Effects of Lersivirine on Canine and Rodent Thyroid Function

Abstract

Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) being developed for the treatment of HIV-1 infection. Like other NNRTIs, lersivirine is a potent enzyme inducer in rodents capable of inducing a number of hepatic enzymes including those involved in its own metabolism. Preclinically lersivirine has been associated with hepatocellular hypertrophy and thyroid gland follicular cell hypertrophy in rats, mice, and dogs. In rodents, we show that development of thyroid hypertrophy is related to the classic mechanism, namely increased thyroxine (T4) clearance secondary to induction of uridine-diphosphoglucuronosyltransferase (UDPGT) in the liver and a resulting increase in thyroidstimulating hormone. Similarly, lersivirine-exposed dogs exhibit a significant increase in hepatic UDPGT enzyme activity along with increased T4 clearance although clear effects on serum thyroid hormone levels were less apparent. These effects on thyroid hormonal clearance in the dog suggest that thyroid gland hypertrophy in this species is due to the same mechanism shown to occur in rodents although, as expected, dogs better adapt to these effects and therefore maintain relatively normal thyroid hormonal balance. It is also notable that the minimal thyroid follicular hypertrophy that occurs in dogs does not progress as is seen in rodents. As is the case with rodents, these adaptive changes in the dog are not considered indicative of a human health risk.

Two-year Carcinogenicity Study in Rats with a Nonnucleoside Reverse Transcriptase Inhibitor

“…Hepatocellular neoplasms, altered foci, and centrilobular hypertrophy in rats given lersivirine were attributed to hepatic microsomal enzyme 358 NAMBIAR ET AL. TOXICOLOGIC PATHOLOGY induction that has been previously reported for lersivirine (Figure 2C; Houle et al 2013;Walker et al 2009). These microscopic findings often manifested as macroscopic findings such as enlarged liver and/or hepatic masses.…”

“…Short-term and chronic nonclinical studies with lersivirine have demonstrated liver and thyroid effects consistent with hepatic enzyme induction. Evidence of hepatic enzyme induction in rats included increased liver weights; hepatocellular hypertrophy; increased hepatocellular smooth endoplasmic reticulum; increased hepatic CYP 3A1, 2B1, and 2B2; increased hepatic uridine diphosphate glucuronosyl transferase (UDP-GT); and thyroid hypertrophy/ hyperplasia (Houle et al 2013;Walker et al 2009). …”

“…Induction of UDP-GT results in increased clearance of thyroxine (T4), chronic low-grade hypothyroidism, compensatory increase in thyroid-stimulating hormone, and subsequent activation, hypertrophy, and hyperplasia of thyroid follicular epithelium in rats that lead to thyroid follicular adenoma and carcinoma (Graham and Lake 2008; Hood, Hashmi, and Klaassen 1999; McClain 1989, 1992). Thyroid follicular cell hypertrophy secondary to UDP-GT induction and increased thyroid-stimulating hormone has been demonstrated in rats, mice, and dogs given lersivirine (Houle et al 2013). Humans are much less sensitive than rats to perturbation of thyroid hormone metabolism and subsequent increases in thyroid-stimulating hormones.…”

“…Lersivirine, like other NNRTIs, is an autoinducer of hepatic microsomal enzymes in preclinical animal species but not in humans (Walker et al 2009). Short-term and chronic studies have shown evidence of liver and thyroid effects consistent with enzyme induction (Houle et al 2013). …”

Nonclinical Safety Profile of Sotorasib, a KRASG12C-Specific Covalent Inhibitor for the Treatment of KRAS p.G12C-Mutated Cancer

“…Light microscopic changes were observed in the liver (hepatocellular hypertrophy), pituitary (hypertrophy of basophils of the pars distalis), and the thyroid gland (decreased colloid and hypertrophy of follicular epithelium); these microscopic changes were attributed to an adaptive or secondary response to hepatocellular enzyme induction. 26,27…”