TO016CLINICAL PHARMACOKINETICS OF SOFOSBUVIR AND DACLATASVIR IN KIDNEY TRANSPLANT RECIPIENTS

Abstract

INTRODUCTION AND AIMS: Very limited data exist analyzing the pharmacokinetic (PK) profile of novel direct acting antivirals in kidney transplant recipients (KTR). Here we report the PK of combinated daclatasvir (DAC) and sofosbuvir (SOF) therapy in a controlled prospective study of HCV positive KTR (EudraCT: 2014-004551-32). METHODS: In this study plasma samples of 16 HCV positive KTR receiving DAC/ SOF were collected at 4 time points (predose, 1h, 2h and 4h after dosing) at d0, d1, d7, d14 and d21, w8 and w12 after start of treatment. Inclusion criteria in this cohort were stable graft function and a GFR>30ml/min. DAC, SOF and GS-331007 (inactive metabolite of SOF) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time of flight mass spectrometry. RESULTS: After 12 weeks of treatment (end of therapy) with DAC/SOF, HCV RNA was not detectable in 100% of KTR. All patients showed a rapid virological response with undetectable HCV viral load at a mean of 21d after start of therapy. Performed liver biopsies before start of therapy showed a medium fibrosis score of 2.1 (according to Desment). Calcineurin inhibitor dose adjustment during treatment was required in 4/16 patients. DAC/SOF therapy was overall well tolerated with no therapy-associated major adverse events and no drug discontinuations. The mean GFR in our cohort was 56.4ml/min (±15.8). 7/16 patients had a GFR<60ml/min at baseline. Mean GS-331007 trough level were 339.5ng/ml(6174.9) in patients with a GFR≥60ml/min and 404.3ng/ ml(±226) in patients with a GFR<60ml/min at d7. At d84 trough levels were 357.8ng/ ml(±200.8) and 404.2(±70.2) in patients with a GFR≥60ml/min and in patients with a GFR<60ml/min, respectively. Overall there were no relevant GS-331007 trough level changes over the treatment period (Fig.1A-C). A GFR<60ml/min did not affect AUCs of DAC, SOF and GS-331007. The measurement of SOF led to a high fluctuation in AUCs. AUCs of GS-331007 were more sable with less deviations(Fig.1D-F). There was only a weak correlation between GFR and GS-331007 through levels (Fig.2) CONCLUSIONS: The administration of DAC/SOF is safe and highly efficient in KTR. An impaired GFR (30-60ml/min) does not lead to a dose accumulation of DAC, SOF and GS-331007. Future studies should address the PK of SOF based HCV treatment in KTR with a GFR <30ml/min.