scholarly journals Effect of the Hepatitis C Virus Protease Inhibitor Telaprevir on the Pharmacokinetics of Amlodipine and Atorvastatin

2011 ◽  
Vol 55 (10) ◽  
pp. 4569-4574 ◽  
Author(s):  
Jee Eun Lee ◽  
Rolf van Heeswijk ◽  
Katia Alves ◽  
Frances Smith ◽  
Varun Garg
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Inhibitory Effect ◽  
Least Square ◽  
Open Label ◽  
Time Curve ◽  
Protease Inhibitor Telaprevir ◽  
Single Sequence

ABSTRACTTelaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin,ortho-hydroxy atorvastatin, andpara-hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (Cmax) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC0-∞); for atorvastatin, they were 10.6 (8.74, 12.9) for theCmaxand 7.88 (6.84, 9.07) for the AUC0-∞. Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents.

scholarly journals Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Luzelena Caro ◽  
Larissa Wenning ◽  
Zifang Guo ◽  
Iain P. Fraser ◽  
Christine Fandozzi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatic Impairment ◽  
Open Label ◽  
Time Curve ◽  
Increased Risk ◽  
Class B ◽  
Hcv Genotype 1 ◽  
End Stage ◽  
Study Participants

ABSTRACT Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0–24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Dynamic Hepatitis C Virus Genotypic and Phenotypic Changes in Patients Treated With the Protease Inhibitor Telaprevir

2007 ◽  
Vol 132 (5) ◽  
pp. 1767-1777 ◽  
Author(s):  
Christoph Sarrazin ◽  
Tara L. Kieffer ◽  
Doug Bartels ◽  
Brian Hanzelka ◽  
Ute Müh ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitor ◽  
Phenotypic Changes ◽  
Protease Inhibitor Telaprevir

scholarly journals Pharmacokinetic Evaluation of the Interaction between Hepatitis C Virus Protease Inhibitor Boceprevir and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Atorvastatin and Pravastatin

2013 ◽  
Vol 57 (6) ◽  
pp. 2582-2588 ◽  
Author(s):  
E. G. J. Hulskotte ◽  
H.-P. Feng ◽  
F. Xuan ◽  
S. Gupta ◽  
M. G. J. A. van Zutven ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Coenzyme A ◽  
Reversible Inhibitor ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Reductase Inhibitors ◽  
Hmg Coa Reductase Inhibitors ◽  
Coa Reductase

ABSTRACTBoceprevir is a potent orally administered inhibitor of hepatitis C virus and a strong, reversible inhibitor of CYP3A4, the primary metabolic pathway for many 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Thus, the aim of the present study was to investigate drug-drug interactions between atorvastatin or pravastatin and boceprevir. We conducted a single-center, open-label, fixed-sequence, one-way-crossover study with 20 healthy adult volunteers. Subjects received single-dose atorvastatin (40 mg) or pravastatin (40 mg) on day 1, followed by boceprevir (800 mg three times daily) for 7 to 10 days. Repeat single doses of atorvastatin or pravastatin were administered in the presence of steady-state boceprevir. Atorvastatin exposure increased in the presence of boceprevir, with atorvastatin area under the concentration-time curve from time zero to infinity after single dosing (AUCinf) increasing 2.3-fold (90% confidence interval [CI], 1.85, 2.90) and maximum observed concentration in plasma (Cmax) 2.7-fold (90% CI, 1.81, 3.90). Pravastatin exposure was slightly increased in the presence of boceprevir, with pravastatin AUCinfincreasing 1.63-fold (90% CI, 1.03, 2.58) andCmax1.49-fold (90% CI, 1.03, 2.14). Boceprevir exposure was generally unchanged when the drug was coadministered with atorvastatin or pravastatin. All adverse events were mild and consistent with the known safety profile of boceprevir. The observed 130% increase in AUC of atorvastatin supports the use of the lowest possible effective dose of atorvastatin when coadministered with boceprevir, without exceeding a maximum daily dose of 40 mg. The observed 60% increase in pravastatin AUC with boceprevir coadministration supports the initiation of pravastatin treatment at the recommended dose when coadministered with boceprevir, with close clinical monitoring.

scholarly journals Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment

2013 ◽  
Vol 57 (12) ◽  
pp. 6097-6105 ◽  
Author(s):  
B. J. Brennan ◽  
K. Wang ◽  
S. Blotner ◽  
M. O. Magnusson ◽  
J. J. Wilkins ◽  
...  
Keyword(s):  
Renal Function ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Renal Impairment ◽  
Normal Renal Function ◽  
Impaired Renal Function ◽  
Severe Renal Impairment ◽  
Moderate Renal Impairment ◽  
Open Label ◽  
Time Curve

ABSTRACTRibavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CLCR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CLCR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CLCR, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC0–12]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC0–12was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.

scholarly journals Pharmacokinetic Interactions between Simeprevir and Ledipasvir in Treatment-Naive Hepatitis C Virus Genotype 1-Infected Patients without Cirrhosis Treated with a Simeprevir-Sofosbuvir-Ledipasvir Regimen

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Stefan Bourgeois ◽  
Yves Horsmans ◽  
Frederik Nevens ◽  
Hans van Vlierberghe ◽  
Christophe Moreno ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Steady State ◽  
Hepatitis C ◽  
Safety Data ◽  
Maximum Plasma ◽  
Genotype 1 ◽  
Virus Genotype ◽  
Open Label ◽  
Time Curve ◽  
Treatment Naïve

ABSTRACT Interactions between simeprevir (hepatitis C virus [HCV] NS3/4A protease inhibitor) and ledipasvir (HCV NS5A replication complex inhibitor) were investigated in treatment-naive HCV genotype 1-infected patients without cirrhosis, treated with simeprevir-sofosbuvir-ledipasvir in a two-panel, phase 2, open-label study. Patients had stable background treatment with sofosbuvir (400 mg once daily [QD]). In panel 1 (n = 20), the effect of ledipasvir (90 mg QD) on simeprevir (150 mg QD) was studied. Patients received simeprevir and sofosbuvir from days 1 to 14; steady-state pharmacokinetics (PK) of simeprevir was assessed (day 14). On day 15, ledipasvir was added and steady-state PK of simeprevir in the combination was evaluated (day 28). In panel 2 (n = 20), the effect of simeprevir on ledipasvir was investigated. From days 1 to 14, patients received ledipasvir and sofosbuvir and steady-state PK of ledipasvir was assessed (day 14). On day 15, simeprevir was added and a full PK profile was obtained (day 28). The least-squares mean maximum plasma concentration and area under the concentration-time curve (90% confidence interval) increased 2.3-fold (2.0- to 2.8-fold) and 3.1-fold (2.4- to 3.8-fold) for simeprevir, respectively (panel 1), and 1.6-fold (1.4- to 1.9-fold) and 1.7-fold (1.6- to 2.0-fold) for ledipasvir, respectively (panel 2), in the presence versus the absence of the other drug. All patients achieved sustained virologic responses 12 weeks after treatment end. Adverse events, mainly grade 1/2, occurred in 80% of patients; the most common was photosensitivity (45%). Due to the magnitude of interaction and the limited amount of safety data available, the use of this treatment combination is not recommended. (This study has been registered at ClinicalTrials.gov under registration no. NCT02421211.)

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