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.

Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels

“…Drugs that are known human teratogens often show teratogenic defects in animal models, although not always [16,17]. Pre-clinical reproductive toxicology studies conducted on rats and rabbits found no DTG-related effects on fertility, embryonic, or fetal development [18], although these studies did not mimic the clinical scenario as they included higher than clinically relevant DTG doses (40À1000 mg/kg/day), tested DTG alone and not as part of an ART regimen, and exposed animals to DTG in specific windows that did not include the entire pregnancy [18]. Given the uncertainty surrounding the link between DTG and NTDs in humans, and the limitations of the pre-clinical DTG fetotoxicity studies, further animal studies modeling the clinical scenario are merited.…”

In response to the Letter to the Editor by Romach et al. re our publication “Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels”

“…We think that it would be unscientific to dismiss our findings of a relationship between therapeutic levels of DTG-based ART and an increase in fetal defects simply because it does not fit the expectation of a classic dose response. We would also like to note that the one NTD observed in the rabbit fetotoxicity study by Stanislaus et al [3] was observed in the lowest DTG dose treatment arm.…”

“…We chose a dose that yielded DTG Cmax concentrations similar to those seen in pregnant women (3000 ng/ml). Further, as the higher rates of NTDs were observed in women who received DTGbased ART from conception, we selected to treat our animals for the entire duration of pregnancy (unlike what was performed in the studies by Stanislaus et al [3]). Our control group was handled identically to the treated group (i.e.…”

No developmental toxicity observed with dolutegravir in rat whole embryo culture

“…In the WEC in vitro model, embryos in the VYS are exposed directly to DTG in media, in contrast to an in vivo embryo‐fetal development (EFD) study whereby embryos are exposed to DTG via maternal blood passing through the placenta. In the rat EFD with DTG (Stanislaus et al, 2019), the mean Cmax value at the no observed adverse effect level (NOAEL) of 1,000 mg/kg/day was 108.9 μg/ml on GD 17. Although the scope of the current WEC study is limited, these results supplement the results from the EFD rat study by demonstrating that direct exposure of a mammalian embryo to DTG also did not result in developmental toxicity.…”

“…In preclinical animal studies conducted prior to original regulatory approval, DTG did not show developmental toxicity up to 30‐fold (rats) and 0.4‐fold (rabbits) the maximum human recommended dose (Stanislaus et al, 2019). These in vivo studies in rats and rabbits further confirm the latest emerging human data that is indicating an absence of a signal for NTDs in humans.…”