Dataset Information

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal.

ABSTRACT: Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5?±?16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8?±?0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3?±?0.11 hours and 22.9?±?7.7 hours, supporting a two-compartment model. PK modeling predicts that a twice-daily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.

SUBMITTER: Van Tassell B

PROVIDER: S-EPMC6797066 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal.

Van Tassell Benjamin B Wohlford George F GF Linderman Joyce D JD Smith Sheila S Yavuz Sahzene S Pucino Frank F Celi Francesco S FS

Thyroid : official journal of the American Thyroid Association 20190912 10

<b><i>Background:</i></b> L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design ...[more]

PMID: 31364488

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Project description:Abstract Background Liothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer patients during the preparation for nuclear medicine procedures, and there is renewed interest in its use in combination with LT4 in patients who do not respond to the standard treatment. This therapy is commonly done on fixed doses potentially resulting in supraphysiologic levels of T3. A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes able to maintain serum T3 levels within normal range, but data on the PK of LT3 are conflicting. Here we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, not receiving LT4. Methods We performed an open label PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived thyroid cancer (Clinicaltrials.gov ID NCT01441154). LT3 was substituted for LT4 at 1:3 mcg/mcg dosage ratio thrice daily for at least thirty days. PK of single dose LT3 and terminal elimination were assessed over eleven days and first dose PK was offered following the nuclear medicine procedures. Results Fourteen patients (7 males, 7 females) age 48.5±16.0 years completed the study. The LT3 daily dose was 53.7±12.3 (0.74±0.1 mcg/Kg). PK studies performed with the morning dose (18.8±4.4 mcg), indicate a Cmax of 320±60 ng/dl, significantly above the upper limit (90-215). Tmax was 1.8±0.5 hours and two distinct phases of linear elimination with a fast distribution phase and slow elimination phases with half-lives of 1.2 hours and 29.9 hours were identified, supporting a two-compartment model. PK modeling for a 50 mcg LT3 total dose predicted that while the mean T3 levels would not significantly differ among single, twice, or thrice daily administration regimens, the variance would differ dramatically, 213.5±126 vs. 214.5±61 vs. 214.5±35 ng/dl, single, twice and thrice daily administration, respectively. We next performed a PK modeling for LT3/LT4 combination therapy, twice daily administration. The results indicate that low dose LT3 (up to 0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the normal range. Conclusions The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapy directed to maintain stable T3 serum levels. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Project description:Patients with metastatic differentiated thyroid cancer (DTC) may be prepared using either thyroid-stimulating hormone withdrawal (THW) or recombinant human thyroid-stimulating hormone (rhTSH) injections before 131I administration for treatment. The objective of this study was to compare the absorbed dose to the critical organs and tumors determined by 124I PET/CT-based dosimetry for 131I therapy of metastatic DTC when the same patient was prepared with and imaged after both THW and rhTSH injections. Methods: Four DTC patients at MedStar Washington Hospital Center were first prepared using the rhTSH method and imaged by 124I PET/CT at 2, 24, 48, 72, and 96 h after administration of approximately 30-63 MBq of 124I. After 5-8 wk, the same patients were prepared using the THW method and imaged as before. The 124I PET/CT images acquired as part of a prospective study were used to perform retrospective dosimetric calculations for 131I therapy for the normal organs with the dosimetry package 3D-RD. The absorbed doses from 131I for the lungs, liver, heart, kidneys, and bone marrow were obtained for each study (rhTSH and THW). Twenty-two lesions in 3 patients were identified. The contours were drawn on each PET image of each study. Time-integrated activity coefficients were calculated and used as input in OLINDA/EXM sphere dose calculator to obtain the absorbed dose to tumors. Results: The THW-to-rhTSH organ absorbed dose ratio averaged over 5 organs for the first 3 patients was 1.5, 2.5, and 0.64, respectively, and averaged over 3 organs for the fourth patient was 1.1. The absorbed dose per unit administered activity to the bone marrow was 0.13, 0.086, 0.33, and 0.068 mGy/MBq after rhTSH and 0.11, 0.14, 0.22, and 0.080 mGy/MBq after THW for each patient, respectively. With the exception of 3 lesions of 1 patient, the absorbed dose per unit administered activity of 131I was higher in the THW study than in the rhTSH study. The ratio of the average tumor absorbed dose after stimulation by THW compared with stimulation by rhTSH injections was 3.9, 27, and 1.4 for patient 1, patient 2, and patient 3, respectively. The ratio of mean tumor to bone marrow absorbed dose per unit administered activity of 131I, after THW and rhTSH, was 232 and 62 (patient 1), 12 and 0.78 (patient 2), and 22 and 11 (patient 3), respectively. Conclusion: The results suggest a high patient variability in the overall absorbed dose to the normal organs per MBq of 131I administered, between the 2 TSH stimulation methods. The tumor-to-dose-limiting-organ (bone marrow) absorbed dose ratio, that is, the therapeutic index, was higher in the THW-aided than rhTSH-aided administrations. Additional comparison for tumor and normal organ absorbed dose in patients prepared using both methods is needed before definitive conclusions may be drawn regarding rhTSH versus THW patient preparation methods for 131I therapy of metastatic DTC.

