BACKGROUND: FDA Guidance for pharmacokinetic (PK) testing of levothyroxine 
(L-T(4)) for interbrand bioequivalence has evolved recently. Concerns remain 
about efficacy and safety of the current protocol, based on PK analysis 
following supraphysiological L-T(4) dosing in euthyroid volunteers, and recent 
recalls due to intrabrand manufacturing problems also suggest need for further 
refinement. We examine these interrelated issues quantitatively, using simulated 
what-if scenarios testing efficacy of a TSH-based protocol and tablet stability 
and absorption, to enhance precision of L-T(4) bioequivalence methods.
METHODS: We use an updated simulation model of human thyroid hormone regulation 
quantified and validated from data that span a wide range of normal and abnormal 
thyroid system function. Bioequivalence: We explored a TSH-based protocol, using 
normal replacement dosing in simulated thyroidectomized patients, switching 
brands after 8 weeks of full replacement dosing. We simulated effects of tablet 
potency differences and intestinal absorption differences on predicted plasma 
TSH, T(4), and triiodothyronine (T(3)) dynamics. Stability: We simulated effects 
of potency decay and lot-by-lot differences in realistic scenarios, using actual 
tablet potency data spanning 2 years, comparing the recently reduced 95-105% 
FDA-approved potency range with the original 90-110% range.
RESULTS: A simulated decrease as small as 10-15% in L-T(4) or its absorption 
generated TSH concentrations outside the bioequivalence target range (0.5-2.5 
mU/L TSH), whereas T(3) and T(4) plasma levels were maintained normal. For a 25% 
reduction, steady-state TSH changed 300% (from 1.5 to 6 mU/L) compared with <25% 
for both T(4) and T(3) (both within their reference ranges). Stability: TSH, 
T(4), and T(3) remained within normal ranges for most potency decay scenarios, 
but tablets of the same dose strength and brand were not bioequivalent between 
lots and between fresh and near-expired tablets.
CONCLUSIONS: A pharmacodynamic TSH-measurement bioequivalence protocol, using 
normal L-T(4) replacement dosing in athyreotic volunteers, is likely to be more 
sensitive and safer than current FDA Guidance based on T(4) PK. The tightened 
95-105% allowable potency range for L-T(4) tablets is a significant improvement, 
but otherwise acceptable potency differences (whether due to potency decay or 
lot-by-lot inconsistencies) may be problematic for some patients, for example, 
those undergoing high-dose L-T(4) therapy for cancer.