The Pharmacokinetics of Dolutegravir, Darunavir/Cobocistat When Co-administered in Healthy Volunteers
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 21
- 试验地点
- 1
- 主要终点
- Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Tmax
研究概览
简要总结
The purpose of this study is to look at the levels of three HIV medications: dolutegravir, darunavir and cobicistat in the blood after drug intake has been stopped, in order to understand how long these drugs persist in the blood. The study will specifically look at blood levels of these three drugs after taking them every day for 14 days.
There will be two groups. Participants in Group 1 will take dolutegravir everyday for 14 days, then nothing for 7 days, then dolutegravir and darunavir/cobicistat together for 14 days, nothing for 7 days, and then darunavir/cobicistat alone for 14 days. If participants go into Group 2 they will begin with darunavir/cobicistat everyday for 14 days, then nothing for 7 days, then dolutegravir and darunavir/cobicistat together for 14 days, nothing for 7 days, and then dolutegravir alone for 14 days. Drug levels for both groups will be measured on days 14, 35 and 56. If the participants decide to take part, the duration of the study will be up to 57 days plus a screening visit which will take place up to 28 days prior to the start of the study, and a follow up visit, which takes place 15 to 22 days after the last dose of study medication. Eligible participants will be randomized (1:1 ratio) to group 1 or group 2. Participants and the study doctor will know which study medications the participant is taking at all times during the study.
详细描述
This is a randomised, cross-over, open label study, which means that the participants will be randomly assigned to the different arms of the study which receive different medications. The participants and the study doctor will know which study medications the participant is taking at all times during the study.This study will be conducted in a single site, in London.
The total duration of the participant's involvement in the study will be up to 57 days plus a screening visit up to 28 days prior to the start of the study, and a follow up visit 27 to 33 days after the last blood measurement.
The participants will be asked to visit the clinic on up to 14 occasions, of which three visits involve staying in the unit for approximately 12 hours (day 14,35 and 56).
Blood samples will be taken from the participants throughout the study to measure the levels of dolutegravir, darunavir and cobicistat in blood. Blood and urine will also be collected throughout the study for safety analysis; this is to ensure the participants are healthy to take part or to continue taking part in the study. The total amount of blood collected from each participant during the study will be approximately 500ml (just below a pint).
Participants will be provided with written information about the study in the form of a participant information sheet and will be allowed adequate time for questions and to consider the study before agreeing to participate. It will be the responsibility of the investigator or the co-investigator to obtain written informed consent prior to undertaking any procedure detailed in the protocol. As part of the consent procedure, participants will also be asked consent to their personal details being entered into TOPS (the over-volunteering protection system).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •The ability to understand and sign a written informed consent form, prior to participation in any screening procedures and must be willing to comply with all study requirements
- •Male or Non-pregnant, non-lactating females.
- •Between 18 to 65 years, inclusive
- •Body Mass Index (BMI) of 18 to 35 kg/m2, inclusive
- •ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A single repeat is allowed for eligibility determination.
- •Women of childbearing potential (WOCBP - definition in Appendix 5) must be using an adequate method of contraception to avoid pregnancy throughout the study and for a period of at least 4 weeks after the study.
- •A female may be eligible to enter and participate in the study if she:
- •is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and ≥ 45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or,
- •is of child-bearing potential with a negative pregnancy test at both Screening and Day 1 and agrees to use one of the following methods of contraception to avoid pregnancy:
- •Complete abstinence from penile-vaginal intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 4 weeks after discontinuation of all study medications;
- •Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
- •Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see protocol appendix 5 for an example listing of approved IUDs);
- •Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject;
- •Approved hormonal contraception (see protocol appendix 5 for a listing of examples of approved hormonal contraception) plus male condom;
- •Any other method with published data showing that the expected failure rate is <1% per year.
- •Any contraception method must be used consistently, in accordance with the approved product label and for at least 4 weeks after discontinuation of IP.
- •Men who have partners who are women of childbearing potential (WOCBP - definition in Appendix 5) must be using an adequate method of contraception to avoid pregnancy in their partner throughout the study and for a period of at least 4 weeks after the study (see inclusion criteria 6);
- •Complete abstinence from penile-vaginal intercourse
- •Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide);
- •Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion, see Appendix 5 for an example listing of approved IUDs);
- •Male partner sterilization confirmed prior to the female subject's entry into the study, and this male is the sole partner for that subject;
- •Any other method with published data showing that the expected failure rate is <1% per year. and not containing hormones.
- •Any contraception method must be used consistently, in accordance with the approved product label and for at least four weeks after discontinuation of IMP.
