Single Center, Open‐Label, Randomized Crossover Trial on Drug–Drug Interactions of Levothyroxine/Magnesium‐Citrate and Levothyroxine/Magnesium‐Aspartate in Healthy Subjects—The <scp>ThyroMag</scp> Trial

Divalent cations such as calcium and ferrous sulfate interfere with the absorption of levothyroxine due to complexing. To our knowledge, the effects of magnesium on levothyroxine absorption have never been studied. The open-label cross-over pharmacokinetic study was conducted in 15 healthy, euthyroid adults. 1 mg of levothyroxine was administered in tablet form alone or co-administered with either magnesium aspartate or magnesium citrate. Participants received all three treatments, separated by a washout period, but were randomly allocated 1:1:1 to one of three treatment sequences. We measured thyroxine (T4) over a 6-h period after ingestion. The primary endpoint was the area under the curve (AUC) of thyroxine; secondary endpoints were C_max and T_max. Coadministration of magnesium aspartate significantly reduced thyroxine AUC by 12% (geometric mean ratio, GMR = 0.88, 95% CI 0.81-0.95, p = 0.002) and coadministration of magnesium citrate reduced thyroxine AUC non-significantly by 7% compared with levothyroxine alone (GMR = 0.93, 95% CI 0.86-1.01, p = 0.076). C_max was significantly reduced by 7% and T_max was significantly increased by 17% when magnesium aspartate was co-administered. The changes in C_max and T_max were smaller when magnesium citrate was co-administered. In conclusion, magnesium reduces the absorption of levothyroxine. However, we found smaller effects compared to those already described for other divalent cations, possibly due to the liquid formulation. Hypothyroid patients should nonetheless take levothyroxine separated from magnesium-containing formulations, especially if TSH levels are desired to be within a narrow range. If taken together, magnesium citrate may be a better option than magnesium aspartate.