SAT-140 A Drug-Drug Interaction Trial of Oral Semaglutide with Levothyroxine and Multiple Coadministered Tablets

Abstract

Introduction: Oral semaglutide contains the GLP-1 analog semaglutide co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). Aims: This trial investigated (A) the effect of oral semaglutide and SNAC alone on the pharmacokinetics (PK) of levothyroxine (thyroxine), a frequently used oral medication with similar dosing instructions to oral semaglutide, and (B) the effect of multiple co-administered tablets on oral semaglutide PK. Methods: This was a 2-part, open-label, one-sequence crossover trial in 45 healthy subjects. Part A comprised three periods during which subjects received single-dose thyroxine 600 μg alone, with SNAC 300 mg, and with oral semaglutide 14 mg at steady-state. Primary endpoint was area under the total thyroxine (T4) serum concentration-time curve (0-48 h) after thyroxine, baseline-corrected for endogenous total T4 ( bc AUC 0-48h,T4 ). No effect of oral semaglutide or SNAC alone was declared if the 90% CI for the treatment ratio (thyroxine ± oral semaglutide or SNAC) was entirely within the pre-defined interval (0.80-1.25). In part B, oral semaglutide 14 mg at steady-state was co-administered with 5 placebo tablets (used as model tablets) once-daily for 5 weeks. Primary endpoint was area under the semaglutide plasma concentration-time curve during a 0-24 h dosing interval at steady state (AUC 0-24h ); no effect was confirmed if the 90% CI for the treatment ratio (oral semaglutide ± placebo) was entirely within the pre-defined interval (0.7000-1.4286). Safety and tolerability were also assessed. Results: In part A, co-administration of steady-state oral semaglutide with thyroxine resulted in a 33% increase in bc AUC 0-48h,T4 ; the 90% CI for the treatment ratio was not within the no effect interval. Oral semaglutide had no effect on baseline-corrected maximum total T4 concentration ( bc C max,T4 ). Co-administration of SNAC alone did not increase exposure of total T4. In part B, co-administration of multiple tablets with steady-state oral semaglutide resulted in decreased semaglutide AUC 0-24 (34%) and C max (32%); part of the treatment ratio 90% CIs were not within the no effect interval for both endpoints. The safety profile was as expected for GLP-1 receptor agonists with gastrointestinal adverse events the most frequent. Conclusion: PK of thyroxine were influenced by co-administration of steady-state oral semaglutide. However, no change in clinical practice is required as close monitoring of co-administered thyroxine is already part of medical guidance. No obvious effect was seen with SNAC alone so increased thyroxine exposure may be due to the known gastric emptying delaying effect of the GLP-1 component. Absorption...

Oral Semaglutide: First-in-Class Oral GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes Mellitus

“…4,9 Drugs that have a narrow therapeutic index may require increased clinical or laboratory monitoring when used in combination with oral semaglutide. 4,9,10 In one study, levothyroxine exposure increased by 33% (90% CI: 125-142) when administered with oral semaglutide. 10 There is currently no guidance on recommendations for administering these medications in practice, and this may present a challenge for patients currently taking levothyroxine because it has similar administration considerations.…”

“…4,9,10 In one study, levothyroxine exposure increased by 33% (90% CI: 125-142) when administered with oral semaglutide. 10 There is currently no guidance on recommendations for administering these medications in practice, and this may present a challenge for patients currently taking levothyroxine because it has similar administration considerations. Patients may have to administer levothyroxine on an alternative schedule, such as at night, 3 to 4 hours after the last meal.…”

Integrating oral semaglutide into clinical practice in primary care: for whom, when, and how?

“…• As food and other tablets can impact the absorption of oral semaglutide [70,78], the patient should be instructed to take oral semaglutide on an empty stomach after they wake up [9]. • The patient should swallow the tablet whole (not split, crushed, or chewed) with a sip of plain water (up to 4 floz/120 mL) and then wait at least 30 minutes before eating, drinking beverages, or taking other oral medications [9].…”

“…An example of such an agent is levothyroxine, which is used as a thyroid hormone replacement therapy and is recommended to be taken on an empty stomach before breakfast [77]. When a single dose of levothyroxine 600 µg was co-administered with oral semaglutide at steady-state in a study in healthy volunteers, thyroxine exposure increased by 33%, potentially due to a delay in gastric emptying caused by oral semaglutide [9,78]. Patients taking concomitant levothyroxine should therefore be advised to comply with the dosing conditions for oral semaglutide [9].…”

“…Patients taking concomitant levothyroxine should therefore be advised to comply with the dosing conditions for oral semaglutide [9]. In line with current medical guidance, close monitoring of thyroxine parameters should be considered and patients could consider taking levothyroxine at least 3 hours after the last meal of the day instead of in the morning [78,79].…”