Transfer of daclatasvir and sofosbuvir’s main metabolite, GS-331007, across the human placenta ex vivo

Abstract

The treatment of hepatitis C virus (HCV) infection during pregnancy is mainly focused on maternal cure, with the secondary aim of also preventing vertical transmission to the fetus. Direct-acting antivirals (DAAs) are commonly being prescribed to nonpregnant patients, but a lack of data on the pharmacokinetics, safety, and efficacy of DAAs hampers their use in pregnant patients.1Kushner T. Terrault N.A. Hepatitis C in pregnancy: a unique opportunity to improve the hepatitis C cascade of care.Hepatol Commun. 2018; 3: 20-28Crossref PubMed Scopus (16) Google Scholar It has been hypothesized that ribavirin-free maternal treatment regimens with DAAs could be appropriate if it can be shown that treatment during pregnancy does not cause reproductive toxic adverse effect.2Bernstein H.B. Dunkelberg J.C. Leslie K.K. Hepatitis C in pregnancy in the era of direct-acting antiviral treatment: potential benefits of universal screening and antepartum therapy.Clin Obstet Gynecol. 2018; 61: 146-156Crossref PubMed Scopus (15) Google Scholar We provide data on the placental transfer of DAAs by describing the placental transfer of sofosbuvir’s main metabolite, GS-331007, and daclatasvir in the ex vivo perfused human placenta. Transfer was studied in human placentas obtained from healthy, term pregnancies (n=3) using the isolated dual-side perfused placental cotyledon technique. At the start of the perfusion period, GS-331007 and daclatasvir, which are the most abundant circulating metabolites present in the human plasma upon administration of a combination of sofosbuvir and daclatasvir, were added to the maternal circulation. The concentrations used were based on the reported maximum plasma concentration in HCV-infected patients. After 180 minutes of cotyledon perfusion, a mean±standard deviation (SD) of 120±50 ng/mL GS-331007 and 250±110 ng/mL daclatasvir were found in the fetal circulation, resulting in a fetal-to-maternal concentration ratio of 0.38±0.15 (mean±SD) for GS-331007 and 0.41±0.14 (mean±SD) for daclatasvir (Figure). In addition to its transfer, daclatasvir exhibited a high affinity for associating with placental tissue. The placental-to-maternal concentration ratio for GS-331007 and daclatasvir amounted to a mean±SD of 0.72±0.02 and 2.56±0.14, respectively. This study describes the placental handling of DAAs and showed that GS-331007 and daclatasvir cross the placenta during 180 minutes of ex vivo perfusion. Although placental transporters, such as P-glycoprotein, may limit fetal exposure to daclatasvir to some extent, fetal concentrations after maternal dosing largely exceeded the established in vitro half maximal effective concentration required for the inhibition of viral replication.3Gao M. Nettles R.E. Belema M. et al.Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect.Nature. 2010; 465: 96-100Crossref PubMed Scopus (812) Google Scholar This indicates that maternal treatment with a combination of sofosbuvir and daclatasvir may be beneficial in terms of fetal pre-exposure prophylaxis, but may also cause adverse effects. Developmental toxicity studies in rats showed that administration of 50 mg/kg/d daclatasvir, resulting in an area under the plasma concentration-time curve value that was 4.6-fold greater than that of the recommended human dose, caused an increased incidence of external and/or visceral fetal malformations.4Assessment report. European Medicines Agency, 2014https://www.ema.europa.eu/en/documents/assessment-report/daklinza-epar-public-assessment-report_en.pdfGoogle Scholar However, large interspecies differences in the placental anatomy and morphology may limit the translation of fetal animal exposure and toxicity data to the human situation.5Carter A.M. Animal models of human placentation--a review.Placenta. 2007; 28: S41-S47Crossref PubMed Scopus (357) Google Scholar In addition to placental transfer, we observed substantial placental accumulation of daclatasvir, which may be attributed to its high lipophilicity. The possible effects of daclatasvir on trophoblast viability and function require further study for a more detailed characterization of its safety profile during human pregnancy.