The Healthcare Business of Merck KGaA, Darmstadt, Germany.
PB DMPK Consulting Ltd., Chinley, UK.
Birth Defects Res. 2024 Aug;116(8):e2389. doi: 10.1002/bdr2.2389.
When developing new antimalarial drugs, considering their potential use during pregnancy as preventive or curative therapy is crucial. This prevents the parasite from affecting embryonic development and reduces maternal and fetal death risks. Consequently, understanding the exposure and safety of antimalarial drugs during pregnancy is crucial, with well-designed animal studies playing a key role in this assessment.
As part of the drug development program for cabamiquine, a series of developmental and reproductive toxicity studies were conducted in rats and rabbits. Additionally, the zebrafish embryo model was used to further improve embryo exposure, minimize confounding factors related to maternal toxicity, and assess developmental risks of cabamiquine.
In these studies, although maternal toxicity was observed, there were no cabamiquine-related adverse effects on fertility, embryonic, or fetal development at maternal exposures representing significant multiples (up to five and 10 times higher in rabbit and rats, respectively) than the exposure at the anticipated efficacious human dose. Similarly, no adverse effects were observed on ZF embryonic development, even though cabamiquine concentrations in the embryos were 10-fold higher than nominal concentrations.
The results obtained in a full set of reproductive toxicity studies did not provide evidence of detrimental effects on the conceptuses and progeny at maternally nontoxic doses and exposures, still representing a multiple of the anticipated systemic exposures in women of childbearing potential (WOCBP). Cabamiquine can therefore be considered a suitable therapeutic option for WOCBP and pregnant women living in malaria-endemic regions by significantly reducing maternal and infant malaria death rates.
在开发新的抗疟药物时，考虑到它们在怀孕期间作为预防或治疗性治疗的潜在用途至关重要。这可以防止寄生虫影响胚胎发育并降低母婴死亡风险。因此，了解抗疟药物在怀孕期间的暴露和安全性至关重要，而设计良好的动物研究在这一评估中起着关键作用。
作为卡巴喹药物开发项目的一部分，在大鼠和兔中进行了一系列发育和生殖毒性研究。此外，还使用斑马鱼胚胎模型来进一步提高胚胎暴露度，最大限度地减少与母体毒性相关的混杂因素，并评估卡巴喹的发育风险。
在这些研究中，尽管观察到母体毒性，但在母体暴露代表高于预期有效人类剂量的显著倍数（兔和大鼠分别高达 5 倍和 10 倍）时，卡巴喹对生育力、胚胎或胎儿发育没有任何不良影响。同样，在斑马鱼胚胎发育中也没有观察到不良反应，尽管胚胎中的卡巴喹浓度比名义浓度高 10 倍。
在一套完整的生殖毒性研究中获得的结果并未在母体非毒性剂量和暴露下对胚胎和后代产生有害影响的证据，仍然代表了生育能力的妇女（WOCBP）预期全身暴露的倍数。因此，卡巴喹可以被认为是 WOCBP 和生活在疟疾流行地区的孕妇的合适治疗选择，因为它可以显著降低母婴疟疾死亡率。
