Simeprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, displays nonlinear pharmacokinetics (PK) at therapeutic doses. Using physiologically based PK modeling, various drug‐drug interactions ...were simulated with simeprevir as victim drug to identify whether saturation of the predominant metabolic enzyme (CYP3A4) or the active hepatic transporters (organic anion‐transporting polypeptide (OATP)1B1/3) could account for the nonlinear PK. Interactions with ritonavir, a strong CYP3A4 inhibitor that does not affect OATP (at 100 mg dose), erythromycin, a moderate CYP3A4 inhibitor, and efavirenz, a moderate CYP3A inducer that does not affect OATP, demonstrated the involvement of CYP3A4. Interaction studies with low‐dose cyclosporine confirmed the role of OATP. The interplay between hepatic uptake and CYP3A4 metabolism was verified by simulations with rifampicin, a potent CYP3A4 inducer and OATP1B1/3 inhibitor, and maintenance doses of cyclosporine. Saturation of gut and liver metabolism by CYP3A4, and saturation of hepatic uptake by OATP1B1/3, seem to account for the observed nonlinear PK of simeprevir.
Summary
The phase 2, open‐label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6‐ or 8‐week regimen of simeprevir, daclatasvir and ...sofosbuvir in treatment‐naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early‐stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early‐stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty‐eight patients were treated (6‐week group: n = 59; 8‐week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early‐stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6‐week group was viral relapse (11.9%; 7/59). One patient had on‐treatment failure due to an early withdrawal (lost to follow‐up due to incarceration). One patient with SVR12 in the 6‐week group had a late viral relapse at post‐treatment week 24. No clinically significant drug‐drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct‐acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment‐naïve, HCV GT1‐infected patients with early‐stage fibrosis or compensated cirrhosis.
Summary
Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as ...decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1‐ or 4‐infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct‐acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment‐naïve or treatment‐experienced adults with Child‐Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7–9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS‐331007 (sofosbuvir metabolite) was 2.2‐, 1.5‐, 1.2‐ and 1.2‐fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.
Summary
This pooled analysis of five Phase IIb and III studies evaluated the safety and tolerability of simeprevir, a once daily, oral hepatitis C virus (HCV) NS3/4A protease inhibitor. Data were ...summarised for patients who received simeprevir 150 mg once daily (n = 924) or placebo (n = 540) plus pegylated interferon‐α/ribavirin for 12 weeks. During the first 12 weeks of treatment, few patients discontinued simeprevir or placebo due to adverse events (AEs) (both 2.2%). Pruritus (23.8% vs 17.4%), rash (any; 22.9% vs 16.7%) and photosensitivity (3.2% vs 0.6%) Correction added on 16 January 2015, after first online publication: In the above sentence, the values in ‘Photosensitivity’ were previously incorrect and have now been changed to 3.2% vs 0.6%. were more prevalent in the simeprevir vs the placebo groups. Most AEs were grade 1/2 (72.4% for simeprevir vs 71.3% for placebo). All grade 3/4 AEs occurred in <5.0% of patients, except neutropenia (9.8% vs 7.6%). Overall incidence of neutropenia was similar (17.3% vs 15.7%). Incidence of anaemia was 13.2% for simeprevir vs 10.9% for placebo, and incidence of increased bilirubin was 8.4% vs 2.8%. Bilirubin increases were mild‐to‐moderate and transient without concurrent transaminase increases or association with hepatic injury. Safety and tolerability did not vary with METAVIR score, although increased bilirubin and anaemia were more frequent in simeprevir‐treated patients with METAVIR F4 (increased bilirubin, 13.0% vs 3.3%; anaemia, 19.0% vs 14.8%). Serious AEs were infrequent (2.1% for simeprevir vs 3.0% for placebo). No deaths were reported during the first 12 weeks of treatment. Patient‐reported fatigue and other outcomes were comparable for both groups, but were of shorter duration for simeprevir due to the use of response‐guided therapy. Simeprevir is well tolerated in HCV genotype 1‐infected patients.
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