH.¹⁷ Similarly, Sachmechi and colleagues showed that chronic lansoprazole use in hypothyroid patients also resulted in increased levothyroxine dose requirements to maintain targeted TSH levels.¹⁸

Volume of Distribution

Levothyroxine has a limited volume of distribution, which has been reported to be 11.6 litres (L) in euthyroid volunteers and 14.7 L in primary hypothyroid subjects.¹⁹ This is approximately equivalent to the extracellular fluid volume of the body.

Metabolism

Although T₄ is subject to multiple metabolic reactions,^20–22 the main metabolic route for T₄ involves deiodination reactions (removal of iodine) by deiodinase enzymes.^23–25 Removal of iodine from the carbon 5 of the outer ring transforms T₄ to T₃, thus T₄ can be regarded somewhat as a pro-hormone for T₃. Deiodination of the inner ring of T₄ can also occur, leading to the formation of inactive reverse T₃ (rT ₃). Approximately half of deiodinised T₄ is metabolised to rT₃ and half to T₃.^25,26 Both T₃ and rT₃ are further metabolised to diiodothyronine (T₂), iodothyronamine (T₁) and reverse T₂ and T₁.^25,26

Elimination

The daily turnover rate for T₄ is approximately 10 % while it is approximately 50–70 % for T₃, with a slightly faster turnover rate in normal volunteers compared with patients with primary hypothyroidism.^1,2 This equates to a half-life for T₄ of 7.5 days in hypothyroid patients and 6.2 days in euthyroid individuals, while the T₃ half-life is approximately 1.4 and 1.0 days for hypothyroid and euthyroid volunteers, respectively.¹⁹ Clearance for T₄ was similar with 0.056 and 0.054 L/h in hypothyroid and euthyroid subjects, respectively.¹⁹ These values are similar to other values reported in hypothyroid patients (0.0385 L/h/70 kg)²⁷ and in normal control subjects (0.053 to 0.064 L/h).^28,29

Protein Binding

Both T₄ and T₃ are highly bound to plasma proteins at greater than 99.8 % (i.e. unbound T₄ = 0.02–0.03 %; unbound T₃ = 0.2 %) in both euthyroid and primary hypothyroid volunteers.^1,19,30,31 Both T₄ and T₃ bind predominantly (>80 %) to thyroxine-binding globulin (TBG), and to a lesser extent to thyroxine-binding prealbumin and albumin.^1,30 Benvenga and Robbins have also demonstrated binding to lipoproteins such as high-density lipoprotein.^32,33 The T₃ affinity for binding to these proteins is approximately one-thirtieth that of T₄,³⁴ which explains the higher turnover rate of T₃ compared with T₄.

Transporters/Cytochrome Enzymes

Active transport of thyroxine into cells has been recognised for some time.^35,36 In vitro studies have shown that organic anion transporting polypeptides (OATP) (such as OATP1A2, OATP1B1, OATP1C1, etc.), monocarboxylate transporter and sodium-taurocholate cotransporting polypeptide are involved at different levels.^37–41

However, few articles have been published on the in vivo significance of these transporters on the PK of levothyroxine. Lilja et al. demonstrated the effects of the influx intestinal OATP transporter inhibition by grapefruit juice consumption on levothyroxine absorption.⁴² They concluded that grapefruit juice had only a minor effect if any on levothyroxine absorption (AUC0-6 dropped by 9 % and Tmax was slightly delayed).⁴²

A transporter that may be induced by levothyroxine is PgP (ABCB1 gene). Jin et al. published results that showed that cyclosporine A trough concentrations were lower in patients taking levothyroxine. In addition, the expression of this transporter was increased and oral cyclosporine A concentrations and bioavailability were lower in rats treated with levothyroxine.⁴³

PK Properties in Special Populations

Table 2 summarises the effects of different conditions on the PK of levothyroxine and additional details are presented below.

Table 2: Pharmacokinetics of Levothyroxine in Special Populations.

	Bioavailability	Metabolism (T4 to T3)	Protein Binding	Elimination	TT4	TT3	fT4	fT3
Renal impairment		↓	↓			↓		↓
Hepatic impairment (cirrhosis)		↓	↓		↑	↓	↑	↑ ↓
Elderly	↓	↓		↓		↓		↓
Children				↑	↓
Obesity					↑ ↓	↑ ↓
Pregnancy				↓			↓
Gastrointestinal disorders	↓	↓
Food	↓	↓

↑ = increase; ↓ = decrease; ↑ ↓ = contradiction in literature about impact. TT4 and TT3= total T4 and total T3; fT4 and fT3= free T4 and free T3.

