The Effects of the Direct Acting Antiviral Agent Boceprevir on the Pharmacokinetics of Maraviroc in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Change in maraviroc AUC
研究概览
简要总结
Infection by both HIV and hepatitis C virus (HCV)is frequent due to similar transmission modes. Near 20% of people living with HIV are also infected by HCV. People living with HIV are treated by anti-HIV medications that may interact with numerous other medications, including new medications against HCV.
Boceprevir is one of these new HCV medications and it is now considered as part of the standard of care for people infected with HCV. Previous research has shown boceprevir may influence the capacity of the liver to breakdown (metabolize) certain medications and when these medications are used in combination with boceprevir, their blood concentrations may be increased or decreased which could increase the risk of side effects or decrease efficacy. Among the drugs having a potential for an interaction with boceprevir is maraviroc, an anti-HIV medication. If concentrations of maraviroc increase, people may experience more side effects. However, if concentrations of maraviroc decrease, people living with HIV may have a lower suppression of the virus. This could increase the risk for the HIV virus to develop resistance, that is that the treatment will no longer be effective. No studies have been conducted to investigate the effects of boceprevir on blood concentrations of maraviroc. This research project addresses this research question. This project, however, cannot be done with people living with HIV since resistance may develop in these people if the concentrations of maraviroc decrease. It is for this reason that the investigators wish to recruit healthy people not infected with HIV nor HCV.
Eleven healthy volunteers will be included. They will receive maraviroc 150 mg (1 tablet) every 12 hours from days 1 to 19 inclusively. On day 5, a total of ten blood samples will be drawn during the following 12 hours (at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours after maraviroc morning dose intake) to measure the blood concentrations of maraviroc. Boceprevir 800 mg (4 capsules) every 8 hours with food will be started on day 6 and continued until day 19 inclusively. On day 19, after the morning maraviroc and boceprevir dose, another ten blood samples will be drawn over a 12 hour period. A phone follow-up will be done on day 26. Thus, the total study duration for subjects is 26 days. The investigators will compare the blood concentrations of maraviroc when given alone to the blood concentrations of maraviroc when given with boceprevir.
详细描述
Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is frequent because of shared modes of viral transmission. Near 20% of HIV-infected patients are also infected with HCV, the prevalence of HCV in the HIV population varying according to the route of transmission. Despite the decrease in mortality and morbidity in HIV-infected individuals since the introduction of potent combination antiretroviral therapy (cART), HCV-related end-stage liver disease (ESLD) now represents a leading cause of death in these patients.
HCV treatment outcomes in terms of sustained virologic response (SVR) are usually worse in co-infected patients, pegylated interferon-alpha (PEG IFN-alpha) / ribavirin treatment leading to success in only 40 to 50% of mono-infected patients and 30 % of co-infected patients. In patients co-infected with HIV, present guidelines recommend a fixed course of PEG IFN-alpha / ribavirin for 48 weeks to optimize HCV treatment.
The recent introduction of boceprevir and telaprevir, two direct acting antiviral agents (DAAs) against HCV, changed the standard of care for the treatment of chronic HCV infection with genotype 1, whereby now the AASLD practice guidelines recommend the use of boceprevir or telaprevir in combination with PEG IFN-alpha/ribavirin in both HCV mono-infected treatment naïve and experienced patients. No studies have yet been published in HCV-HIV co-infected patients.
Boceprevir is a novel HCV NS3 serine protease inhibitor (PI). In clinical studies of treatment-naïve and experienced patients, this agent, in combination with standard of care (PEG IFN-alpha/ribavirin), achieved much greater SVR rates, reaching rates higher than 70 % in clinical studies.
