No Effect of Levothyroxine and Levothyroxine-Induced Subclinical Thyrotoxicosis on the Pharmacokinetics of Sorafenib in Healthy Male Subjects.

Background: Patients receiving the multikinase inhibitor sorafenib for locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine often receive concomitant levothyroxine for thyrotropin (TSH) suppression. In the Phase 3 DTC trial (DECISION), sorafenib exposure was approximately twofold higher than that observed in other cancers. This study assessed sorafenib pharmacokinetics without and with concomitant levothyroxine to examine whether a levothyroxine interaction or levothyroxine-induced subclinical thyrotoxicosis results in increased sorafenib exposure in patients with DTC.

Methods: This was an open-label, two-period sequential treatment study in healthy male subjects. In period 1, day 1, subjects received a single oral dose of sorafenib 400 mg, followed by a minimal 10-day washout. In period 2, day 1, levothyroxine 300 μg was administered orally once daily (q.d.) for 14 days. After 10 days, a single oral concomitant dose of sorafenib 400 mg was given. Blood samples for sorafenib pharmacokinetic analyses were obtained pre-dose and at time points up to 96 hours after sorafenib dosing. Samples for thyroid tests were collected before and after levothyroxine dosing.

Results: Twenty-five subjects completed the study and were evaluable for pharmacokinetic analysis. Levothyroxine 300 μg q.d. was well tolerated and induced subclinical thyrotoxicosis, producing full suppression of TSH (M ± SD = 0.032 ± 0.027 mIU/L) and increased free thyroxine (from 0.94 ± 0.09 to 1.77 ± 0.33 ng/dL) and free triiodothyronine (from 2.87 ± 0.28 to 4.24 ± 0.66 pg/mL) levels by day 11 of period 2. The geometric mean (%CV) sorafenib maximum concentration (C) without and with levothyroxine was 2.09 (68.1) and 1.78 (63.9) mg/L, respectively, with a corresponding geometric mean area under the curve of 68.1 (68.2) and 64.3 (66.3) mg·h/L. Median (range) time to C was 4.00 (2.98-16.0) and 4.02 (1.98-36.0) hours, respectively. Mean (%CV) half-life was 24.0 (25.3) and 25.7 (21.0) hours. All study drug-related adverse events were mild and included headache and fatigue for sorafenib, and headache, increased alanine aminotransferase and glutamate dehydrogenase, fatigue, and nervousness for levothyroxine.

Conclusions: Levothyroxine 300 μg q.d. for 14 days was well tolerated, induced subclinical thyrotoxicosis, and did not affect sorafenib pharmacokinetics. The findings suggest that concomitant use of levothyroxine with sorafenib is not likely responsible for the previously reported increase in sorafenib exposure in patients with DTC. However, the possible effects of long-term levothyroxine dosing were not assessed.