Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal
Pharmacokinetics of L-Triiodothyronine in Patients Undergoing Thyroid Hormone Therapy Withdrawal
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DOI：
10.1089/thy.2019.0101
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发表时间：
2019-09-12
期刊：
影响因子：
6.6
通讯作者：
Celi, Francesco S.
中科院分区：
文献类型：
--
作者：
Van Tassell, Benjamin;Wohlford, George F.;Celi, Francesco S.
背景资料：L-三碘甲状腺原氨酸（LT 3）是甲状腺癌（TC）患者在核医学程序准备期间左旋甲状腺素（LT 4）的替代品，它与LT 4联合用于对甲状腺功能减退症标准治疗无反应的患者。这种疗法通常通过使用固定剂量来完成，可能导致三碘甲状腺原氨酸（T3）的超生理水平。充分了解LT 3药代动力学（PK）对于设计能够将血清T3水平维持在参考范围内的联合治疗方案是必要的，但关于LT 3 PK的数据相互矛盾。在这里，我们提出了一项研究，旨在描述缺乏内源性甲状腺激素产生的患者中LT 3的PK，并且没有接受LT 4治疗。研究方法：我们在接受甲状腺激素戒断的患者中进行了一项开放标签、PK研究，以准备核医学程序来评估和治疗卵泡源性TC。以1：3 mcg/mcg剂量比每日三次用LT 3替代LT 4，持续至少30天。在11天内评估了最后一次LT 3给药在稳态和终末消除时的PK。此后，在自愿参加第二项研究的患者中进行了核医学程序后的PK研究。结果：14例年龄为48.5 ± 16.0岁的患者完成了末次给药研究，5例完成了第二次PK研究。PK分析表明，达到最大血清浓度的时间为1.8 +/- 0.32小时，有两个不同的线性消除相，快速分布相和缓慢消除相，半衰期分别为2.3 +/- 0.11小时和22.9 +/- 7.7小时，支持二室模型。PK建模预测，低剂量LT 3（0.07 mcg/kg，每日两次）联合LT 4每日两次给药可预测地增加血清T3浓度，且无高于参考范围的显著峰值。结论：LT 3的PK可以通过两室模型很好地描述，该模型假设仅从采样室中消除，具有快速分布相和缓慢消除相。这些信息将有助于设计用于LT 3/LT 4联合治疗的治疗策略，以维持稳定的T3血清水平。
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.