Boceprevir has to be taken 800 mg (four 200 mg capsules) three times a day (every 7-9 hours) with food. Boceprevir is usually well tolerated according to single and multiple dose pharmacokinetics studies in healthy volunteers with adverse effects similar to placebo. The serious adverse effects related to boceprevir are seen when boceprevir is coadministered with PEG-IFN alpha/ribavirin. These include anemia, neutropenia and thrombocytopenia.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Male
- 接受健康志愿者
- 是
入选标准
- •Caucasian males
- •healthy individuals based on history/physical examination and laboratory evaluations (no out-of-range results from hematology tests (hemoglobin (Hb) > 130 g/L in men; absolute neutrophil count (ANC) > 2000 cells/uL; platelets > 159 x 109/L), biochemistry (AST < 35 IU/L, ALT < 40, IU/L, alkaline phosphatase < 100 IU/L, total bilirubin < 17 umol/L, lipase < 45 IU/L, creatinine < 120 umol/L, normal coagulation tests (INR < 1.2, aPPT < 40 seconds) and urinalysis.
- •LDL-cholesterol </= 5 mmol/L, triglycerides </= 1.7 mmol/L and a 10 year estimate of cardiovascular (CV) disease risk of </= 10% ("low risk") as per the Framingham risk score modified for family history (doubling of CV risk if any CV disease in a first-degree relative before 60 years of age); the modified Framingham risk score takes into account age, HDL-cholesterol, total cholesterol, systolic blood pressure, smoker status, presence of diabetes and family history of CV disease
- •normal 12-lead electrocardiogram
- •systolic blood pressure between 105 and 130 mmHg
- •diastolic blood pressure between 60 and 90 mmHg
- •supine heart rate between 60 and 100 beats per minutes
- •no evidence of HIV infection (ELISA test and Western Blot), no evidence of hepatitis B virus infection (HBsAg negative and anti-HBcAg negative or HBsAg negative with positive anti-HBsAg and positive anti-HBcAg) or HCV infection at screening (anti-HCV serology)
- •using an effective barrier method of contraception
- •non-smoker
- •drinking less than 14 units of alcohol per week with a maximum of 4 units per day where one unit of alcohol corresponds to 341 mL of standard beer or 142 mL of wine or 43 ml of spirits
- •negative illicit drug test at screening;
- •with a body mass index between 18.0 to 30.0 kg/m2
- •aged from 18 to 50 years old
- •volunteers must be able to understand and comply with the protocol requirements and willing to sign the informed consent form prior to any study procedure;
- •absence of exclusion criteria.
排除标准
- •history of postural hypotension
- •cardiac disease
- •acute or chronic liver disease or any hepatic impairment
- •acute or chronic kidney disease or any renal impairment
- •use of prescription drugs, over the counter drugs, recreational drugs, herbal or dietary supplements including vitamins and grapefruit juice within 15 days of study initiation (day 1) except for acetaminophen and/or ibuprofen on an as needed basis. These products will also be prohibited during the study (except for as needed acetaminophen and/or ibuprofen)
- •subjects who received any experimental medication within the last 2 months and/or donated blood during the previous 2 months or intends to donate blood within 2 months following completion of the study will also be excluded;
- •subjects who had unprotected sexual activities during the last 6 months with a new or recent partner
- •subjects who injected intravenous drugs over the last 6 months
- •subjects with a social condition, psychological or addictive disorder that would impair protocol adherence.
研究组 & 干预措施
Maraviroc Boceprevir
干预措施: Maraviroc (5 days) (Drug)
Maraviroc Boceprevir
干预措施: Maraviroc and boceprevir (14 days) (Drug)
结局指标
主要结局
Change in maraviroc AUC
时间窗: Day 19
次要结局
- Change in maraviroc Tmax(Day 19)
- Change in maraviroc Cmax(Day 19)
- Change in maraviroc Cl/F(Day 19)
- Change in maraviroc Vd(Day 19)
- Change in maraviroc T1/2(Day 19)
- Adverse events(Up to day 26)
- Change in maraviroc Cmin(Day 19)
研究者
Nancy Sheehan
Associate Clinical Professor
Centre hospitalier de l'Université de Montréal (CHUM)