Pharmacokinetics,Safety, and Tolerability of Ledipasvir/Sofosbuvir and Sofosbuvir/Velpatasvir in Healthy Chinese Subjects

PurposeLedipasvir/sofosbuvir and sofosbuvir/velpatasvir have been approved worldwide for the treatment of chronic hepatitis C virus (HCV) infection. Although both have been approved in China, there are currently no data on their pharmacokinetic profiles in Chinese individuals. Two studies investigated the pharmacokinetic properties, safety, and tolerability of ledipasvir/sofosbuvir and sofosbuvir/velpatasvir, respectively, in healthy Chinese subjects.MethodsTwo Phase I, open-label, single- and multiple-dose studies were conducted in healthy Chinese subjects. Ledipasvir/sofosbuvir (90/400 mg) or sofosbuvir/velpatasvir (400/100 mg), respectively, was administered orally once daily under fasted conditions. Subjects received a single dose (day 1) and multiple doses (days 8–17 [ledipasvir/sofosbuvir]; days 8–14 [sofosbuvir/velpatasvir]). Plasma pharmacokinetic parameters were estimated by using noncompartmental models, and safety was assessed through clinical evaluation and monitoring of adverse events.FindingsFourteen subjects were enrolled in each study (7 men, 7 women each; mean age, 30 years [ledipasvir/sofosbuvir] and 29 years [sofosbuvir/velpatasvir]). The pharmacokinetic parameters for sofosbuvir, GS-566500, GS-331007, and ledipasvir or velpatasvir were similar to historical values in non-Chinese subjects. Consistent with the t_1/2 of ledipasvir relative to 24-h dosing, accumulation of 177% (AUC) and 107% (C_max) was observed. There was no significant accumulation of velpatasvir, sofosbuvir, GS-566500, or GS-331007. Both drugs were generally well tolerated; no serious adverse events or discontinuations due to adverse events were reported.ImplicationsOverall, ledipasvir/sofosbuvir and sofosbuvir/velpatasvir exhibited pharmacokinetic and safety profiles in healthy Chinese subjects similar to those in non-Chinese subjects in historical studies, supporting their use in the Chinese population with HCV infection. ChinaDrugTrials.org.cn identifiers: CTR20160149 (ledipasvir/sofosbuvir); CTR20160602 (sofosbuvir/velpatasvir)     

Direct-acting antiviral treatment of acute hepatitis C virus infections

Introduction: Hepatitis C contributes to significant morbidity and mortality worldwide. AHCV is defined as documented infection within 6 months of exposure. Treating acute hepatitis C virus (AHCV) with direct-acting antiviral agents in persons who inject drugs, HIV-positive men who have sex with men, and patients who acquire HCV nosocomially can contribute to the elimination of disease globally, preclude the morbidity and mortality of chronic disease, and prevent further transmission.

Areas covered: In this review, we describe the epidemiology of AHCV, its natural history, the considerations involved in the decision of whether to treat AHCV, and the most current DAA therapy guidelines. PubMed was queried using key words and bibliographies were evaluated for relevant articles.

Expert commentary: Despite the obvious benefits of AHCV treatment, clinical management is limited by the ability to identify asymptomatic cases and the absence of fully supported guidelines. However, clinical research is advancing and identifying specific regimens, decreasing treatment durations, and creating strategies to target at risk groups and screen for AHCV.     

Antiviral Activity,Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3

Purpose

Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3.

Pharmacokinetics and Pharmacodynamics of Setrobuvir,an Orally Administered Hepatitis C Virus Non-Nucleoside Analogue Inhibitor