Renally Impaired Patients

The kidney plays a significant role in the peripheral metabolism of T₄ to T₃.¹ Therefore, this metabolic route is significantly reduced in renally impaired patients, partially due to accumulated uremic toxins.^44,45 In patients with renal disease, there is a reduction in total and free T₃ while T₄ is less affected;^46,47 however, some patients with end-stage renal disease are also diagnosed with hypothyroidism.⁴⁸ It has also been reported that other metabolic routes may be enhanced, resulting in higher T₃ sulphate concentrations.⁴⁹ The proteinuria associated with the nephrotic syndrome may cause urinary loss of the thyroid hormones bound to the thyroid hormone transport proteins.^50,51

The volume of distribution of thyroxine is also increased in patients with renal failure, which is probably due to the decreased protein binding of thyroxine.⁵² Haemodialysis does not have an impact on levothyroxine requirements in this patient population.^47,48 However, kidney transplantation has been shown to affect the levels of thyroid hormones.⁴⁷ Some authors report that levels of T₃ increase with time after transplantation and doses of levothyroxine can consequently be reduced,^45,47 while others report the contrary.⁵³ The increased levothyroxine dose could also be due to drug–drug interactions with the medications patients are required to take after kidney transplantation.⁴⁷

Hepatically Impaired Patients

The liver is a major site for T₄ deiodination to T₃.^1,2 In addition, T₃ and T₄ are conjugated with glucuronic and sulphuric acids and then excreted in the bile.⁶ Approximately 20 % of T₄ is eliminated in faeces.¹ Therefore, it is expected that patients with hepatic impairment would have different levels of circulating T₄ and T₃ compared with patients with normal hepatic activity. Indeed, several studies have reported similar or higher levels of total and free T₄,^54,55 decreased levels of total and free T₃ and elevated concentrations of rT₃^56–59 in patients with severe cirrhosis compared with normal patients. Other authors have not shown significant reduction in T₃ concentrations in patients with different degrees of liver impairment except when patients had severe cirrhosis.⁶⁰

The clinical impact of severe cirrhosis on thyroid hormone levels is also influenced by other factors, such as lower levels of thyroxine binding proteins such as albumin. Overall, this possibly leads to an increase in free T₄ concentrations or the ratio of free T₃ to bound T₃, meaning that despite overall lower levels of T₃, more free T₄ and T₃ is available. Thus, because levothyroxine is a low-extraction drug, changes in protein binding will affect total levels but not free levels of hormone. Furthermore, increasing the dose of levothyroxine may not compensate for the lack of liver metabolism of T₄ to T₃.

Obesity

TSH values are increased in obese patients, which could be attributed to leptin, a hormone produced by adipose tissue that may increase TSH secretion.^61,62 Therefore, in such patients, increased levels of TSH do not necessarily indicate hypothyroidism, and TSH should not be the only criteria used to adjust doses.

Some authors have reported higher circulating concentrations of T₄ and T₃ in obese patients while others have reported lower levels.^63,64 Santini et al. reported the lack of a correlation between serum leptin concentrations and the total dose of levothyroxine administered and that adipose tissue had a minor impact on levothyroxine requirements.⁶⁵ The authors also indicated that lean body mass was superior to actual weight as a predictor of dosage, which is in line with levothyroxine’s small volume of distribution. Greater dose requirements in obese patients are probably attributed to a slightly higher volume of distribution (i.e. higher lean body mass and peripheral mass) compared to non-obese patients rather than to a greater overall weight (fat weight). If weight is used to determine a starting dose in obese patients, total weight may lead to supra-therapeutic doses, therefore using lean body mass might be a better alternative.⁶⁵

Pregnancy

Following conception in euthyroid women, TBG increases quickly with a rise in total T₄ concentrations, and decreases in free T₄ and TSH in the first trimester.⁶⁶ T₄ production increases 20–40 % in the early part of the first trimester and this continues throughout the pregnancy.⁶⁷ In hypothyroid women who become pregnant, T₄ requirements are also similarly increased, often necessitating an increase in levothyroxine dosage.⁶⁸ It should be noted that as TSH values are normally lower in the first trimester, increased T₄ requirements may not be recognised if TSH is the only marker used to adjust levothyroxine administration doses. Soldin et al. reported that levothyroxine clearance was faster in non-pregnant women at 7.0 L/h versus 4.5 L/h in pregnant women, despite similarities in Tmax and Cmax.⁶⁷ In addition, PK parameters in pregnant women appeared to be more variable.⁶⁷

