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Thyroid Disorders Hypothyroidism A Review of the Pharmacokinetics of Levothyroxine for the Treatment of Hypothyroidism Philippe Colucci, 1 Corinne Seng Yue, 2 Murray Ducharme 3 and Salvatore Benvenga 4 1. Principal Scientist, Learn and Confirm Inc.; 2. Principal Scientist, Learn and Confirm Inc. and PhD Candidate, Faculty of Pharmacy, University of Montreal, 3. President and CEO, Learn and Confirm Inc., St Laurent and Associate Professor, Faculty of Pharmacy, University of Montreal, Montreal, Canada, 4. Professor of Medicine, Director, Master Program on Childhood, Adolescent and Women’s Endocrine Health, and Chief, Interdepartmental Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, University of Messina, Messina, Italy. 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. Keywords Pharmacokinetics, drugs formulations, levothyroxine, intestinal absorption, interactions between drugs, hypothyroidism Disclosure: Philippe Colucci, Corinne Seng Yue and Murray Ducharme are employees of Learn and Confirm Inc. and received funding from Institut Biochimique SA (IBSA). Salvatore Benvenga received from IBSA new L-thyroxine formulations for the conduct of clinical studies. Received: 30 January 2013 Accepted: 17 February 2013 Citation: European Endocrinology, 2013;9(1):40–7 Correspondence: Salvatore Benvenga,
Interdepartmental Program of Molecular & Clinical Endocrinology and Women’s Endocrine Health, Policlinico Universitario di Messina padiglione H, 4 piano 98125 Messina, Italy. E: [email protected]; [email protected] 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 (TSHs) 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 40 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 1,217 and 147 publications, respectively. © To uch ME dical ME dia 2013