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.

Keywords: L-triiodothyronine; combination therapy; hypothyroidism; pharmacokinetics; thyroid hormone withdrawal.

FIG. 1.

Study design. Top panel: timeline of the study. After enrollment, study volunteers were treated with LT3 for at least 30 days before admission to the Clinical Center for last-dose PK and terminal elimination studies. An abbreviated PK study was offered following the nuclear medicine procedures. Bottom panel: time of PK blood sampling. LT3, L-triiodothyronine; LT4, levothyroxine; PK, pharmacokinetics; T3, triiodothyronine; TSH, thyrotropin.

FIG. 2.

CONSORT chart.

FIG. 3.

PK analysis of last-dose LT3 and terminal elimination (A). Once the data were plotted on a logarithmic scale (B) two distinct phases of linear elimination, a fast distribution phase and a slow elimination phase with half-lives of 1.2 and 29.9 hours, became evident. LOD, limit of detection for total T3.

FIG. 4.

A PK modeling of 50 mcg of LT3 administered on a thrice (A), twice (B), or single (C) daily regimen was generated. Solid lines: reference range of T3. Dashed line: mean concentration of T3. All the proposed treatment schemes result in mean T3 concentrations near the upper limit of reference range, but with dramatic differences in the variance (see Results for details).

FIG. 5.

A PK modeling of LT3/LT4 combination therapy with 3.25 (A), 5 (B), and 10 (C) mcg of LT3 administered on a twice-daily regimen was generated. Solid lines: reference range of T3. Dashed line: mean concentration of T3 (see Results for details).