Apalutamide treatment and refractory hypothyroidism: effects of apalutamide on levothyroxine metabolism

Apalutamide, a selective androgen receptor antagonist, is a new treatment for prostate cancer. Among the side effects observed during apalutamide treatment, an increased risk of hypothyroidism has been reported, particularly in patients previously treated with levothyroxine compared with untreated patients. Apalutamide is thought to stimulate hepatic UDP-glucuronosyltransferase activity, resulting in increased clearance and stimulation of the thyroxine enterohepatic cycle. A 65-year-old man on 150 μg/day levothyroxine treatment after total thyroidectomy for Graves' disease was euthyroid. Treatment with apalutamide (240 mg/day) was started for metastatic prostate neoplasia. After 1 month, the TSH level was 47.9 μIU/mL, and the dose of levothyroxine was gradually increased. In the presence of refractory hypothyroidism (TSH 38 μIU/mL) despite 275 μg/day of levothyroxine (3.25 μg/kg/d), a levothyroxine absorption test was performed: the basal concentration of total T4 was 5.8 μg/dL; after oral absorption of 1,000 μg of levothyroxine, total T4 concentration increased, peaking at 8.1 μg/dL after 2 h. The percentage absorption of levothyroxine was 27.1% (normal: >60%). After 14 h, total T4 concentration fell to 5.7 μg/dL before rising again to 8.5 μg/dL at 20 h. In the absence of further levothyroxine intake, the second peak of total T4 concentration may be related to stimulation of UDP-glucuronosyltransferase activity, with increased T4 solubility in the bile, released into the small intestine, and finally absorbed, with increased T4 concentration at 20 h in the patient, attesting to the stimulated T4 enterohepatic cycle during apalutamide treatment. Overall, the result of this clinical study suggests that apalutamide reduces the digestive absorption of levothyroxine, in addition to stimulating the activity of hepatic UDP-glucuronosyltransferase, explaining the higher prevalence of hypothyroidism during apalutamide treatment in patients previously treated with levothyroxine.