PurposeNew antiviral agents with activity against hepatitis C virus (HCV) are needed to optimize treatment for chronic hepatitis C (CHC). We evaluated the pharmacokinetics of setrobuvir (a non-nucleoside HCV polymerase inhibitor) in healthy volunteers (study 1 & 2) and its antiviral efficacy in patients with genotype 1, noncirrhotic treatment-naive CHC (study 3).MethodsThree studies investigated the pharmacokinetics and pharmacodynamics of setrobuvir. First, sequential cohorts of volunteers were randomly assigned to receive single oral doses of setrobuvir 400 to 3000 mg or placebo in a double-blind, ascending dose study. In the second study, volunteers were randomly assigned to receive multiple doses of setrobuvir (400 or 800 mg once daily [QD] or 600 mg twice a day [BID]). In the third study, patients with genotype 1 CHC received setrobuvir (200, 400, or 800 mg) or placebo BID for 3 days.FindingsAfter single doses of setrobuvir (400–3000 mg) to volunteers in a fasted state, peak C_max and AUC_0–∞ increased in a less than dose-proportional manner. The mean apparent t_½z ranged from 22.0 to 31.3 hours and was not dose related. C_max and AUC increased significantly (4.3- and 6.3-fold, respectively) in volunteers who received 2000 mg with a high-fat meal versus fasting. After multiple oral doses, steady state was achieved after 7 days of dosing (400 or 800 mg QD and 600 mg BID) and accumulation was dose-independent. Mean day 14 plasma exposure increased in a less than dose-proportional manner in volunteers who received 400 and 800 mg QD, but it was more than dose-proportional in volunteers receiving 600 mg BID. Dose did not affect the mean t_½z (range, 24.1–26.6 hours), apparent oral clearance (0.254–0.516 L/h), or apparent volume of distribution (9.60–18.1 L). In patients with CHC, dose-related reductions in HCV RNA concentration were apparent within 24 hours of the start of treatment. Reductions from baseline to the end of treatment (day 3) in patients treated with setrobuvir 200, 400, and 800 mg BID were –2.1, –2.2, and –2.9 log₁₀ IU/mL, respectively (vs ≤0.1 log₁₀ IU/mL with placebo). Reductions in HCV RNA were greater in patients with genotype 1b (range, –2.7 to –3.1 log₁₀ IU/mL) than in patients with genotype 1a (range, –1.3 to –2.7 log₁₀ IU/mL). Setrobuvir was well tolerated, with no serious adverse events.ImplicationsThe steady state pharmacokinetics of setrobuvir appear to be dose proportional, and setrobuvir produces a mean reduction of 2.9 log₁₀ IU/mL in HCV RNA over 3 days in patients with genotype 1 (a and b) treated with 800 mg BID. ClinicalTrials.gov identifier: NCT00782353     

HCV-IgG、HCV-cAg与HCV-RNA对丙型肝炎诊断的评价

目的评价丙型肝炎病毒核心抗原(HCV-cAg)、丙型肝炎病毒抗体(HCV-IgG)及丙型肝炎病毒RNA(HCV-RNA)3种检测方法在丙型肝炎实验室诊断中的意义。方法收集84例丙型肝炎疑似患者和87例健康对照者血清,采用ELISA法检测HCV-cAg和HCV-IgG,实时荧光定量聚合酶链式反应法(RT-PCR)检测HCV-RNA。结果 84例丙型肝炎疑似患者中HCVIgG阳性率为84.5%,HCV-cAg阳性率为13.1%,HCV-RNA阳性率为52.4%;71例HCV-IgG阳性患者中HCV-RNA阴性35例,假阳性率为49.3%,11例HCV-cAg阳性患者中HCV-RNA阴性5例,假阳性率为45.5%;44例HCV-RNA阳性的丙型肝炎确诊患者中HCV-IgG假阴性率为18.2%,HCV-cAg假阴性率为86.4%;HCV-cAg和HCV-IgG联合检测的假阴性率为13.6%,真阳性率为100.0%。结论 HCV-cAg和HCV-IgG在丙型肝炎的实验室诊断中均存在一定的假阴性和假阳性,将二者联合检测或在必要时与HCV-RNA三者联合检测可降低漏诊率。     

Short-term Safety,Tolerability, and Pharmacokinetics of MRX-I,an Oxazolidinone Antibacterial Agent,in Healthy Chinese Subjects

Purpose

This study was designed to evaluate the safety and pharmacokinetic profiles of MRX-I tablet, an oxazolidinone antibacterial agent, in healthy Chinese subjects.

