Poster (15W156)

Determination of on-treatment pharmacokinetics of sofosbuvir and ledipasvir in patients with decompensated cirrhosis – the potential for therapeutic drug monitoring in predicting treatment response

Author(s)

Omar El-Sherif1, Diarmaid Houlihan2, Stephen Stewart3, Colm Bergin4, Liam Fanning5, Orla Crosbie5, Susan McKiernan1, Saye Khoo6, Suzanne Norris1

Department(s)/Institutions

1Hepatology Centre, St. James's Hospital; 2St. Vincent's Hospital; 3Mater Hospital, 4Department of Infectious Diseases, SJH; 5Cork University Hospital 6University of Liverpool

Introduction

With the availability of interferon-free direct acting antiviral therapy (DAA) for hepatitis C, patients with decompensated cirrhosis can now be considered for antiviral therapy.

Aims/Background

The combination of sofosbuvir-ledipasvir with ribavirin was associated with high sustained virological response rates (SVR) in decompensated cirrhotics in the SOLAR-1 trial, although real world outcomes are awaited. It is unclear whether interindividual pharmacokinetic variability affects treatment outcome.

Method

Plasma trough samples were prospectively collected in 35 decompensated cirrhotic patients receiving 12 weeks of sofosbuvirledipasvir and ribavirin therapy for HCV genotype 1 infection. GS- 331007 (major circulating metabolite of sofosbuvir) and ledipasvir plasma trough samples were collected at treatment days 7, 14, 28, 84 and measured using validated LC-MS/MS. Mean age was 53.6 + 10.3 and 62% were male. The median MELD score was 10 + 3.3. Trough GS-331007 and ledipasvir concentrations were compared in patients achieving a rapid virologic response (RVR) vs no RVR and SVR4 vs non-SVR4.

Results

All 35 patients achieved an on-treatment virologic response, and the SVR4 rate per protocol is 82%. GS-331007 Cmin¬ ranged from 47 – 1097 ng/ml, and ledipasvir C¬min ranged from 36.1 – 366ng/ml. There was no relationship between trough GS-331007 levels and RVR or SVR. However, mean day 28 ledipasvir Cmin levels were higher in patients achieving SVR4 compared to early relapsers (182ng/ml vs 102 ng/ml - p=0.062).

Conclusions

These novel data suggests that on-treatment trough ledipasvir may predict treatment response and the need for extended treatment in decompensated cirrhotics treated with 12 weeks sofosbuvir and ledipasvir. This relationship between sofosbuvir and ledipasvir pharmacokinetics and treatment response is being further examined in a larger cohort of patients.