TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T₄Bioequivalence

Abstract

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.

TSH and Thyrotropic Agonists: Key Actors in Thyroid Homeostasis

“…As a result of increased confidence in modelling results, attempts have been made to apply some of the newer approaches [11, 23, 49, 113, 116] to clinical research [23, 117–119] and medical decision making [11, 116, 120]. …”

Thyroid Function and Obesity

“…al-Adsani et al [10] found changes in REE of 7–8% when the dose of L-T 4 to hypothyroid patients was modified to change serum TSH by a factor of 10, corresponding to the difference from the lower to the upper limit of the laboratory reference range for serum TSH (0.4–4.0 mU/l). Based on data from many studies, Eisenberg and Distefano [11] developed a model on the association between the absorbed doses of L-T 4 given as supplement to a thyroidectomized patient and serum TSH. In this model, a change in serum TSH from 4.0 to 0.4 mU/l corresponds to a quite substantial (approx.…”

Subcutaneous application of levothyroxine as successful treatment option in a patient with malabsorption

“…Therefore, after ruling out compliance problems and drug interactions, fecal fat excretion and a gastroscopy should be performed to rule out these causes [11]. Other causes for malabsorption of levothyroxine could be different preparations of the medication, though absorption differences turned out to be as small as 10–15% [14], making this theory unlikely in our patient. In other cases, levothyroxine taken at bedtime lead to higher blood concentrations of thyroid hormones and lower TSH than taken in the morning, probably due to better absorption over night [9].…”