- •Willing to consent to their personal details being entered onto the TOPS database
- •Willing to provide proof of identity by photographic ID at screen and any subsequent visit
- •Registered with a GP in the UK
排除标准
- •Any clinically significant acute or chronic medical illness
- •Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG or clinical laboratory determinations
- •Positive blood screen for hepatitis B surface antigen or C antibody
- •Positive blood screen for HIV-1 or 2 by antibody/antigen assay
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
- •History or presence of allergy to the study drugs and their components: darunavir, cobicistat, dolutegravir or excipients (sodium methyl parahydroxybenzoate, lactulose, Hypromellose Colloidal silicon dioxide, Silicified microcrystalline cellulose Crospovidone, Magnesium stearate, Polyvinyl alcohol- partially hydrolysed, Macrogol 3350,Titanium dioxide, Talc, Iron oxide red, Iron oxide black, Lactose monohydrate, Magnesium stearate, Gelatine Yellow iron oxide, Indigocarmin (E132), White ink, Shellac,Titanium dioxide (E171), Ammonium hydroxide, Propylene glycol , Simethicone, Hypromellose, Polyvinyl alcohol-partially hydrolysed, Macrogol 3350) Mannitol (E421) Microcrystalline cellulose Povidone K29/32, Sodium starch glycolate, Sodium stearyl fumarate, Polyvinyl alcohol-partially hydrolyzed, Titanium dioxide (E171), Macrogol Talc Iron oxide yellow (E172)
- •Current or recent (within three months) gastrointestinal disease
- •Known intolerance of lactose monohydrate, sunset yellow aluminium lake (E110), and patients with galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption
- •Clinically relevant alcohol or drug use (positive urine drug screen) or history of alcohol or drug use considered by the Investigator to be sufficient to hinder compliance with treatment, follow-up procedures or evaluation of adverse events. Smoking is permitted, but tobacco intake should remain consistent throughout the study
- •Exposure to any investigational drug (or placebo) or participation in a clinical study involving the donation of blood samples within three months of first dose of study drug
- •Use of any other drugs (unless approved by the Investigator), including over-the-counter medications and herbal preparations, within two weeks prior to first dose of study drug, unless approved/prescribed by the Principal Investigator as known not to interact with study drugs.
- •Females of childbearing potential without the use of effective non-hormonal birth control
- •Methods, or not willing to continue practising these birth control methods for at least four weeks after the end of the treatment period
研究组 & 干预措施
Group One
Tivicay (Dolutegravir 50 mg) for 14 days OD (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 43-56)
干预措施: Tivicay (Drug)
Group One
Tivicay (Dolutegravir 50 mg) for 14 days OD (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 43-56)
干预措施: Rezolsta (Drug)
Group Two
Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Tivicay (Dolutegravir 50 mg) for 14 days OD (days 43-56)
干预措施: Tivicay (Drug)
Group Two
Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 1-14) WASH OUT for 7 days (days 15-21) Tivicay (Dolutegravir 50 mg) OD plus Rezolsta (darunavir/cobicistat 800/150 mg) OD for 14 days (days 22-35) WASH OUT for 7 days (days 36-42) Tivicay (Dolutegravir 50 mg) for 14 days OD (days 43-56)
干预措施: Rezolsta (Drug)
结局指标
主要结局
Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Tmax
时间窗: 8 weeks
Tmax = time point at Cmax
Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Cthrough
时间窗: 8 weeks
Trough concentration (Ctrough) is defined as the concentration at 24 hours after the observed drug dose
Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by Cmax
时间窗: 8 weeks
Cmax defined as the maximum observed plasma concentration.
Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by t1/2
时间窗: 8 weeks
t1/2 = Elimination half-life
Assess the pharmacokinetics of dolutegravir and darunavir/cobicistat during co-administration in HIV negative healthy volunteers as measured by total drug exposure
时间窗: 8 weeks
Total drug exposure is expressed as the area under the plasma concentration-time curve from 0-24 hours after dosing (AUC0-24h)
次要结局
- Assess the safety and tolerability of the studied drugs when co-administered to HIV negative healthy volunteers, assessed by The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events(10 weeks)
- Exploratory: the impact of antiretroviral drugs on platelet function(8 weeks)
- investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by Peak plasma concentration (Cmax)(8 weeks)
- investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by trough concentration (Ctrough)(8 weeks)
- investigate the association between genetic polymorphisms in drug disposition genes and drug exposure as measured by Area under the plasma concentration versus time curve (AUC)(8 Weeks)