丙型肝炎病毒感染者自身抗体的检测及临床研究

目的 检测丙型肝炎患者血清肝特异性自身抗体并分析其临床意义。方法 采用间接免疫荧光法，对220例丙型肝炎病毒感染者血清进行肝特异性自身抗体的检测；应用聚合酶链反应定量检测血清HCV-RNA含量，HCV抗体的检测用ELISA法；结果 220例丙型肝炎患者总自身抗体检出率为34．55％；单纯Ant-HCV阳性的检出率为29．57％；HCVRNA和Ant-HCV均阳性自身抗体检出率为40．59％，单纯Ant-HCV阳性与HCV-RNA和Ant-HCV均阳性组比较差异显著（P〈0．01）。各组与正常对照比较差异均非常显著（P〈0．01）；自身抗体以低滴度为主，主要为抗核抗体。自身抗体阳性的检出与性别无关（P〉0．05）而与年龄关系密切（P〈0．01），且自身抗体随年龄的增加检出率升高。结论 HCV感染可诱导自身免疫反应，使患者血清中出现多种自身抗体，检测其自身抗体及滴度对丙型肝炎患者的诊断和治疗有一定的参考价值。     

The Safety and Antiviral Activity of BZF961 with or without Ritonavir in Patients Infected with Hepatitis C Virus: A Randomized,Multicenter Trial

Purpose

Infection with hepatitis C virus is the leading cause of infectious disease mortality in the United States. BZF961 is a novel small molecule inhibitor of the hepatitis C virus NS3-4A protease. Here we present the results of a randomized, double-blinded, placebo-controlled, multicentered study in treatment-naïve patients with chronic hepatitis C virus genotype-1 infection.

Hepatitis C virus--biology, host evasion strategies, and promising new therapies on the horizon

Hepatitis C reduces the quality of life for some 170 million people around the globe and is one of the most prevalent diseases on the planet. It is caused by the hepatitis C virus (HCV) that is replicated by an error-prone polymerase and therefore undergoes rapid evolution. To date, although much has been learned about the biology of HCV, only a partially effective combination therapy comprised of ribavirin and pegylated-interferon-alpha is available to hepatitis C sufferers. Given the prevalence of hepatitis C, together with the fact that almost half the chronically infected HCV patients are refractory to current therapy, there is an urgent need for an efficacious immunoprophylactic that protects individuals from HCV infection, as well as drugs that impede the viral life cycle effectively and eradicate infection. Herein, I provide an overview of the molecular biology of HCV, highlighting the functions of different virally encoded proteins in terms of how they alter signaling pathways of host cell to establish an infection and discuss whether a more promising therapy for treating hepatitis C is anywhere in sight.     

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

Ribavirin (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 [CL_CR], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CL_CR, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CL_CR, >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 [AUC_0–12]) 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 AUC_0–12 was 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.     

拔牙术中乙型、丙型肝炎病毒污染的调查及对策

目的对常规拔牙术中乙型、丙型肝炎病毒污染情况进行调查,进一步控制医源性感染。方法随机抽取500例门诊拔牙患者的术中止血棉球,分别浸入2个（A、B）盛有1ml生理盐水的无菌试管内,其浸出液分别用两种方法进行肝炎病毒检测。结果A组（HBsAg）检测到40例阳性（8．00％）,B组（IgG）检测到12例阳性（2．40％）,HBsAg和IgG检测到A组和B组同时阳性2例（0．40％）;500例门诊拔牙患者中检测到被肝炎病毒感染的有54例,占调查总人数的10．8％。结论口腔门诊乙型、丙型肝炎感染率很高,迫切要求口腔医务工作者要加强职业防护,有效防治肝炎病毒通过口腔科诊疗传播。     

Role of Ribavirin in the Era of Direct–Acting Antiviral Therapies of Chronic Hepatitis C

ABSTRACT

Background

The efficacy of adding ribavirin (RBV) to direct antivirals (DAAs) in HCV treatment is still debatable, with allegations of insecure profiles.     

Pharmacokinetics and Safety of Subcutaneous Pasireotide and Intramuscular Pasireotide Long-acting Release in Chinese Male Healthy Volunteers: A Phase I,Single-center,Open-label,Randomized Study

Purpose

The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).

Methods

In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, C_max, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.

Findings

Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70–1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (C_max in single-dose SC administration) or significantly decreased (C_min,ss in multiple BID SC doses and first peak C_max in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.

Implications

The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.     

