Annual Meeting of the Japanese Society of Toxicology

The purpose of this study was to evaluate the toxicity of lenvatinib, VEGF receptor inhibitor, in juvenile rats.
In the DRF study, lenvatinib was administered orally once daily for 2 weeks to Sprague-Dawley rats at doses of 0, 0.2, 0.4, 1 or 5 mg/kg/day from postnatal day (PND) 7 or at doses of 0, 0.4, 1, 5 or 25 mg/kg/day from PND 21 followed by a 2-week recovery period. The toxicologic profile of lenvatinib was similar to that in adult rats in both group of rats in this study, but the toxicity in PND 7 rats was more severe compared to PND 21 rats and mortality was observed in PND 7 rats. The cause of death was considered due to severe intestinal change and peritonitis. The histopathologic changes in duodenal glands were observed in only PND 21 rats.
In the main study, rats were administered lenvatinib via oral gavage at doses of 0, 0.4, 2 or 10 mg/kg/day for 8 weeks from PND 21 followed by a 4-week recovery period. At 2 mg/kg/day and above, severe growth retardation (suppression of body weight gain with decreased food consumption), which correlated with a decrease in the width and/or length of femur and tibia, delayed physical development (prepuce separation and vaginal opening at 10/mg/kg/day) and reproductive organ immaturity was observed.
At 10 mg/kg/day, mortality observed with histological changes in the gastrointestinal tract, choroid plexus, and adrenals that were similar to previous findings in adult rats. Toxicities were mostly reversible, although residual changes were observed at the end of the 4-week recovery period. No toxicologically significant change was observed at 0.4 mg/kg/day.

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In order to assess the hazard potential of air-borne Polyethylene Glycol 200 (Vehicle), a repeated dose inhalation study in male and female rats was performed, following the OCSPP (OPPTS) test guidelines.

The rats were exposed to compressed air (G1) and 2.018 mg/L air (G2) for 6 h/day, 5 days/week for consecutive 4 weeks, respectively, in a 28-day study. The biological clinical chemistry, haematology, urine analysis, organ weight, and histopathology examination were performed.

In this study, microscopic lesions (kidneys: regenerative/basophilic tubules, liver: infiltration, MNC, prostate: infiltration, MNC, thyroid: ultimobranchial cyst & ectopic thymus and uterus: dilatation) were at lower rate of occurrence and with minimal to mild severity. Hence, those lesions were considered to be spontaneous or incidental in nature representing the normal physiological/metabolic/cyclical or congenital changes encountered in rats of this age kept under laboratory conditions. In the absence of clinical pathology and histopathological findings, it is concluded that repeated inhalation for 28 consecutive days did not produce any adverse effect in Wistar rats.

No Observed Adverse Effect Concentration (NOAEC) and No Observed Effect Concentration (NOEC) of Polyethylene Glycol 200 was found to be ≥2.018 mg/L air, when administered through inhalation route, for consecutive 28 days, to Wistar rats, based on the procedures and conditions followed in this study. Hence, it is concluded that Polyethylene Glycol 200 can be used as a vehicle for long term inhalation study.

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Nonclinical studies are mandated to be formatted in CDISC SEND format under a published schedule. The trial designs used for SEND data sets are different from the traditional study design used by Study Directors to report their findings in tabulated human readable form. However this machine-readable format offers new opportunities to consider Histopathology and Gross Pathology findings in nonclinical studies to provide important indicators of drug toxicity. The location of a finding, the incidence counts, dose dependency on the findings, their qualifiers, and their severity are part of the effect of the drug on the organ systems just as DMPK/PK/TK and in-life measurements complete that picture. Drug candidates are put through multiple types of nonclinical studies with varying dose ranges and duration.

It is important for the toxicologist to review these histopathology incidences across studies to identify any persistent patterns related to effects of the drug on the subjects. Significant changes to organs and tissues that manifest as Histopath findings are likely to be correlated to changes in the clinical pathology during the in-life period as well as the PK behavior. Therefore providing the ability to look at Histopath findings in relation to other in-life domains such as lab tests and weight and food measurements, or PK/TK can be important in understanding the drug’s mechanisms.

This paper discusses the challenges and opportunities presented by the use of CDISC SEND standards for exchanging Histopath data both in terms of how to represent it well and to review and understand the data. The paper suggests that advanced immersive and interactive techniques must be considered to provide toxicologists and reviewers the ability to understand the data in depth.

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