Ledipasvir plus sofosbuvir in pregnant women with hepatitis C virus infection: a phase 1 pharmacokinetic study

Abstract

Background: Hepatitis C virus (HCV) infection is increasing among pregnant women because of the opioid epidemic, yet there are no interventions to reduce perinatal HCV transmission or to treat HCV during pregnancy. Physiological changes in pregnancy alter the pharmacokinetics of some medications; thus, our aim was to compare the pharmacokinetic parameters of ledipasvir 90 mg plus sofosbuvir 400 mg during pregnancy with non-pregnant women.

Methods: This was an open-label, phase 1 study of pregnant women with genotype 1 HCV infection and their infants. A reference group of women who had participated in pharmacokinetic studies of ledipasvir-sofosbuvir during phase 2 and 3 trials was used. Participants were enrolled at Magee-Womens Hospital (Pittsburgh, PA, USA) between 23 and 24 weeks' gestation and had a 12-week course of oral ledipasvir-sofosbuvir (daily 90 mg ledipasvir plus 400 mg sofosbuvir). Three 12-h intensive pharmacokinetic visits were done at 25-26, 29-30, and 33-34 weeks' gestation and individual pharmacokinetics were summarised by geometric mean across the three visits. The primary outcome, analysed in all participants without suspected dosing errors, was the ledipasvir-sofosbuvir area under the concentration-time curve of the dosing interval (AUC_tau) during pregnancy compared with the reference group by geometric mean ratio. This study is registered with ClinicalTrials.gov, NCT02683005.

Findings: From Oct 1, 2016, to Sept 30, 2018, 29 pregnant women were screened and nine (31%) were enrolled. Eight (89%) women were included in the primary analysis. Ledipasvir and sofosbuvir exposures were similar in the pregnant women versus the non-pregnant reference group (geometric mean ratio of AUC_tau ledipasvir 89·3% [90% CI 68·7-116·1]; sofosbuvir 91·1% [78·0-106·3]).

Interpretation: Ledipasvir-sofosbuvir was safe and effective without clinically meaningful differences in drug exposure among pregnant versus non-pregnant women.

Funding: National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institutes of Health/Office of Research on Women's Health, and Gilead Sciences.

Figure 1:. Mean concentration–time curves at each intensive pharmacokinetic visit

(A) Sofosbuvir plasma profiles. (B) GS-331007 plasma profiles. (C) Ledipasvir plasma profiles. One participant was excluded from all the primary pharmacokinetic analyses because of a dosing error.

Figure 2:. Ledipasvir and sofosbuvir plasma protein binding in the study group compared with the reference group

(A) Sofosbuvir plasma protein binding. (B) Ledipasvir plasma protein binding.

Figure 3:. HCV viral response to ledipasvir–sofosbuvir during pregnancy

Data stated below the chart are median (range). PK-1 visit was between 10 and 21 days after treatment initiation. PK-2 visit was between 32 and 47 days after treatment initiation. PK-3 visit was between 59 and 74 days after treatment initiation. HCV=hepatitis C virus. PK-1=first pharmacokinetic visit. PK-2=second pharmacokinetic visit. PK-3=third pharmacokinetic visit. SVR12=sustained virological response 12 weeks after completion of treatment.