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Abstract：
BACKGROUND: Despite efforts made to reduce morbidity and mortality associated with malaria, especially in sub-Saharan Africa, malaria continues to be a public health concern that requires innovative efforts to reach the WHO-set zero malaria agenda. Among the innovations is the use of artemisinin-based combination therapy (ACT) that is effective against Plasmodium falciparum. Generic artemether-lumefantrine (AL) is used to treat uncomplicated malaria after appropriate diagnosis. AL is metabolized by the cytochrome P450 family of enzymes, such as CYP2B6, CYP3A4 and CYP3A5, which can be under pharmacogenetic influence. Pharmacogenetics affecting AL metabolism, significantly influence the overall anti-malarial activity leading to variable therapeutic efficacy. This study focused on generic AL drugs used in malarial treatment as prescribed at health facilities and evaluated pharmacogenomic influences on their efficacy.
METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP.
RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors.
CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.
METHODS: Patients who have been diagnosed with malaria and confirmed through RDT and microscopy were recruited in this study. Blood samples were taken on days 1, 2, 3 and 7 for parasite count and blood levels of lumefantrine, artemisinin, desbutyl-lumefantrine (DBL), and dihydroartemisinin (DHA), the active metabolites of lumefantrine and artemether, respectively, were analysed using established methods. Pharmacogene variation analysis was undertaken using iPLEX microarray and PCR-RFLP.
RESULTS: A total of 52 patients completed the study. Median parasite density from day 1 to 7 ranged from 0-2666/μL of blood, with days 3 and 7 recording 0 parasite density. Highest median plasma concentration for lumefantrine and desbutyl lumefantrine, which are the long-acting components of artemisinin-based combinations, was 4123.75 ng/mL and 35.87 ng/mL, respectively. Day 7 plasma lumefantrine concentration across all generic ACT brands was ≥ 200 ng/mL which potentially accounted for the parasitaemia profile observed. Monomorphism was observed for CYP3A4 variants, while there were observed variations in CYP2B6 and CYP3A5 alleles. Among the CYP3A5 genotypes, significant differences in genotypes and plasma concentration for DBL were seen on day 3 between 1/*1 versus *1/*6 (p = 0.002), *1/*3 versus *1/*6 (p = 0.006) and *1/*7 versus *1/*6 (p = 0.008). Day 7 plasma DBL concentrations showed a significant difference between *1/*6 and *1/*3 (p = 0.026) expressors.
CONCLUSIONS: The study findings show that CYP2B6 and CYP3A5 pharmacogenetic variations may lead to higher plasma exposure of AL metabolites.
摘要：
背景：尽管努力降低与疟疾相关的发病率和死亡率，尤其是在撒哈拉以南非洲，疟疾仍然是一个公共卫生问题，需要创新努力才能实现世卫组织设定的零疟疾议程。创新之一是使用基于青蒿素的联合疗法（ACT），可有效对抗恶性疟原虫。在适当的诊断后，使用通用蒿甲醚-本美素（AL）治疗无并发症的疟疾。AL由细胞色素P450家族的酶代谢，如CYP2B6，CYP3A4和CYP3A5，它们可能受到药物遗传的影响。影响AL代谢的药物遗传学，显着影响整体抗疟疾活性，导致不同的治疗效果。这项研究的重点是医疗机构规定的用于疟疾治疗的通用AL药物，并评估了药物基因组学对其疗效的影响。
方法：本研究招募了被诊断为疟疾并通过RDT和显微镜检查确诊的患者。在第1天、第2天、第3天和第7天采集血样，以检测寄生虫计数和血药浓度。青蒿素,去丁基-氟烷碱(DBL)，和双氢青蒿素（DHA），本特林和蒿甲醚的活性代谢产物，分别,使用既定的方法进行了分析。使用iPLEX微阵列和PCR-RFLP进行药物源变异分析。
结果：共有52名患者完成了研究。第1天至第7天的寄生虫密度中位数为0-2666/μL血液，第3天和第7天记录寄生虫密度为0。本美曲碱和去丁基本美曲碱的血浆中值最高，是青蒿素组合的长效成分，分别为4123.75ng/mL和35.87ng/mL，分别。在所有通用ACT品牌的第7天血浆本美素浓度均≥200ng/mL，这可能是观察到的寄生虫血症特征的原因。观察到CYP3A4变体的单构性，同时观察到CYP2B6和CYP3A5等位基因的变异。在CYP3A5基因型中，在1/*1与*1/*6之间的第3天观察到DBL的基因型和血浆浓度的显着差异（p=0.002），*1/*3对*1/*6（p=0.006）和*1/*7对*1/*6（p=0.008）。第7天血浆DBL浓度显示*1/*6和*1/*3(p=0.026)表达子之间的显著差异。
结论：研究结果表明，CYP2B6和CYP3A5的药理学变异可能导致血浆中AL代谢物的暴露增加。
方法：本研究招募了被诊断为疟疾并通过RDT和显微镜检查确诊的患者。在第1天、第2天、第3天和第7天采集血样，以检测寄生虫计数和血药浓度。青蒿素,去丁基-氟烷碱(DBL)，和双氢青蒿素（DHA），本特林和蒿甲醚的活性代谢产物，分别,使用既定的方法进行了分析。使用iPLEX微阵列和PCR-RFLP进行药物源变异分析。
结果：共有52名患者完成了研究。第1天至第7天的寄生虫密度中位数为0-2666/μL血液，第3天和第7天记录寄生虫密度为0。本美曲碱和去丁基本美曲碱的血浆中值最高，是青蒿素组合的长效成分，分别为4123.75ng/mL和35.87ng/mL，分别。在所有通用ACT品牌的第7天血浆本美素浓度均≥200ng/mL，这可能是观察到的寄生虫血症特征的原因。观察到CYP3A4变体的单构性，同时观察到CYP2B6和CYP3A5等位基因的变异。在CYP3A5基因型中，在1/*1与*1/*6之间的第3天观察到DBL的基因型和血浆浓度的显着差异（p=0.002），*1/*3对*1/*6（p=0.006）和*1/*7对*1/*6（p=0.008）。第7天血浆DBL浓度显示*1/*6和*1/*3(p=0.026)表达子之间的显著差异。
结论：研究结果表明，CYP2B6和CYP3A5的药理学变异可能导致血浆中AL代谢物的暴露增加。
