Absence of developmental and reproductive toxicity in animals exposed to dolutegravir

Abstract

The success of new antiretroviral medicines for HIV resulted in a change to guidelines of standard therapy where continuation of antiretroviral therapy is recommended to maintain the low viral load during pregnancy, thereby preventing transmission of the virus to the fetus. As a result, pregnancy related exposure to HIV medicines has increased. Understanding the safety of these medicines during pregnancy is of paramount importance to ensure health of mothers and their offspring; well-designed animal studies that evaluate the reproductive life cycle play a key role in this effort. As part of the medicine development program for dolutegravir (DTG), a series of reproductive and developmental toxicity studies were conducted using rats and rabbits. In a fertility study, where exposure to DTG occurred in female rats before mating through conception and up to implantation of the embryo, no effects on reproductive cycles, ovulation, fertility) or preimplantation embryonic growth were observed. In rat and rabbit embryo-fetal development studies, where exposure to DTG occurred during organogenesis, no malformations or other developmental abnormalities were observed. In a rat pre- and post-natal development study, where DTG exposure to the pups occurred during pregnancy and postnatally via milk, no malformations or other developmental abnormalities were observed. In these studies, no DTG-related effects occurred on fertility, embryonic (pre- and post-implantation loss, resorptions, abortions, and malformations) or fetal development where the multiples of exposure at the maximum recommended human dose were up to 27 times higher in rats or below the human exposure in rabbits.

Keywords: antiretroviral; dolutegravir; malformations; safety.