Project description:Thyroid dysfunction is associated with changes in coagulation. The aim of our study was to gain more insight into the role of thyroid hormone in coagulation control. C57Black/6J mice received a low-iodine diet and drinking water supplemented with perchlorate to suppress endogenous triiodothyronine (T3) and thyroxine (T4) production. Under these conditions, the impact of exogenous T3 on plasma coagulation, and hepatic and vessel-wall-associated coagulation gene transcription was studied in a short- (4 hours) and long-term (14 days) setting. Comparing euthyroid conditions (normal mice), with hypothyroidism (conditions of a shortage of thyroid hormone) and those with replacement by incremental doses of T3, dosages of 0 and 0.5 μg T3/mouse/day were selected to study the impact of T3 on coagulation gene transcription. Under these conditions, a single injection of T3 injection increased strongly hepatic transcript levels of the well-characterized T3-responsive genes deiodinase type 1 (Dio1) and Spot14 within 4 hours. This coincided with significantly reduced mRNA levels of Fgg, Serpinc1, Proc, Proz, and Serpin10, and the reduction of the latter three persisted upon daily treatment with T3 for 14 days. Prolonged T3 treatment induced a significant down-regulation in factor (F) 2, F9 and F10 transcript levels, while F11 and F12 levels increased. Activity levels in plasma largely paralleled these mRNA changes. Thbd transcript levels in the lung (vessel-wall-associated coagulation) were significantly up-regulated after a single T3 injection, and persisted upon prolonged T3 exposure. Two-week T3 administration also resulted in increased Vwf and Tfpi mRNA levels, whereas Tf levels decreased. These data showed that T3 has specific effects on coagulation, with Fgg, Serpinc1, Proc, Proz, Serpin10 and Thbd responding rapidly, making these likely direct thyroid hormone receptor targets. F2, F9, F10, F11, F12, Vwf, Tf and Tfpi are late responding genes and probably indirectly modulated by T3.

Project description:BACKGROUND:Tyrosine kinase inhibitors (TKIs) have been associated with elevated TSH as a drug class effect. Prior studies of vandetanib in adults with medullary thyroid carcinoma (MTC) described an increase in levothyroxine (LT) requirement. We studied TSH, free T4, and LT dosing in children and adolescents enrolled in the phase I/II trial of vandetanib for medullary thyroid cancer (MTC). METHODS:Data from 13 patients with multiple endocrine neoplasia type 2B (MEN 2B) and MTC were analyzed [6 M, 7 F, median age 13.0 y (9.1-17.3)] Eleven patients (85%) had undergone prior thyroidectomy and all received single-drug therapy with vandetanib for?>?6 months. Confirmed compliance with vandetanib (67-150 mg/m(2)/day) and LT was a necessary inclusion criterion. RESULTS:While on vandetanib treatment, all 11 athyerotic patients exhibited significantly increased TSH levels. The baseline TSH level was 4.37 mclU/ml (0.08 - 23.30); in comparison, the first peak TSH concentration on vandetanib was 15.70 mclU/ml (12.50 - 137.00, p?=?0.0010). The median time to reach the initial peak of elevated TSH was 1.8 months (0.3 - 9.3). Free T4 levels remained within the normal reference range. An increase from a baseline LT dose of 91 mcg/m(2)/day (±24) to 116 mcg/m(2)/day (±24) was required in order to resume normative TSH levels (p?=?0.00005), equal to an increase of 36.6% (±16.56) in the dosage of LT in mcg/day. For the 2 patients with intact thyroid glands, free T4 and TSH remained normal over a combined 6 patient years of follow up. CONCLUSIONS:In our cohort of pediatric MTC patients, athyreotic patients with preexisting hypothyroidism developed increased TSH and reduced free T4 during the first few months of treatment with vandetanib, necessitating an increase in LT dosage. Additional patients with normal thyroid function before treatment and intact glands (n?=?2) maintained normal thyroid function tests during treatment. Elevated TSH in athyreotic patients may be due to an indirect effect of vandetanib on the metabolism of thyroid hormone, or to altered TSH sensitivity at the pituitary. Proper recognition and management of abnormal thyroid hormone levels is critical in growing children on TKIs. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00514046.

Project description:Amphibian metamorphosis is an excellent example of hormone-dependent control of development. Thyroid hormones (THs) regulate almost all aspects of metamorphosis, including brain development and larval neuroendocrine function. Sex steroids are also important for early brain function, although little is known about interactions between the two hormonal systems. In the present study, we established brain developmental profiles for thyroid hormone receptors (tralpha and trbeta), deiodinases (dio1, dio2 and dio3), aromatase (cyp19) mRNA and activity, oestrogen receptors (eralpha and erbeta), androgen receptor (ar) and 5alpha-reductases (srd5alpha1 and srd5alpha2) mRNA during Silurana (Xenopus) tropicalis metamorphosis. Real-time reverse transcriptase-polymerase chain reaction analyses revealed that all of the genes were expressed in the brain and for most of the genes expression increased during development, with the exception of dio2, srd5alpha1 and srd5alpha2. The ability of premetamorphic tadpoles to respond to exogenous THs was used to investigate the regulation of TH- and sex steroid-related genes in the brain during development. Exposure of premetamorphic tadpoles to triiodothyronine (T3; 0, 0.5, 5 and 50 nm) for 48 h resulted in concentration-dependent increases in trbeta, dio2, dio3, eralpha and erbeta. Expression of srd5alpha2 showed large increases (six- to 7.5-fold) for all three concentrations of T3. No changes were detected in dio1, ar and cyp19 transcript levels; however, cyp19 activity increased significantly at 50 nm T3. The results obtained suggest that expression of TH-related genes and er during development could be regulated by rising levels of THs, as previously documented in Lithobates (Rana) pipiens. The positive regulation of srd5alpha by T3 in the brain suggests that endogenous TH levels help maintain or control the rate at which srd5alpha mRNA levels decrease as metamorphosis progresses. Finally, we have identified sex steroid-related genes that are responsive to T3, providing additional evidence of crosstalk between THs and sex steroids in the tadpole brain.

Dataset Information

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal.

Publications

Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal.

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