Children

Heskel et al. reported a shorter half-life for T₄ in euthyroid children compared with adults (4.95 days for children and almost 7 days in adults).⁶⁹ They concluded that when considering weight, there was a decreased pool of T₄ and an increased elimination rate of thyroxine. Furthermore, Mainwaring et al. reported a shorter half-life for T₃ in children undergoing cardiopulmonary bypass compared with adults having the same procedure (seven hours versus close to one day).⁷⁰ According to the American Thyroid Association⁷¹ and the levothyroxine product monograph,⁷² infants and children require higher doses per weight or per body surface area compared with adults.⁷³ The typical dose can be as high as 10–15 mcg/kg/day for infants from 0–3 months old and it decreases towards adulthood where the typical dose is 1.7 mcg/kg/day.

Elderly

In healthy elderly individuals, secretion of T₄ and T₃ and metabolism of T₄ to T₃ are reduced while rT₃ levels appear to increase.^74,75 Accordingly, the elimination half-life for T₄ is longer and reported to be 9.3 days in patients older than 80 years old.⁷⁶ Absorption of T₄ is also slightly lower for patients above 70.⁷⁷ Although T₄ concentrations do not appear to be decreased in older euthyroid patients, total and free T₃ concentrations are reportedly lower in individuals 61–90 years old compared with younger individuals⁷⁴, which is expected due to their decreased metabolism. Therefore, measurements of only T₄ may be insufficient to explain changes in elderly patients’ thyroid function.

Gastrointestinal Disorders

Certain gastrointestinal disorders, including celiac disease⁷⁸ and Helicobacter pylori infection¹⁷, can impede the absorption of levothyroxine. As levothyroxine is mainly absorbed through the small intestine, its absorption is compromised in patients with coeliac disease.⁷⁸ Higher levothyroxine doses were reportedly required in patients with coeliac disease and when patients followed a gluten-free diet, levothyroxine dose requirement was reduced.^78,79 H. pylori infection causes chronic gastritis and affects gastric acid secretion in the stomach.¹⁷ Levothyroxine doses have been reported to be higher in hypothyroid patients with this disease.^17,80 However, following resolution of the infection, Bugdaci et al. recommend that doses be lowered.⁸⁰ Other gastrointestinal disorders such as inflammatory bowel disease, lactose intolerance and atrophic gastritis have also been demonstrated to affect levothyroxine absorption.

Drug and Food Interactions

Many substances are known to influence T₄ or T₃ levels and the impact appears to be more significant in hypothyroid patients being treated with exogenous supplementation compared with patients without thyroid pathology, probably due to their intact feedback mechanisms. In addition, interactions with levothyroxine can also occur indirectly via modulation of the HPT axis. All these will be described below and are summarised in Table 3.

Table 3: Drugs Interfering with Thyroid Function or with Levothyroxine Pharmacokinetics.

Drug or Drug Class	Relative Bioavailability	Synthesis	Metabolism	Protein Binding	Thyroid-stimulating Hormone	Overall Effect on Thyroid Hormones		Clinical Recommendation
						Total T4	Free T4
Aluminium hydroxide	↓					↓		Avoid concomitant use (separate intake by 4 to 6 hours)
Amiodarone	↑ ↓	↑ ↓	↓			↔ ↑ ↓		Monitor thyroid function
Anabolic steroids				↓		↓	↔	Lower dose may be necessary
Androgens				↓		↔	↔	Lower dose may be necessary
Beta blockers	↓a	↓a	↓a	↓b		↓ (transientb)		Monitor thyroid function
Calcium carbonate/citrate/acetate	↓					↓		Avoid concomitant use (separate intake by 4 to 6 hours)
Carbamazepine			↑	↓		↓	↓ ↔	Monitor thyroid function
Cholestyramine	↓					↓		Avoid concomitant use (separate intake by 4 to 6 hours)
Colsevelam	↓					↓		Avoid concomitant use (separate intake by 4 to 6 hours)
Dopamine (≥0.4 mcg/kg/min)					↓	↓ (transient)		Dose modification unnecessary
Ethinyl oestradiol				↑		↑		Higher dose may be necessary
Ferrous sulphate	↓					↓		Avoid concomitant use (separate intake by 4 to 6 hours)
Fluorouracil				↑		↑	↔	Dose modification unnecessary
Furosemide (high dose)				↓		↓ (transient)	↑ (transient)	Dose modification unnecessary
Glucocorticoids (dexamethasone ≥0.5 mg/day or hydrocortisone ≥100 mg/day)			↓ (initial)	↓	↓ (transient)	↓ (transient)		Lower dose may be necessary
Heparin				↓		↓ (transient)		Dose modification unnecessary
Heroin				↑		↑	↔	Monitor thyroid function
Iodide		↑ ↓				↓		Monitor thyroid function
Lithium		↓				↓		Monitor thyroid function
Methadone				↑		↑	↔	Dose modification unnecessary
Mitotane				↑		↑	↔	Dose modification unnecessary
Nicotinic acid				↓		↓		Dose modification unnecessary
Octreotide (≥ 100 mcg/day)								No dose modification necessary
Orlistat	↓					↓		Monitor thyroid function
Phenobarbital			↑			↓		Increase levothyroxine dosage
Phenytoin			↑	↓		↓	↔ ↓	Monitor thyroid function
Phosphate binders	↓					↓	↓	Separate intake by four or more hours
Proton pump inhibitors (omeprazole, lansoprazole)	↓					↓		Increase levothyroxine dosage
Rifampin			↑			↓		Increase levothyroxine dosage
Salicylates (>2 g/day)				↓		↓ (transient)	↓ (long-term use)	Dose modification unnecessary
Sucralphate	↓					↓		Separate intake by four or more hours
Sulphonamides		↓				↓		Monitor thyroid function
Tamoxifen				↑		↑	↔	Higher dose may be necessary
Tolbutamide		↓				↓		Monitor thyroid function

