Insights on Sofosbuvir levels in pregnant women.
Treating hepatitis C virus (HCV) in pregnant women can potentially eliminate maternal HCV during prenatal care and reduce the risk of mother-to-child transmission. Previous research shows how plasma levels of sofosbuvir (SOF), a medication in HCV treatment, were 38% higher in pregnant women, while levels of its inactive metabolite (007) were 38% lower than in non-pregnant individuals. Inside cells, SOF is transformed into its active metabolite, 007-triphosphate (007-TP), serving as a measure of drug activation in various tissues and as a marker of medication adherence.
This study, presented at the
When comparing data with that from non-pregnant adults (n=58), the study found that 007-TP concentrations in PBMCs were similar or higher during pregnancy, while 007-TP levels in DBS were about 50% lower. The geometric mean (95% CI) for 007-TP in DBS was reported as 340 (287, 403), 340 (278, 418), and 356 (275, 461) fmol/punch at 3, 6, and 9 weeks (A), respectively. For PBMCs, the corresponding figures were 2111 (1096, 4066), 2808 (1559, 5058), and 2212 (1267, 3864) fmol/10^6 cells at the same intervals (B), respectively.
In this phase 1 trial, HIV-negative pregnant women with chronic HCV were enrolled between 23-25 weeks of gestation and underwent treatment with SOF 400mg/velpatasvir (VEL) 100mg daily for 12 weeks. Samples for DBS and PBMCs were collected before dosing and at weeks 3, 6, and 9 during the treatment period.
Participants in this study included 10 pregnant individuals (9 white, 1 Black) with a median age of 31 years (range 25-29) and a weight of 75.5 kg (range 64.6-102.3). The median values for serum creatinine, glomerular filtration rate, and hematocrit were 0.5 mg/dL (0.4-0.6), 126.1 mL/min/1.73 m^2 (122.3-140.8), and 36.1% (33.2-37.8%), respectively.
Levels of 007-TP in both DBS (1x7mm punch) and PBMCs (normalized to 1 million cells) were determined using established LC/MS-MS techniques, and findings were analyzed using descriptive statistics. Moreover, these results were juxtaposed with 007-TP levels in non-pregnant individuals with HCV to evaluate adherence (NCT02573376).
The observed reduction in DBS concentrations may be partly attributed to the physiological hemodilution during pregnancy, suggesting a need for adjustment when using DBS samples for adherence measurement in future studies. An international multicenter trial (NCT05140941) is underway to assess the safety and efficacy of SOF/VEL treatment during pregnancy.
Reference
Chappell C, Brooks K, Kiser J, et. al. Intracellular Sofosbuvir Concentrations in Pregnant Women With Hepatitis C Virus. Poster #710 presented at CROI 2024. March 3-6, 2023. Denver, CO.
