Thyroid dysregulation underlies altered ovarian cyclicity in rats exposed to PF-06835919, a ketohexokinase inhibitor.

PF-06835919, a ketohexokinase inhibitor intended for the treatment of non-alcoholic fatty liver disease, caused decreased/absent corpora lutea in the ovary in a 6-month rat repeat-dose toxicity study. These findings occurred in the presence of liver and thyroid effects, and it was hypothesized that the decreased/absent corpora lutea was due to hypothyroidism secondary to PF-06835919-related UGT (UDP-glucuronosyltransferase) enzyme induction. An investigative study was conducted to evaluate the onset of ovarian changes by monitoring daily estrous cycles with daily administration of 100 mg/kg/day, and thyroid hormone levels were also measured. Estrous cycle disruption (persistent estrus) was noted in 10 of 15 females, with onset occurring between days 33 and 81. Higher TSH (3.8x control) and altered T3 and T4 were noted on day 37, indicating that thyroid hormone dysregulation preceded the estrous cycle disruption. Recovery of the estrous cycle disruption occurred in 30% of the animals before the study was terminated due to onset of reproductive senescence. Liver UGT enzyme induction, including UGT1A1, was confirmed to be induced in a separate 2-week rat study. All available data support the hypothesis that PF-06835919-related induction of one or more UGT enzymes and consequent thyroid dysregulation were the cause of ovarian changes in the rat.