Pharmacokinetics,Tolerability, and Bioequivalence of Two Formulations of Rotigotine in Healthy Chinese Subjects

Purpose

The pharmacokinetic (PK) profile of the rotigotine transdermal patch is well characterized in Caucasian patients with Parkinson's disease (PD) but not in Chinese subjects. This article reports the PK variables, safety, and tolerability of the rotigotine transdermal patch (2 mg/24 hours and 4 mg/24 hours cold-chain PR2.1.1 formulation) in healthy Chinese subjects (SP0913; NCT01675024). A second study (PD0011; NCT02070796) evaluated the relative bioavailability of cold-chain (PR2.1.1) and room temperature–stable (PR2.2.1) formulations of rotigotine in healthy Chinese men.

Retinol Supplements Antiviral Action of Interferon in Patients with Chronic Hepatitis C: A Prospective Pilot Study

Sustained virologic response with peg-interferon and ribavirin combination therapy for 48 weeks is still inadequate. Our study examined whether short-term administration of retinol clinically influences the anti-viral activity of interferon early during interferon and ribavirin combination therapy. The control group received 6 MIU of interferon α-2b every day for two weeks and then 3 times a week for 22 weeks intramuscularly plus 600 mg or 800 mg per day of ribavirin orally for 24 weeks. The retinol group, in addition to above treatment, received retinol 30,000 units per day orally for 3 weeks from one week before the start of interferon α-2b plus ribavirin combination therapy. The hepatitis C virus (HCV) RNA negativity rate at 1 week after the end of interferon α-2b and ribavirin combination therapy was 46.7% (28/60) for the retinol group and 31.7% (19/60) for the control group, which was significantly higher for the retinol group. The level of serum HCV RNA in the retinol group was significantly lower at 1 week after beginning treatment as compared to the control group (p<0.01). Furthermore, serum 2,5''AS protein at 1 week after beginning treatment was significantly higher in the retinol group (p = 0.0002). The results suggest that retinol supplement increases the antiviral effect of interferon α-2b plus ribavirin only during the administration of IFN α-2b, ribavirin and retinol in patients with chronic hepatitis C.     

丙肝病毒核心总抗原定量检测的临床应用

目的 探讨定量检测丙型肝炎病毒核心总抗原（total HCV-cAg,tHCV-cAg）在丙型肝炎诊断中的作用及与病毒载量的相关性.方法 随机选取广州军区武汉总医院2010年10月-2013年3月丙肝患者血清标本66例,分别采用化学发光法检测血清tHCV cAg,酶联免疫法（ELISA）检测血清丙型肝炎游离核心抗原（free HCV-cAg,fHCV-cAg）及丙型肝炎抗体（hepatitis C virus antibody,HCV-Ab）,实时荧光定量PCR方法检测血清HCV-RNA,全自动生化分析仪检测血清谷氨酸氨基转移酶（ALT）.比较HCV-RNA,tHCV-cAg及fHCV-cAg阳性率差异,同时分析tHCV-cAg与HCV-RNA及ALT相关性,探讨tHCV-cAg联合检测HCV-Ab与HCV-RNA检测符合率.结果 66例丙型肝炎患者血清中,tHCV-eAg阳性率与HCV-RNA阳性率差异无统计学意义（χ^2=0.165,P＞0.05）;tHCV-cAg量与HCV-RNA呈正相关：logHCV Ag=0.81 log HCV RNA-1.31（γ=0.83,P＜0.05）.tHCV-cAg阳性率与fHCV cAg阳性率差异有统计学意义（χ^2 =12.53,P＜0.05）.HCV-cAg阳性组ALT值异常率与HCV-eAg阴性组ALT值异常率差异有统计学意义（P＜0.05,χ^2=17.47）.tHCV-cAg联合检测HCV-Ab符合率与HCV-RNA检测达100.00％.结论 化学发光法定量检测血清tHCV-cAg阳性率显著高于fHCV-cAg,与HCV RNA阳性符合率达96.08％ （49/51）,是丙型肝炎早期诊断的特异性指标.tHCV-cAg和HCV-RNA呈正相关性,与肝功能损害相关,是反映病毒的复制指标.tHCV-cAg联合检测HCV-Ab可减低丙型肝炎的漏诊率.