Comparative bioavailability of sublingual vs. oral levothyroxine in patients with post-thyroidectomy hypothyroidism: A single-dose pilot study

AIM: To evaluate the relative bioavailability of sublingual vs. oral levothyroxine (L-T4) in post-thyroidectomy patients, aiming to overcome gastrointestinal absorption variability. METHODS: This open-label, randomized, parallel-group pilot study enrolled 15 de novo hypothyroid patients following total thyroidectomy (oral: n = 7, sublingual: n = 8). Participants received a single 700-μg L-T4 dose under fasting conditions. Pharmacokinetic parameters, including baseline-corrected AUC, Cmax and Tmax, were determined via noncompartmental analysis. RESULTS: Sublingual administration resulted in a Geometric Mean Ratio (GMR) of 1.283 (90% CI: 0.849-1.938) for total systemic exposure (AUC0-∞) and 1.123 (90% CI: 0.815-1.547) for early exposure (AUC0-48) compared to the oral route. Due to the small sample size and inter-subject variability, these differences did not reach statistical significance. Elimination kinetics (T1/2, MRT) were route-independent, while sublingual delivery showed lower apparent clearance (CL/F), supporting improved bioavailability. CONCLUSION: Sublingual L-T4 achieved numerically higher systemic exposure with comparable elimination kinetics to the oral route. These findings suggest sublingual delivery is a promising, practical alternative that mitigates fasting constraints. Large-scale crossover studies are needed to definitively establish bioequivalence and long-term efficacy.