Quantification of maternal and fetal valaciclovir exposure in a pharmacokinetic study of cytomegalovirus-infected pregnant women treated to prevent vertical transmission.

Background: In cases of maternal primary infection with cytomegalovirus (CMV-MPI) maternal treatment with oral valaciclovir 8 g/day has been shown to reduce the risk of fetal infection. The pharmacological profile of this high dosage during pregnancy is not yet known.

Objectives: To quantify maternal-fetal exposure to valaciclovir 8 g/day in a population pharmacokinetic (popPK) study.

Methods: Between October 2019 and April 2023, pregnant women referred for CMV-MPI were offered to participate following: (i) CMV-MPI <14 weeks of gestation; (ii) acceptance of valaciclovir 8 g/day; and (iii) consent for amniocentesis. Amniotic fluid was tested for (i) CMV PCR for prenatal diagnosis; and (ii) dosage of aciclovir concentration (the active form of valaciclovir). Maternal serum levels of aciclovir were also measured. Aciclovir assays in both compartments were used for popPK analysis. Pharmacokinetics were described using non-linear mixed-effect modelling.

Results: We prospectively included 119 women with their 122 fetuses. CMV-MPI occurred at a median of 3.0 (range: -12; + 14) weeks of gestation. CMV-infected pregnant women were treated at a median of 12.3 (range: 4.6-21.4) weeks of gestation for a median duration of 35 days (range: 7-90 days). Median pharmacokinetic parameters (Cmin, Cmax and AUC0-24) were all successfully defined in both maternal blood and amniotic fluid compartments. No differences in aciclovir exposure were observed between infected (n = 12, 9.8%) and non-infected fetuses. Simulations showed that after a last maternal dose, aciclovir concentration would be undetectable in the amniotic fluid after 43-47 h.

Conclusions: In this popPK study, maternal and fetal pharmacokinetics were established using in vivo data. The results provide a better understanding of how this fetal therapy works.