Effects of Toceranib Phosphate on the Hypothalamic‐Pituitary‐Thyroid Axis in Tumor‐Bearing Dogs

Abstract

BackgroundThyroid dysfunction is associated with the use of tyrosine kinase inhibitors (TKI) in people.Hypothesis/ObjectivesTo determine whether dysfunction in the hypothalamic‐pituitary‐thyroid axis occurs in dogs receiving the TKI, toceranib phosphate.AnimalsForty‐three client‐owned dogs with cancer.MethodsProspective, observational study. Concentrations of total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine (TT3), and thyroid‐stimulating hormone (TSH) were evaluated on day 0, 30, and 90. Dogs also were evaluated for the presence of thyroglobulin autoantibodies.ResultsThe proportion of dogs with low TT4, low FT4, low TT3, high TSH, or primary hypothyroidism (increased TSH and decreased TT4, FT4 or both) did not change over 90 days. Hormone concentrations remained within laboratory reference intervals, but FT4 (P = 0.0032) and TSH (P < 0.0001) changed over time. Mean FT4 was 1.22 ng/dL (95% confidence interval [CI], 1.10–1.34) on day 0 and 1.00 ng/dL (95% CI, 0.86–1.16) on day 90. Mean TSH was 0.17 ng/mL (95% CI, 0.13–0.23) on day 0 and 0.34 ng/mL (95% CI, 0.24–0.48) on day 90. Furthermore, TT4/TT3 ratio also changed over time (P = 0.0086). Mean TT4/TT3 ratio was 2.57 (95% CI, 2.26–2.88) on day 0 and 2.02 on day 90 (95% CI, 1.61–2.44). Thyroglobulin autoantibodies were not detected in any dog.Conclusions and Clinical ImportanceToceranib phosphate can disrupt the hypothalamic‐pituitary‐thyroid axis in dogs. Periodic evaluation of TT4, FT4, TT3, and TSH should be carried out in dogs receiving long‐term treatment with this medication.

Toceranib phosphate in the treatment of canine thyroid carcinoma: 42 cases (2009‐2018)

“…One concern was the development of iatrogenic hypothyroidism. Toceranib has previously been reported to alter thyroid hormone equilibrium in dogs 68 . One dog in our study reportedly developed hypothyroidism.…”

“…Toceranib has previously been reported to alter thyroid hormone equilibrium in dogs. 68 One dog in our study reportedly developed hypothyroidism. However, this dog also completed a course of hypofractionated radiation therapy 24 months prior to the documentation of hypothyroidism.…”

Spontaneous primary hypothyroidism in 7 adult cats

“…In addition, human patients treated with some medications (eg, metoclopramide, amiodarone) can develop slightly increased serum TSH concentrations . Similarly, transiently high serum TSH concentrations can develop in dogs with nonthyroidal disease (with hypoadrenocorticism being the best characterized example), as well as during treatment with certain drugs . Therefore, it is clear that more studies evaluating serum TSH concentrations in a larger population of cats are needed—especially in cats with nonthyroidal illness during the recovery phase of illness, as well as after treatment with medications known to increase serum TSH in other species.…”

Influence of medications on thyroid function in dogs: An update

“…Two recent prospective, uncontrolled studies have evaluated the effects of toceranib on thyroid function in tumor‐bearing dogs. Administration of toceranib for 12 weeks resulted in an increase in serum TSH 66,67 concentration whereas serum TT4 66,67 and TT3 67 concentrations remained unchanged. One study found a decrease in serum fT4 concentration, but methodologic shortcomings (utilization of different fT4 assays and assigning the same reference interval to each assay despite different mean serum fT4 concentrations) confounded interpretation of the results 67 .…”

“…Administration of toceranib for 12 weeks resulted in an increase in serum TSH 66,67 concentration whereas serum TT4 66,67 and TT3 67 concentrations remained unchanged. One study found a decrease in serum fT4 concentration, but methodologic shortcomings (utilization of different fT4 assays and assigning the same reference interval to each assay despite different mean serum fT4 concentrations) confounded interpretation of the results 67 . Although no dog in either study developed clinical signs of hypothyroidism, 19% 67 and 0% 66 of dogs had thyroid function test results consistent with primary hypothyroidism (low serum TT4 with or without low fT4 and high serum TSH) on at least 1 evaluation during the study.…”