Keywords

Lifelong treatment with LT4, guided by levels of thyrotropin, is the mainstay of management of hypothyroidism. The bioavailability of LT4 is about 70% following an oral dose, with absorption occurring mainly in the ileum and jejunum. Maximum plasma concentrations of LT4 are achieved about 3 h after an oral dose in patients with hypothyroidism. The long terminal half-life of orally administered LT4, about 7.5 days, is consistent with once-daily dosing. Pregnancy, several medical conditions (especially) those affecting the gut, and a number of drugs, supplements, or foodstuffs can reduce the absorption and absolute bioavailability of LT4, or can alter the secretion of TSH, with detrimental consequences for long-term control of thyroid function. Poor adherence to LT4 therapy is also a common challenge. The introduction of novel formulations of LT4, with more precise delivery of the active ingredient and higher levels of bioequivalence with existing products will facilitate accurate titration of LT4 for patients with hypothyroidism.

1 Introduction

Oral administration of levothyroxine (LT4), which targets the circulating level of thyrotropin (thyroid-stimulating hormone, TSH) to within a predefined reference range, is the mainstay of treatment of hypothyroidism [1,2,3]. This chapter summarises the administration, absorption, distribution, metabolism, and elimination of LT4. In addition, it addresses the therapeutic significance of pharmacologic and other factors that can alter exposure to LT4, and of changing regulatory requirements concerning the manufacture of LT4 tablets.

2 Absorption, Distribution, Metabolism, and Elimination of Levothyroxine

2.1 Absorption and Distribution

In general, about 70–80% of an oral dose of LT4 is absorbed from the intestine [4], which may involve transport of the LT4 molecule on the Organic Acid Transporting Polypeptide 2B1 (OATP2B1) transporter [5]. One study did not find significant differences in absorption of LT4 between subjects with and without hypothyroidism, whereas another study demonstrated higher bioavailability of LT4 in subjects with hypothyroidism or hyperthyroidism, compared with euthyroid subjects [6]. It has been shown that about half of an oral dose of the hormone was absorbed in the jejunum and ileum following administration of radiolabelled LT4 [7]. A modest reduction in LT4 absorption was noted in elderly subjects (>70 years), compared with younger adults [8]. In routine clinical practice, titration of the LT4 dose in an elderly patient to an appropriate age-specific reference range would account for this effect of age on LT4 absorption (see chapter, “Levothyroxine in the Older Patient”, of this book) [9]. Unlike T4, T3 is essentially completely absorbed (100%) from the intestine following an oral dose [10].

Fig. 1 shows the plasma concentration-time curve from a pharmacokinetic evaluation of two formulations of LT4 in healthy subjects [11]. The time to maximal plasma concentration (T max) of LT4 has been reported as 3 h in subjects with primary hypothyroidism and 2 h in euthyroid controls [12]. Concomitant food intake reduces the bioavailability of LT4, hence the labelling requirement to take LT4 tablets on an empty stomach, e.g. 30 min before breakfast, or 3 h after the evening meal [12, 13]. In plasma, LT4 is highly bound to plasma proteins (>99.9%) and distributes within a volume equal approximately to the human body’s total extracellular space (about 11–15 L) [14, 15].

Fig. 1
figure 1

Plasma concentration-time curves from a comparison of an existing LT4 tablet formulation with a new LT4 tablet formulation designed to meet new regulatory requirements for the manufacture of such products. (Reproduced with permission from Ref. [11])

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2.2 Metabolism and Elimination

The main route of metabolism of LT4, and the route most relevant to its physiological actions, is conversion to T3 and deactivation, mediated by three peripheral deiodinases (Table 1) [16, 17]. Briefly, deiodinases D1 and D2 can mediate the conversion of T4 to T3, enhancing the availability of T3 to local tissues. Accordingly, LT4 may be considered to act largely as a prodrug for delivery of T3 to peripheral tissues. D2 is more important than D1 for generating T3; D1 is especially important for clearing the inactive thyroid hormone metabolite, reverse T3 (rT3), from the system via conversion to a further inactive deiodinated thyroid hormone metabolite. The main function of deiodinase D3 is the degradation of thyroid hormones. Polymorphisms of deiodinases may inhibit the conversion of LT4 to T3 in the periphery and have been proposed to explain an incomplete effect of exogenous LT4 treatment in resolving symptoms of hypothyroidism in some patients [18].

