Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children
Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children
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DOI：
10.1128/aac.02590-16
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发表时间：
2017-05-01
影响因子：
4.9
通讯作者：
ter Heine, Rob
中科院分区：
文献类型：
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作者：
Goncalves, Bronner P.;Pett, Helmi;ter Heine, Rob
在受青蒿素耐药性威胁的地区和旨在消除疟疾的地区，建议使用低剂量伯氨喹预防恶性疟原虫疟疾传播。青蒿素类复方疗法结合杀配子细胞剂伯氨喹的社区治疗运动针对所有年龄组，但迄今没有研究评估这种杀配子细胞剂在非洲儿童中的药代动力学。我们在布基纳法索招募了40名参加伯氨喹疗效试验的儿童，以研究伯氨喹的药代动力学。这些儿童接受蒿甲醚-苯芴醇和0.25或0.40 mg/kg伯氨喹剂量。从每名参与者中采集7份血液样本用于伯氨喹和羧基伯氨喹血浆水平测定：根据部分重叠的采样时间表，在伯氨喹给药前采集1份样本，在伯氨喹给药后采集6份样本。生理群体药代动力学模型用于评估体重、年龄和CYP 2D 6基因型对伯氨喹和羧基伯氨喹药代动力学的影响。尽管线性体重标准化给药，伯氨喹和羧基伯氨喹的血浆浓度-时间曲线下面积和峰浓度均随年龄和体重增加。CYP 2D 6弱代谢型儿童的母体化合物水平较高，表明CYP 2D 6介导的伯氨喹代谢较低。我们的数据表明，伯氨喹和羧基伯氨喹的药代动力学受年龄，体重和CYP 2D 6基因型的影响，并建议给药策略可能要重新考虑，以最大限度地提高伯氨喹的传播阻断性能。
Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine.