Safety of Sofosbuvir in People With Advanced Kidney Failure

Study Overview
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Brief Summary
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Infection with hepatitis C virus (HCV), a hepatotropic RNA virus, is often chronic, and causes liver cirrhosis and liver cancer. The virus is transmitted through parenteral exposure. This infection is particularly common in those on maintenance hemodialysis. Sofosbuvir, an inhibitor of HCV RNA-dependent RNA polymerase, forms the backbone of DAA-based anti-HCV treatment regimens. In pre-clinical pharmacokinetic studies, administration of the usual 400 mg daily dose to in presence of advanced kidney failure (estimated glomerular filtration rate [eGFR] of <30 ml/min) showed that serum levels of the sofosbuvir and GS-331007, the primary metabolite of sofosbuvir, were elevated by several folds. Hence, sofosbuvir is not approved for use in people on maintenance hemodialysis. The newer DAAs (e.g. grazoprevir/elbasvir combination), which have been approved for use in people with eGFR <30 ml/min, are very costly and are not available in Asian countries including India. Hence, as a rescue measures, several physicians, including our group, have tried half-daily dose (i.e, 200 mg daily or 400mg on alternate days) of sofosbuvir and 60 mg daclatasvir in dialysis-dependent people, with good results in terms of both safety and efficacy. In fact, the use of this empirical 200 mg daily dose schedule has become common in clinical practice. However, this use is not based on any pharmacokinetic data. Hence, it is proposed to study the pharmacokinetics of low-dose (200 mg daily or 400 mg alternate day) of sofosbuvir and GS-331007 metabolite in people with eGFR <30/min and active HCV infection.

Detailed Description
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Study design Three arms, observational, pharmacokinetic study Study duration Two years (March 2019-February 2020) Study participants Two groups of participants will be included (i) People without chronic kidney disease, i.e, normal eGFR and infected with HCV infection (ii) People with chronic kidney disease and eGFR <30 ml/min and infected with HCV infection We will include a total of thirty participants with ten in each of the three groups: Group A (ESRD, alternate day dose), Group B (ESRD, daily dose) and Group C (normal eGFR) Drug schedule Participants with eGFR <30 ml/min: will be given daclatasvir 60 mg once daily along with either sofosbuvir (200 mg) daily once or sofosbuvir 400mg once every alternate day Participants with normal renal function will be treated with sofosbuvir 400mg and daclatasvir 60 mg once daily. The treatment duration will be 12 weeks for alll there three study groups. Dialysis schedule A four to five hour hemodialysis sessions will be provided twice in a week Plan for pharmacokinetic study (i) Molecules: Sofosbuvir and GS331007 (ii) Method: Liquid chromatography-tandem mass spectrometry (iii) Specimen collection ( 2 ml each time) will be done as follows: Hour '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 [Day 1]; hour 36 [Day 2]; hour 84 [Day 4], and hour 156 [Day 7]. Sample Collection, Transport and Storage Soon after sample collection, serum will be separated by centrifugation at 4000×g for 10 min at 4°C and separated serum will stored at -80°C till analysis. Analysis will be done using validated bioanalytical method at CSIR-CDRI, Lucknow. Inactivation of hepatitis C virus in the stored sample HCV inactivation will be done by heat treatment. Before heat treatment, water bath chamber will be cleaned, filled with fresh RO water and temperature calibration will be checked for accuracy. The specimens will be heated at 60 C for 10 minutes or 65 C for 5 minutes to inactivate the virus. Immediately after heat treatment, the specimens will be put in crushed ice to stop the heat effect. The specimens will be transported in frozen condition for analysis. Sample preparation: The sample preparation consists of the simple liquid-liquid extraction and/or protein precipitation. Liquid chromatography-mass spectroscopy HPLC system consisting of Shimadzu UFLC system consisting of LC-20AD binary pumps and SIL-HTc autosampler (Shimadzu Corporation, Kyoto, Japan) will be used to inject 10 µL aliquots of the processed samples on a C18 column (4.6 mm × 50 mm, 5.0 µm). The separation will be achieved by running the mobile phase in isocratic mode containing acetonitrile and 10mM ammonium acetate buffer in suitable ratio (%v/v) at a flow rate capable of sufficient resolution to be optimized during method development and validation. The mobile phase will be duly filtered through 0.22 µm filter and degassed ultrasonically before use. Mass spectrometric detection will be performed on an API 5500 Q Trap mass spectrometer (Applied Biosystems, MDS Sciex Toronto, Canada) equipped with an API electron spray ionization (ESI) source. The ion spray voltage will be set at 5500 V. The instrument related parameters viz., nebulizer gas, curtain gas, auxiliary gas and collision gas and coompound related parameters viz., declustering potential (DP), collision energy (CE), entrance potential (EP) and collision cell exit potential (CXP) respectively will be optimized before validating the method . Zero air will be used as source gas while nitrogen will be used as both curtain and collision gas. The mass spectrometer will be operated at ESI positive as well as ESI negative ion mode and detection of the ions will be performed in the multiple reaction monitoring (MRM) mode monitering the transitions of the analytes. Quadrupole 1 and quadrupole 3 will be maintained at unit resolution and dwell time will be set at 200 ms. Analyst 1.6 software (version 1.6, Built 3773; AB Sciex, Toronto, Canada) will be used for data acquisition and quantitation. Pharmacokinetic parameters estimation The pharmacokinetic parameters will be estimated using WinNonlin software either through compartment/non-compartment modeling.