Table 1 Metabolism of levothyroxine by peripheral deiodinases
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Multiple metabolites of thyroid hormones exist, and some of these may have intriguing biological actions that are the focus of current research [19,20,21]. Pathways for biotransformation of LT4 include decarboxylation and oxidative deamination, which results in, e.g. 3-iodothyroacetic acid. The biological activity of metabolites of LT4 remains to be established; 3-iodothyroacetic acid, for example, has been shown to induce antidepressant effects, and to promote itching and discomfort, in animal models [21].

The elimination half-life of LT4 after oral dosing averages 7.5 days in patients with hypothyroidism, consistent with once-daily dosing [14]. A slightly lower elimination half-life was reported in euthyroid subjects (average 6.2 days) [14]. Interestingly, the elimination half-life of T3 is much lower (1–1.4 days, on average) [14], which may complicate future attempts to deliver LT4–T3 combination therapies [22].

3 Factors That May Alter Exposure to an Oral Dose of Levothyroxine

3.1 Factors That May Reduce Exposure to Levothyroxine

3.1.1 Diurnal Variation

Taking LT4 at bedtime (e.g. 3 h after the evening meal) rather than in the morning modestly but significantly increased LT4 levels and reduced TSH levels in the blood [23]. Consequently, it has been proposed to move the routine administration of LT4 from morning to evening, especially as a range of secondary measures (creatinine, lipids, body mass index, heart rate, quality of life) were unchanged between morning and bedtime administration. However, the usually recommended time of intake of LT4 remains in the morning (but at least 30 min before consumption of tea, coffee, or breakfast).

3.1.2 Malabsorption of, and Suboptimal Adherence to, Levothyroxine

Numerous factors may inhibit the absorption of LT4 into the bloodstream, including pre-existing intestinal disorders (e.g. celiac disease, prior gut resection or some forms of bariatric surgery), or concomitant intakes of certain supplements that contain metal ions (e.g. antacids, calcium, iron), drugs (e.g. laxatives, sevelamer, proton pump inhibitors), or soya protein [24,25,26,27,28,29]. The solubility of LT4 increases as pH decreases [30]. Proton pump inhibitors reduce the acidity (and increase the pH) of the stomach, and thus may reduce the bioavailability of LT4 by about 40% [29]; conversely, co-administration of ascorbic acid (vitamin C) reduces gastric pH and increases the absorption of LT4 [29, 30].

Malabsorption of LT4 results in lower than expected blood levels of LT4 and higher than expected levels of TSH, sometimes even in the setting of high doses of exogenous LT4. Alternative formulations to the usual tablet may be considered for patients with documented LT4 malabsorption [27, 31]. In cases where suboptimal adherence to LT4 therapy is suspected [32], the LT4 absorption test, where thyroid hormone levels are measured after a supervised dose of LT4, can be useful in distinguishing non-adherence of LT4 from genuine cases of malabsorption of LT4 [33]. Intramuscular LT4 treatment has been proposed for patients with severe intestinal malabsorption of LT4 though this approach remains within the research domain at present [34].

3.2 Factors That May Alter the Measured Level of Thyrotropin

A series of other factors influences the TSH test result, and therefore have clinical implications for the administration of LT4. This has been reviewed elsewhere [27], and is summarised briefly as follows:

Pregnancy

The requirement for, and production of, thyroid hormones increase markedly during pregnancy, with a consequent fall in TSH levels. Current guidelines recommend use of locally derived, trimester-specific reference ranges for testing thyroid function in pregnant women [35].

Drugs

Substances that alter the level of TSH will impact on the required dosage of LT4, as the TSH level is used to guide therapy. Several medications have the potential to decrease the TSH result, including dopamine antagonists, glucocorticoids, alemtuzumab, proton pump inhibitors, interferon-alpha, and metformin. Other drugs may increase or decrease the TSH test result, including lithium or amiodarone [27, 36,37,38,39,40].

