Table 2.
Safety data from reproductive teratogenicity studies of DAAs in pregnancy
| DAA therapy | Prenatal and postnatal development | Placental transfer | Lactation | |||
|---|---|---|---|---|---|---|
| DAA combination | Drug | Safety concerns? | Tested animal species (Dose and duration) | Transfer across placenta | Tested animal species (% of maternal plasma levels) | Transfer into milka (% of maternal plasma levels) |
| SOF/DAC | SOFb | No |
Rats: 10x RHD, GD6‐18, GD6‐LD20 Rabbits: 28x RHD, GD6‐19 |
Yes | Rats | Yes (80%) |
| DAC | Yesc |
Rats: 4x RHD, GD7‐19 Rabbits: 16x RHD, GD6‐15 |
Yes | Rats | Yes (170%‐200%) | |
| SOF/LDV | SOFb | No |
Rats: 10x RHD, GD6‐18, GD6‐LD20 Rabbits: 28x RHD, GD6‐19 |
Yes | Rats | Yes (80%) |
| LDV | Possiblec |
Rats: 4x RHD, GD6‐18 Rabbits: 2x RHD, GD7‐20 |
Unknown | Not tested | Yes | |
|
SOF/VEL SOF/VEL/VOX |
SOFb | No |
Rats: 10x RHD, GD6‐18, GD6‐LD20 Rabbits: 28x RHD, GD6‐19 |
Yes | Rats | Yes (80%) |
| VEL | Possibled |
Rats: 6x RHD, GD6‐17, GD6‐LD20 Rabbits: 0.5‐0.7x RHD, GD7‐20 Mice: 31x RHD, GD6‐15 |
Not evident | Rats | Yes (173%) | |
| VOX | No |
Rats: 141x RDH, GD6‐LD20 Rabbits: 4x RHD, GD7‐19 |
Unknown | Not tested | Yes | |
| GZR/ELB | GZR | No |
Rats: 117x RHD, GD6‐20, GD6‐LD20 Rabbits: 41x RHD, GD7‐20 |
Yes |
Rats (89%) Rabbits (7%) |
Yes (400%) |
| ELB | No |
Rats: 10x RHD, GD6‐20, GD6‐LD20 Rabbits: 18x RHD, GD7‐20 |
Yes |
Rabbits (0.8%) Rats (2.2%) |
Yes (87%) | |
| GLE/PIB | GLE | Possiblee |
Rats: 53x RHD, GD6‐18, GD6‐LD20 Rabbits: 0.07x RHD, GD7‐19 |
Yes | Rats | Yes (<8%) |
| PIB | No |
Rabbits: 1.5x RHD GD7‐19 Mice: 51x RHD GD6‐15, GD6‐LD20 |
Yes | Mice | Yes (150%) | |
Abbreviations: DAC, daclatasvir; ELB, elbasvir; GD, gestation day; GLE, glecaprevir; GZR, grazoprevir; LD, lactation day; LDV, ledipasvir; PIB, pibrentasvir; RHD, recommended human dose; SOF, sofosbuvir; VEL, velpatasvir; VOX, voxilaprevir.
Transfer into milk was studied in rats.
Exposure to predominant circulating metabolite of sofosbuvir (GS‐331007).
At a high dose (4.6‐fold RHD), an increased incidence of skeletal variations (vertebrae, sternea, ribs) in rats was observed. These effects are likely related to a decrease in maternal body weight gain and decreased food intake.
A possible teratogenic effect was indicated in rabbits where an increase in total visceral malformations was seen in exposed animals at AUC exposures up to 0.7‐fold RHD for SOF/VEL and 0.5‐fold RHD for SOF/VEL/VOX.
Maternal toxicity with some embryofoetal toxicity precluded the ability to evaluate glecaprevir in the rabbit at human clinical exposures.