Official Title
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Pharmacokinetics of Low-dose Sofosbuvir in Dialysis-dependent Patients With Hepatitis C Virus Infection

Conditions
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Kidney Failure, Chronic, Hepatitis C

Intervention / Treatment
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* Drug: Sofosbuvir
* Drug: Daclatasvir 60 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with: hepatitis C virus infection with detectable HCV RNA in blood naïve to direct acting antiviral drugs based anti-HCV treatment Exclusion Criteria: Hepatitis B virus co-infection Human immunodeficiency virus co-infection Clinical evidence of cirrhosis or portal hypertension such as ascites, esophageal or gastric varices on esophago-gastro-duodenoscopy, liver stiffness more than 15 KPa as measured with transient elastography or history of hepatic encephalopathy.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a three arm, case control study aimed at studying the pharmacokinetics of sofosbuvir and its major metabolite (GS-331007) in people with estimated GFR (eGFR) <30 ml/min. Two arms will include participants with advanced renal failure with eGFR below 30 ml/min and third arm will include participants with normal eGFR. Participants with eGFR <30 ml/min will receive sofosbuvir in doses of either 400mg on alternate days or 200mg daily. The participants with normal eGFR will receive the standard of care, i.e, 400mg of sofosbuvir daily
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ESRD, alternate day dose<br>Participants with end stage renal disease (eGFR <30 ml/min) and hepatitis C virus active infection and treated with sofosbuvir 400 mg on alternate days. Total duration of treatment will be 12 weeks | Drug: Sofosbuvir<br>* Sofosbuvir is the backbone of the most of the currently used anti-HCV treatment regimens<br>Drug: Daclatasvir 60 mg<br>* Daclatasvir, in combination with sofosbuvir, is approved for the treatment of hepatitis C virus infection in absence of liver cirrhosis<br>|
| Experimental: ESRD, daily dose<br>Participants with end stage renal disease (eGFR <30 ml/min) and hepatitis C virus active infection and treated with sofosbuvir 200 mg daily doses. The total duration of treatment will be 12 weeks | Drug: Sofosbuvir<br>* Sofosbuvir is the backbone of the most of the currently used anti-HCV treatment regimens<br>Drug: Daclatasvir 60 mg<br>* Daclatasvir, in combination with sofosbuvir, is approved for the treatment of hepatitis C virus infection in absence of liver cirrhosis<br>|
| Active Comparator: Control<br>Participants with normal eGFR and hepatitis C virus infection and treated with sofosbuvir 400 mg daily dose. The total duration of treatment will be 12 weeks | Drug: Sofosbuvir<br>* Sofosbuvir is the backbone of the most of the currently used anti-HCV treatment regimens<br>Drug: Daclatasvir 60 mg<br>* Daclatasvir, in combination with sofosbuvir, is approved for the treatment of hepatitis C virus infection in absence of liver cirrhosis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics study | To study the Maximum Plasma Concentration [Cmax] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR. | At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7 | 
| Pharmacokinetics study | To study the Area Under the Curve [AUC] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR. | At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7 | 
| Pharmacokinetics study | To study the Terminal Half Life [t1/2] of sofosbuvir and its metabolite (GS-331007) in participants with eGFR below 30 ml/min who are treated with low-dose of sofosbuvir and compare it with that in people with normal eGFR. | At hour (from the time of drug administration) '0', 0.25, 0.5, 1, 2, 4, 8, 12, 16, 24 on Day 1; hour 36 on Day 2; at hour 84 on Day 4; and at hour 156 on Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Proportion of participants with sustained virologic response at 12 weeks [SVR12] after discontinuation of anti-HCV treatment | 12 weeks after stopping anti-HCV treatment |