Effect of Atazanavir-ritonavir on the Pharmacokinetics and Toxicity of Lumefantrine in People Living With HIV Attending Lagos University Teaching Hospital
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Day 7 lumefantrine concentration
研究概览
简要总结
A case control pharmacokinetic study evaluating the effects of atazanavir-ritonavir on the pharmacokinetics and toxicity of lumefantrine in people living with HIV attending APIN clinic of the Lagos University Teaching Hospital
详细描述
Atazanavir-ritonavir (ATVr) based antiretroviral therapy and artemether-lumefantrine (AL) are commonly used drugs for the treatment of Human Immune Deficiency Virus (HIV) infection and malaria respectively in Nigeria. However, both drugs interact with Cytochrome P 3A4 (CYP 3A4) isoenzymes which may spawn clinically significant pharmacokinetic interactions.
The study was aimed at evaluating the effects of atazanavir-ritonavir on the pharmacokinetics and toxicity of lumefantrine.
In a case control pharmacokinetic study, twenty participants who tested positive for Plasmodium falciparum malaria were recruited and divided into two groups (ATVr-arm, n=10; and Control-arm, n= 10). All the participants were administered with 6 doses of AL 80-480 mg (Coartem). Thereafter, blood samples were collected from them at different time intervals over seven days. The lumefantrine concentration in each sample was determined with high-performance liquid chromatography (HPLC) and entered into WinNonlin® software to determine the pharmacokinetic parameters of lumefantrine which were compared between the test and control groups. Toxicity was evaluated with adverse events monitoring, electrocardiography, haematological and blood chemistry tests at pre and post doses of artemether-lumefantrine.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Adult male or non-gravid female ≥18 years of age,
- •Informed written consent,
- •Malaria parasitaemia
- •Axillary temperature ≥37.5°C or history of fever within 24 hours before visiting the clinic and with, at least, any of the following signs and symptoms of uncomplicated malaria: chills, sweats, headaches, muscle aches, nausea, vomiting, diarrhoea, body weakness, poor appetite and pallor.
- •Hemoglobin (Hb) ≥8 g/dl
- •Body weight ≥35 kg
- •HIV positive (ATVr arm), HIV negative (AL/control arm)
排除标准
- •Severe anaemia' (Haemoglobin levels < 8g/dl)
- •Smokers/alcoholics and users of substances which inhibit or induce CYP3A4 iso enzymes
- •Withdrawal of consent
- •Known allergy to any of the study drugs
- •Development of complications or severe adverse effects
- •Smokers/alcoholics and users of caffeine, drugs which induce or inhibit CYP3A4 and CYP2B6
- •Evidence of chronic illnesses such as diabetes, hypertension, psychiatric illnesses
- •Subject taking any drugs or having any condition known to prolong QT-intervals
- •Signs of severe malaria
- •Use of anti-tubercular drugs for at least three months prior to enrolment
- •Being on anti-malarial drugs within four weeks prior to enrolment
- •Pregnant or nursing mother.
研究组 & 干预措施
ATVr-arm
10 participants living with HIV and having uncomplicated Falciparum malaria were administered: Atazanavir-ritonavir (300/100 mg) one tablet once daily continuously + tenofovir-lamivudine (300/300 mg) one tablet once daily continuously and artemether-lumefantrine (80/480 mg) one tablet twice daily for three days at 0, 8, 24, 36, 48 and 60 hour.
干预措施: Artemether-lumefantrine (Drug)
ATVr-arm
10 participants living with HIV and having uncomplicated Falciparum malaria were administered: Atazanavir-ritonavir (300/100 mg) one tablet once daily continuously + tenofovir-lamivudine (300/300 mg) one tablet once daily continuously and artemether-lumefantrine (80/480 mg) one tablet twice daily for three days at 0, 8, 24, 36, 48 and 60 hour.
干预措施: Atazanavir-ritonavir 300/100 mg (Drug)
AL-arm (Control)
10 participants who were HIV negative but having uncomplicated Falciparum malaria were administered: Artemether-lumefantrine 80/480 mg, one tablet twice daily for three days at 0, 8, 24, 36, 48 and 60 hour.
干预措施: Artemether-lumefantrine (Drug)
结局指标
主要结局
Day 7 lumefantrine concentration
时间窗: 2 weeks
This the plasma concentration of lumefantrine at the seventh day of commencement of the first dose. Efficacy is indicated when it is 280 ng/mL and above.
QTc-interval
时间窗: One week
Change in mean or median QTc-interval above therapeutic range at post-dose of artemether-lumefantrine indicates cardio-toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels
时间窗: One week
Change in mean or median ALT and AST levels above therapeutic range at post-dose of artemether-lumefantrine indicates liver toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.
Drug exposure (Area under the curve) of lumefantrine
时间窗: 2 weeks
Change in drug exposure (AUC) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction
Haemoglobin level
时间窗: One week
Change in mean or median hemoglobin level above therapeutic range at post-dose of artemether-lumefantrine indicates haemotoxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.
Maximum plasma concentration (Cmax) of lumefantrine
时间窗: 2 weeks
Change in maximum plasma concentration (Cmax) of lumefantrine may indicate interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction
Creatinine level
时间窗: One week
Change in mean or median creatinine level above therapeutic range at post-dose of artemether-lumefantrine indicates renal toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.
Adverse events
时间窗: Two weeks
Change in frequency of adverse events post-dose of artemether-lumefantrine indicates toxicity caused by interaction between atazanavir-ritonavir and lumefantrine via Cytochrome P3A4 induction.
次要结局
未报告次要终点
研究者
Sikiru Olatunji Usman
Principal Investigator
Fogarty International Center of the National Institute of Health