Role of Pharmacogenetics in Efavirenz and Nevirapine Pharmacokinetics, Efficacy and Safety in Mother-infant Pairs During Pregnancy and Lactation
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 460
- 试验地点
- 3
- 主要终点
- Maximum plasma drug concentration (Cmax) during pregnancy.
研究概览
简要总结
Mother-to-child transmission of HIV (MTCT) during pregnancy and breastfeeding is prevented with maternal antiretroviral drugs (ARV) and infant nevirapine post-exposure prophylaxis (PEP). However, the pharmacokinetics of certain ARVs is associated with marked inter-individual variability. This variability has been associated with single nucleotide polymorphisms (SNPs) in genes encoding metabolising enzymes, transporters and transcriptional regulators. Pregnancy is also associated with additional changes in pharmacokinetics. The resulting sub-therapeutic or supra-therapeutic drug exposures may have serious consequences for virological control, MTCT, emergence of drug resistance, and toxicity. Foetal and infant exposure to maternal ARV during pregnancy and breastfeeding is believed to play a role in the prevention of mother-to-child transmission of HIV (PMTCT). However, such exposures may also result in toxicity. For example, efavirenz is contraindicated in children less than 3 years old or 10kg but transferred to breastfed babies through breast milk. On the other hand, double exposure to nevirapine from breast milk and PEP may also predispose breastfed infants to nevirapine-associated toxicity.
In the proposed study, the influence of selected SNPs in certain drug disposition genes on the pharmacokinetics of efavirenz and nevirapine during pregnancy and lactation, as well as the level of infant exposure to both drugs through breast milk, will be studied. Mathematical models will be developed to predict potential dose optimisation strategies during pregnancy, and to predict infant exposure to maternal drugs through breast milk.
详细描述
Study design: This is an observational study that will be conducted in two phases. In the preliminary phase, associations between selected SNPs in drug disposition genes and mid-dose plasma and breast milk efavirenz and nevirapine concentrations will be explored in an unselected cohort of HIV positive pregnant women and nursing mothers and their breastfed infants taking either drug as part of combination antiretroviral therapy for PMTCT. In the second phase, the SNP independently associated with the highest predictive power will be used to stratify pregnant women and mother-infant pairs into three groups: non-carriers, heterozygotes, and homozygotes. Randomly selected pregnant women or mother-infant pairs from each group were re-recruited and invited for the intensive pharmacokinetic phase.
Samples collection: In the preliminary phase, mid-dose paired dried blood spots (DBS) (and dried breast milk spots in nursing mothers) samples will be collected at a single, recorded time point post dose. In the intensive pharmacokinetic phase, DBS (and dried breast milk spots in nursing mothers) samples will be collected at multiple time points after an observed dose of efavirenz or nevirapine. Samples will be shipped at room temperature to the Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom for analysis.
DNA extraction and SNP genotyping: Genomic DNA will be extracted using available commercial kits in accordance with the manufacture's protocol and genotyping will be performed by allelic discrimination real-time polymerase chain reaction using TaqMan® chemistry-based assays.
Drug quantification and pharmacokinetic analysis: Liquid chromatography-mass spectrometry methods will be developed for the quantification of efavirenz and nevirapine in DBS and dried breast milk spots. Pharmacokinetic parameters will be determined using standard procedures.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •HIV positive
- •breastfeeding
- •enrolled in PMTCT programme
- •started efavirenz- or nevirapine-containing regimen during pregnancy
排除标准
- •exclusive replacement feeding
- •mixed feeding before 6 months
- •severe maternal or infant illness
- •maternal or infant treatment with other drugs or herbal medication with known or uncertain interaction with study drug
研究组 & 干预措施
Pregnant women - efavirenz
Pregnant women taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health
干预措施: Efavirenz (Drug)
Nursing mothers - efavirenz
Nursing mothers taking 600 mg efavirenz daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies
干预措施: Efavirenz (Drug)
Pregnant women - nevirapine
Pregnant women taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health
干预措施: Nevirapine (Drug)
Nursing mothers - nevirapine
Nursing mothers taking 200 mg nevirapine twice daily as part of combination antiretroviral therapy for PMTCT and for their own health and their breastfed babies
干预措施: Nevirapine (Drug)
结局指标
主要结局
Maximum plasma drug concentration (Cmax) during pregnancy.
时间窗: Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.
Plasma and breast milk area under the concentration-time curve (AUC0-24 for efavirenz, AUC0-12 for nevirapine) during lactation.
时间窗: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
Plasma and breast milk clearance over systemic availability (Cl/F) during lactation.
时间窗: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
Plasma and breast milk minimum drug concentration (Cmin) during lactation.
时间窗: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
Clearance over systemic availability (Cl/F) during pregnancy.
时间窗: Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.
Area under the concentration-time curve (AUC0-24 for efavirenz, AUC0-12 for nevirapine) during pregnancy.
时间窗: Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.
Minimum plasma drug concentration (Cmin) during pregnancy.
时间窗: Patients will be followed for an average of 6 months for the preliminary and intensive pharmacokinetic phase which will occur mainly between the second and third trimester of pregnancy.
Plasma and breast milk maximum plasma drug concentration (Cmax) during lactation.
时间窗: Pharmacokinetic visits in the preliminary or intensive pharmacokinetic phase will occur mainly from 1 week to 26 weeks postpartum.
次要结局
- Rate of mother-to-child transmission of HIV.(Infants will be followed up from birth until 18 months of age when all exposure to breastfeeding would have stopped.)
- Effect of pregnancy on CD4 count change (immunological recovery).(CD4 counts will be determined every 6 months during pregnancy and postpartum, starting from recruitmnent.)
研究者
Adeniyi Olagunju
Lecturer
Obafemi Awolowo University