Biorhythms

TSH secretion follows a diurnal variation, with the lowest value recorded around the middle of the day [41]. A circannual variation in TSH has also been observed in a large database study, with lower values during the summer [42], although the functional significance of this observation remains uncertain [43].

Demographics

TSH levels increase with age and are higher in women vs. men [43, 44]. Ethnicity also influences thyroid hormone levels [43, 44], which adds weight to the importance of using relevant reference populations for determining “normal” TSH results.

Smoking

TSH levels may be lower in smokers vs. non-smokers [45].

Obesity

Obesity is often considered to be a consequence (or a symptom) of hypothyroidism [1]. However, TSH levels correlate positively with BMI, consistent with a mechanism in which increased leptin secretion in obese subjects may drive increased secretion of TSH [46, 47]. The relationships between obesity, the TSH level, and the LT4 requirement are therefore complex.

Interference with TSH assays

Different commercial TSH assays may have different ability to recognise “macro-TSH”, which is TSH attached to IgG autoantibodies [48]. Macro-TSH is secreted variably between individuals with hypothyroidism.

Other substances in the patient’s circulation may interfere directly with the operation of the TSH test, such as autoantibodies to LT4, rheumatoid factors (IgM antibodies directed against human IgG), and heterophilic antibodies (particularly human anti-mouse IgG antibodies [HAMA]), leading to variable test results [49].

4 Levothyroxine Tablets in a Changing Regulatory Environment

The manufacture of pharmaceutical products is subject to regulatory supervision to ensure maintained, high quality and consistency of successive batches; in particular, new formulations of currently available LT4 products must be bioequivalent to the existing formulation [50]. A small change in the level of T4 in the bloodstream will result in a much larger relative change in TSH secretion [28]. Accordingly, LT4 is regarded as a “narrow therapeutic index” drug in Europe (similar terms are used in other countries). According to the standard criteria for bioequivalence between an equivalent oral dose of two pharmaceutical preparations, the 90% confidence intervals (90%CI) for the geometric mean ratio of the area under the concentration-time curve (AUC) and the peak plasma concentration (C max) must be contained between 80% and 125% [51, 52]. For most narrow therapeutic index drugs, including LT4, current specifications now require that the 90% CI for the geometric mean ratio of the AUC and C max values must lie between 90% and 111%, for the products to be considered to be bioequivalent [51, 52]. Updated regulations in several countries now also require the actual LT4 content of LT4 tablets to lie between 90% or 95% (depending on the country) and 105% of the amount declared on the package, throughout the shelf life of the product [53,54,55].

A randomised clinical trial compared the clinical pharmacokinetics of a new formulation of LT4 that meets these updated, narrowed requirements for bioequivalence with the previous formulation, in 216 healthy subjects [11, 56]. Fig. 1 showed that the plasma concentration-time curves and C max values of the two formulations were essentially identical [11]. A formal evaluation of bioequivalence showed that the new formulation with improved specifications met the updated, stricter criteria for bioequivalence for a new formulation of a narrow therapeutic index drug (Fig. 2).

Fig. 2
figure 2

Formal demonstration of bioequivalence according to updated regulatory criteria between the new and former LT4 tablet formulations shown in Fig. 1. (Reproduced with permission from Ref. [56])

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5 Conclusions

LT4 is absorbed well and quickly from the gastrointestinal tract after oral administration. Once-daily dosing is feasible, based on its long half-life. Several medical conditions, particularly those affecting the gut, a number of drugs, pregnancy, and ingestion of supplements or food can interfere with the absorption of LT4 or the corresponding TSH test. As a consequence, care must be taken to identify and exclude these factors, as well as suboptimal adherence to therapy, when a patient presents with symptoms of hypothyroidism in spite of LT4 prescriptions. The introduction of novel formulations of LT4, with improved drug stability over time, more precise delivery of the active ingredient, and higher levels of bioequivalence compared with existing products promises to simplify accurate titration of LT4 for patients with hypothyroidism.