The absorption, distribution, metabolism and elimination characteristics of small interfering RNA therapeutics and the opportunity to predict disposition in pregnant women.

Small interfering RNA (siRNA) therapeutics represent an emerging class of pharmacotherapy with the potential to address previously hard-to-treat diseases. Currently approved siRNA therapeutics include lipid nanoparticle-encapsulated siRNA and tri-N-acetylated galactosamine-conjugated siRNA. These siRNA therapeutics exhibit distinct pharmacokinetic characteristics and unique absorption, distribution, metabolism, and elimination (ADME) properties. As a new drug modality, limited clinical data are available for siRNA therapeutics in specific populations, including pediatrics, geriatrics, individuals with renal or hepatic impairment, and pregnant women, making dosing challenging. In this Minireview, a mechanistic overview of the ADME properties of the 5 currently approved siRNA therapeutics is presented. A concise overview of the clinical data available for therapeutic siRNAs in special populations, focusing on the potential impact of physiologic changes during pregnancy on siRNA disposition, is provided. The utility of physiologically based pharmacokinetic (PBPK) modeling as a tool to elucidate the characteristics and disposition of siRNA therapeutics in pregnant women is explored. Additionally, opportunities to integrate known physiologic alterations induced by pregnancy into PBPK models that incorporate siRNA ADME mechanisms to predict the effects of pregnancy on siRNA disposition are discussed. Clinical data regarding the use of therapeutic siRNA in special populations remain limited. Data for precise parameterization of maternal-fetal siRNA PBPK models are lacking presently and underscore the need for further research in this area. Addressing this gap in knowledge will not only enhance our understanding of siRNA pharmacokinetics during pregnancy but also advance the possible development of siRNA therapeutics to treat pregnancy-related conditions. SIGNIFICANCE STATEMENT: This Minireview proposes a framework on how small interfering RNA (siRNA) disposition can be predicted in pregnancy based on mechanistic absorption, distribution, metabolism, and elimination (ADME) information using physiologically-based pharmacokinetic (PBPK) modeling. The mechanistic ADME information and available clinical data in special populations of currently Food and Drug Administration-approved siRNA therapeutics are summarized. Additionally, how physiological changes during pregnancy may affect siRNA disposition is reviewed, and the opportunities to use PBPK modeling to predict siRNA disposition in pregnant women is explored.