TMC278 did not show teratogenic potential in animal models

TMC278 (ripivirine) is a novel NNRTI currently under investigation. The embryo-foetal toxicity was evaluated in rats and rabbits.

In this study, pregnant Sprague-Dawley rats (by oral gavage) and New Zealand white rabbits (by oral dosing) received doses of TMC278 during the period of organogenesis (days 6-17 and 6-19 in rats and rabbits respectively). Doses observed were: 400, 120 and 40 mg/kg/day in rats; and 20, 10 and 5 mg/kg/day in rabbits. Both animal models had a control group.

The investigators reported moderate maternal toxicity (reduced food consumption, and body weight gain, and increased thyroid weight) in rats at the two higher doses. In rabbits they did not observe any maternal toxicity.

They reported no teratogenetic effect in either animal and there was no effect of treatment on pregnancy parameters. In rats in the two higher dose groups they observed an increase in incidence of dilated renal pelvis (visceral variant) 120 mg/kg/day, p<0.05 and 400 mg/kg/day, p<0.01 compared to the control group. This was the only finding on embryo-foetal development in rats. The maternal and embryo-foetal development no observable adverse effect level (NOAEL), was 40 mg/kg/day, associated with a maternal AUC0-24h of 37 ug.h/mL.

With rabbits, the only finding was a slight increase in the incidence of minor variations of the left subclavian artery, p<0.05 and hypoplastic interparietal bone, p<0.05 compared to the controls in the group receiving 20 mg/kg/day.

The maternal toxicity and embryo/foetal NOAELs were 20 mg/kg/day and 10 mg/kg/day, respectively, which were associated with maternal AUC0-24h of 232 ug.h/mL and 170 ug.h/mL.

The investigators concluded that TMC278 did not show teratogenic potential in rat and rabbit models at drug exposures 13-80 times higher than those in HIV positive patients receiving 25 mg/qd at steady state (TMC278-C204 Study AUC0-24h was 2.8 ug.h/mL). Based on this data they suggest that further studies in women of child bearing potential are warranted.

Ref: Desmidt M et al. Absence of a teratogenic potential from a novel next-generation NNRTI, TMC278. 12tth EACS. 11-14 November, 2009. Cologne. Abstract PE7.1/4.