For so many years, patients have been insisting that levothyroxine tablets from different manufacturers, even different dosages from one manufacturer, have different effects on them. Now a paper which pretty clearly shows that stomach acidity is probably a significant factor. Albeit a "virtual" paper using modelling techniques.
Quite sensibly, the authors suggest the modelling could help to identify medicines for which more extensive testing would be required.
This backs up calls for levothyroxine bioequivalence being tested in those who suffer from hypothyroidism - not just healthy volunteers (in whom we could expect "normal" stomach acidity).
Yet again, real science (I hope the quality of the paper is high enough to be regarded in that light) and patients in agreement: medical establishment in denial and unable to accept the criticism implicit in these results.
Note the comparison was between Synthroid (branded levothyroxine) and Tirosint (gel capsule) - across a range of levels of acidity. (The range of acidities was 7 to 1.2 with 7 being neutral, and 1.2 being strongly acidic.)
Virtual bioequivalence for achlorhydric subjects: The use of PBPK modelling to assess the formulation-dependent effect of achlorhydria
Author Kosuke Doki, Adam S.Darwich, Nikunjkumar Patel, Amin Rostami-Hodjegan
doi.org/10.1016/j.ejps.2017...
open access
Abstract
Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulation more than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivo relationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations.
