L-T 4 Bioequivalence and Hormone Replacement Studies via Feedback Control Simulations

Abstract

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 T₄ 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.