↔ = unchanged, ↑ = increase, ↓ = decrease, ↑ ↓ = either increase or decrease; a = propranolol; b = acebutolol, oxprenolol, timolol.

Food

The oral absorption of levothyroxine can be impaired by various substances, such as food^13,81–83, soy bean,^84–91 papaya⁹² and grapefruit.⁴² Benvenga and colleagues have demonstrated that coffee can also impair the absorption of certain levothyroxine formulations.^93,94

Drugs

Drugs can alter the PKs of thyroid hormones in various ways.⁹⁵ Drugs that decrease TSH secretion (dopamine,^96–100 glucocorticoids,^101,102 octreotide^103,104 and rexinoids^105,106) lead to decreased thyroid hormone concentrations, while thyroid hormone synthesis is interfered with by other drugs,¹⁰⁷ such as lithium, iodine¹⁰⁸, tolbutamide, sulphonamides and amiodarone.^109,110

Proton-pump inhibitors, such as omeprazole¹⁷ and lansoprazole,¹⁸ have also been shown to influence the absorption of levothyroxine, as assessed by TSH levels in patients, since normal gastric acid secretion plays a major role in the absorption of thyroxine. Interestingly, others found that in healthy volunteers, famotidine and esomeprazole had no such effect.¹¹¹ Aluminium hydroxide^112–114, dietary fibre¹¹⁵, calcium carbonate,^116–119 calcium citrate,¹²⁰ calcium acetate, ferrous sulphate,^121–123 cholestyramine¹²⁴ and colsevelam^125,126 decrease levothyroxine absorption by binding to it and forming complexes that are not absorbed. Sucralphate¹²⁷ may decrease levothyroxine absorption by interfering with its intra-luminal transport or by binding to it.⁸².Other products such as phosphate binders,^126,128,129 orlistat¹³⁰ and cimetidine¹³¹ also appear to decrease the absorption of levothyroxine, although the interaction mechanism/s is/are not as clearly defined.

Drug interactions can also influence other PK processes. For instance, the administration of beta blockers such as acebutolol, oxprenolol and timolol appear to modify the extracellular distribution of T₃, thereby decreasing T₃ levels.¹³² Changes in protein binding can also influence the PK of levothyroxine, as decreased protein binding is associated with greater levels of free levothyroxine, which is then more readily eliminated from the systemic circulation. Drugs that decrease levothyroxine protein binding include carbamazepine,¹³³ androgens, anabolic steroids,^134,135 and nicotinic acid.^136,137 Certain drugs are associated with transient increases in free T₄ levels due to inhibition of protein binding,¹⁰⁷ including high-dose furosemide,¹³⁸ salicylates^139–141 and heparin.^140,142 Conversely, drugs that increase protein binding are associated with a reduced clearance of levothyroxine. Such drugs include ethinyl oestradiol,^143–145 tamoxifen,¹⁴⁶ heroin, methadone,^147–150 mitotane and fluorouracil.^151,152

Finally, some drug interactions with levothyroxine can be explained by an effect on its metabolism, such as the extrathyroidal conversion rate of T₄ to T₃. Certain drugs, such as propranolol^{28,29,153,154} and amiodarone,¹⁰⁷ reduce this metabolism. Conversely, carbamazepine,^{133,155–158} phenobarbital,^159,160 rifampin¹⁰⁷ and phenytoin^155,161 induce liver microsomal enzymes and increase this peripheral metabolism.

