When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets

Abstract

-Purpose:Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole. Methods: Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 g) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baselineadjusted pharmacokinetic parameters were calculated: C max (maximal concentration), T max (time to C max ), AUC 0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC 0-6 and AUC 0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare lntransformed C max and AUC. Non-parametric T max analyses were done. Results: In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for C max , 18% vs. 14% for AUC 0-6 , 17% vs. 5% for AUC 0-12 and 10% vs. 8% for AUC 0-t ). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in T max were found. Conclusions: Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

l-Thyroxine in an Oral Liquid or Softgel Formulation Ensures More Normal Serum Levels of Free T4 in Patients with Central Hypothyroidism

“…liquid or softgel capsule, compared to the classical tablet ( 1 – 3 ). Subsequent literature ( 4 – 10 ) confirmed our conclusions, which was not surprising considering the favorable pharmacokinetics profile of either liquid or softgel l -T4 ( 1 , 3 , 11 , 12 ). Precisely, the setting in which the superiority of either novel formulations of l -T4 over tablet l -T4 was malabsorption of l -T4 caused by food, coffee, proton pump inhibitors, and calcium salts or iron salts.…”

Authors’ Reply to Castello-Bridoux et al.: “Comment on Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?”

“…Regarding the potential impact of mannitol on bioavailability and bioequivalence, in the case of levothyroxine, we refer to the review entitled “Impact of Osmotically Active Excipients on Bioavailability and Bioequivalence of BCS Class III Drugs” [ 11 ]. On the question of levothyroxine BE in patients vs. healthy volunteers, we cite publications reporting that BE in healthy volunteers is not indicative of BE in some sub-groups of patients [ 12 , 13 ].…”

The Economic Impact of Changing Levothyroxine Formulations in Difficult-to-Treat Hypothyroid Patients: An Evidence-Based Model

“…There is also evidence indicating that hypothyroid patients treated with levothyroxine gel caps may experience less thyroid hormone fluctuation than with treatment using levothyroxine tablets [23][24][25][26][27][28].…”