FDA Guidance for testing bioequivalence of levothyroxine (L-T4) preparations has been challenged by several groups, based on multiple issues. The efficacy of single versus combined hormone therapy also is receiving additional scrutiny. To examine these concerns, we developed a new nonlinear feedback system simulation model of whole-body regulation mechanisms involving dynamics of T3, T4, TSH, plasma protein binding, extravascular regulatory enzyme systems, and the hypothalamic-pituitary-thyroid axis, all quantified from human data. To address bioequivalence, we explored how to best account for varying and unmeasured endogenous T4 following dosing with exogenous oral L-T4 in euthyroid volunteers in required pharmacokinetic (PK) studies, by simulating various dosing scenarios and developing a new and simple correction method. We computed and assessed dosing error effects and baseline corrections using simulator-predicted endogenous T4 level variations, due to actual closed-loop effects, and compared these with approximate corrections computed directly from PK data. Predicted dose-responses were quite linear, and for constant baseline, 7-day half-life, and our new formula-correction methods, we established some bounds on bioequivalent dosages. Simulated replacement after thyroidectomy required 141 μg L-T4 only to normalize T3 tissue levels and 162 μg L-T4 to normalize plasma T3 levels. A combined dose of approximately 103 μg L-T4 plus approximately 6 μg T3 (∼18:1 ratio) was needed to normalize both plasma T3 and T 4 and average tissue T3 levels. However, simulated average tissue T3 levels were normalized with standard L-T4-only therapy, and plasma T3 levels were still within the normal range. We suggest a simple and more accurate correction for endogenous T4 in PK studies. Current standard L-T4-only treatment is supported for routine replacement needs.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism