Abstract
Purpose :
To assess the potential of tarcocimab after intravenous (IV) administration to elicit adverse effects on pregnant New Zealand White (NZW) female rabbits and the development of the embryo and fetus consequent to exposure from implantation to closure of the hard palate, and evaluate toxicokinetics (TK) and immunogenicity (ADA).
Methods :
Groups of female NZW rabbits (n=20) were administered a single IV injection (Gestation Day [GD] 6, 11, or 16) of tarcocimab at a dose of 0 or 5 mg/kg. A TK group (n=3) was dosed on GD 26. Blood was collected pre-dose and 1, 8, 24, 72, 120, 192, and 288 hr post-dose for TK, and pre-dose and GD 29 for ADA. At necropsy (GD 29), maternal ovarian and uterine exams, gross necropsy of viscera, and tissue samples were collected, as well as fetal exams (external, visceral, and skeletal).
Results :
There were no tarcocimab related mortality or abortions, clinical observations, and macroscopic findings at necropsy. Maternal body weight gains were lower than controls with minimal reductions in food consumption over a 5-day interval after dosing. There was no overall impact on cumulative mean maternal body weight gains or food consumption. There were no tarcocimab related effects on any ovarian, uterine, or litter parameter (including fetal viability and growth), and malformations or variations observed at fetal external, visceral, or skeletal examination. Mean C0, Cmax, and AUC0-288hr values of tarcocimab were 307000 ng/mL, 378000 ng/mL, and 38600000 hr*ng/mL, respectively, on GD 6; were 176000 ng/mL, 181000 ng/mL, and 10500000 hr*ng/mL (mean AUCTlast), respectively on GD 11; and were 141000 ng/mL, 146000 ng/mL, and 14700000 hr*ng/mL, respectively on GD 16. Plasma concentration-time profiles appeared to be impacted by a possible immune response. The fetal to maternal concentration was 0.37%
Conclusions :
Maternal administration of tarcocimab by IV injection at 5 mg/kg, once on GD 6, 11, or 16, during the organogenesis period of pregnancy to NZW female rabbits was well tolerated. There were no tarcocimab related mortality or abortions for any dosage regimen, and no effects on embryo-fetal viability or fetal body weights, as well as no malformations or variations at external, visceral, or skeletal examination. Based on these results, the maternal and developmental no observed adverse effect level (NOAEL) was considered to be 5 mg/kg.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.