TSH-based protocol, tablet instability, and absorption effects on L-T4 bioequivalence.

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.

• Authors: Marisa Eisenberg, Joseph J Distefano
• Journal: Thyroid : official journal of the American Thyroid Association (Thyroid) Vol. 19 Issue 2 Pg. 103-10 (Feb 2009) ISSN: 1557-9077 [Electronic] United States
• PMID: 19191742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Tablets
• Triiodothyronine
• Thyrotropin
• Thyroxine

Topics

• Computer Simulation
• Drug Stability
• Humans
• Intestinal Absorption (physiology)
• Tablets
• Therapeutic Equivalency
• Thyrotropin (blood)
• Thyroxine (pharmacokinetics)
• Triiodothyronine (blood)