Available Formulations

Commercial levothyroxine oral formulations available in North America and Europe include powders for intravenous solutions, tablets (e.g. Synthroid®, Levo-T™, Levothroid®, Levoxyl®, Unithroid®, Eltroxin®, Elthyrone®, Euthyrox®, Eferox®, Berlthyrox®, Letrox®, Tirosint®), soft gel capsules (Tirosint®) and oral solutions (Eltroxin®, Tirosint® oral drops and Tirosint® oral solution in unit-dose ampules).

There are advantages and disadvantages that are unique to the formulation type and not to levothyroxine per se. For instance, while tablets and capsules offer the advantage of precise dosing, solutions and liquids can be easier to swallow for children or the elderly. Formulation differences that are specific to levothyroxine also exist. The influence of pH on dissolution profiles of tablets and soft gel capsules is dissimilar,¹⁶² as well as the negative impact of coffee intake on levothyroxine absorption.^93,94

Bioequivalence

The existence of multiple levothyroxine formulations is also the result of the availability of many generic versions of these compounds. Many studies have been published describing comparisons of the PK properties of various levothyroxine formulations^163–181 and various approaches have been employed since bioequivalence assessments of levothyroxine are complicated by baseline levels, feedback mechanisms and by the fact that levothyroxine is considered by some to be a ‘narrow therapeutic index’ (NTI) drug, which some believe merit more stringent criteria (confidence intervals of 90–111 % rather than the standard 80–125 %, or stability throughout the shelf-life of +/-5 % instead of +/-10 %). For this reason, specific guidelines pertaining to assessing the bioequivalence of levothyroxine formulations have been published, in particular by the US Food and Drug Administration (FDA).

Current regulatory guidelines published by the FDA recommend that bioequivalence of levothyroxine formulations be assessed by comparing PK measures of T₄.¹⁸² The underlying assumption regarding the use of T₄ rather than TSH or T₃ is that systemic T₄ levels reflect the levels at the site of action, and that a relationship exists between the efficacy and safety of the product and its systemic levels. Despite TSH sensitivity to changes in thyroid hormone level, TSH is not used to assess bioequivalence of thyroid formulations because it is a secondary response to levothyroxine and there is a significant time delay between the administration of exogenous levothyroxine and the changes noted in TSH levels. In addition, it is simply not a direct measure of levothyroxine- administered product, as are baseline-adjusted T₄ concentrations.

Because levothyroxine is an endogenous compound, it is important to take baseline levels into consideration when performing bioequivalence assessments to avoid biasing comparisons which can lead to failure in distinguishing true differences between formulations.¹⁸³ Current FDA bioequivalence guidelines require that supra-therapeutic doses of levothyroxine (600 mcg) be administered and that levothyroxine PK parameters be corrected for individual baseline values. This minimises the effect of endogenous concentrations on bioequivalence assessments^182,184 by ensuring a high signal (concentrations related to exogenous levothyroxine) to noise (endogenous levels) ratio.

In addition to some of the recommendations described above, the FDA also stipulates that a levothyroxine product must have a 95–105 % potency specification over its entire shelf-life instead of previously accepted potency limits of 90–110 %.¹⁸⁵ This was established to ensure greater consistency in levothyroxine administered to patients and to reduce possibly large fluctuations in drug concentrations.

Thus, recommendations from current regulatory guidelines regarding study design and baseline adjustment of PK parameters ensure that a conservative approach to bioequivalence of levothyroxine formulations is adopted.

Summary

Although levothyroxine has long been a mainstay in the treatment of hypothyroidism, its optimal use often remains elusive. Not only are thyroid hormones levels governed by sensitive and complicated feedback mechanisms, but they are also subject to the influence of disease, the intake of food and the use of concomitant medication. While these competing factors can pose a challenge for clinicians, a thorough comprehension of these elements as well as other PK considerations will ultimately be beneficial for the patient.

For details about the basic and clinical thyroid effects of tyrosine kinase inhibitors, including enhanced dose of levothyroxine, the reader is referred to a review just released by Makita and Iiri.

(Ref: Makita N, Iiri T, Tyrosine kinase inhibitor-induced thyroid disorders: a review and hypothesis, Thyroid, 2013 Feb;23(2):151–9.)