School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
Antimicrob Agents Chemother. 2012 Jun;56(6):3288-97. doi: 10.1128/AAC.06232-11. Epub 2012 Apr 2.
Pharmacokinetic differences between piperaquine (PQ) base and PQ tetraphosphate were investigated in 34 Papua New Guinean children aged 5 to 10 years treated for uncomplicated malaria with artemisinin-PQ (ART-PQ) base or dihydroartemisinin-PQ (DHA-PQ) tetraphosphate. Twelve children received ART-PQ base (two daily doses of 3 mg of ART and 18 mg of PQ base as granules/kg of body weight) as recommended by the manufacturer, with regular clinical assessment and blood sampling over 56 days. PQ concentrations in plasma samples collected from 22 children of similar ages with malaria in a previously published pharmacokinetic study of DHA-PQ tetraphosphate (three daily doses of 2.5 mg of ART and 20 mg of PQ tetraphosphate as tablets/kg of body weight) were available for comparison. The disposition of ART was also assessed in the 12 children who received ART-PQ base. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and ART was assayed using liquid chromatography-mass spectrometry. Multicompartment pharmacokinetic models for PQ and ART were developed using a population-based approach. ART-PQ base was well tolerated, and initial fever abatement and parasite clearance were prompt. There were no differences between the two treatments in the values for the PQ area under the concentration-time curve from time zero to infinity (AUC(0-∞)), with medians of 49,451 (n = 12) and 44,556 (n = 22) μg · h/liter for ART-PQ base and DHA-PQ tetraphosphate, respectively. Recurrent parasitemia was associated with lower PQ exposure. Using a two-compartment ART model, the median AUC(0-∞) was 1,652 μg · h/liter. There was evidence of autoinduction of ART metabolism (relative bioavailability for the second dose, 0.27). These and previously published data suggest that a 3-day ART-PQ base regimen should be further evaluated, in line with World Health Organization recommendations for all artemisinin combination therapies.
在 34 名年龄在 5 至 10 岁的巴布亚新几内亚儿童中，研究了哌喹（PQ）碱和 PQ 四磷酸盐之间的药代动力学差异。这些儿童因患有无并发症疟疾，接受了青蒿素-PQ（ART-PQ）碱或双氢青蒿素-PQ（DHA-PQ）四磷酸盐治疗。其中 12 名儿童按照制造商的建议，接受了 ART-PQ 碱（每日两次，每次 3 毫克的 ART 和 18 毫克的 PQ 碱作为颗粒/公斤体重）治疗，同时在 56 天内进行了定期的临床评估和血液采样。此前，在一项关于 DHA-PQ 四磷酸盐的药代动力学研究中，采集了 22 名年龄相似的患有疟疾的儿童的血浆样本，这些样本中 PQ 浓度可供比较。对接受 ART-PQ 碱治疗的 12 名儿童的 ART 处置情况也进行了评估。通过高效液相色谱法结合紫外检测法测定血浆 PQ，通过液相色谱-质谱法测定 ART。采用基于人群的方法，建立了 PQ 和 ART 的多室药代动力学模型。ART-PQ 碱耐受良好，初始退热和寄生虫清除迅速。两种治疗方法的 PQ 药时曲线下面积（AUC(0-∞)）值无差异，ART-PQ 碱的中位数为 49,451（n = 12）μg·h/L，DHA-PQ 四磷酸盐的中位数为 44,556（n = 22）μg·h/L。复发性寄生虫血症与 PQ 暴露量较低有关。使用两室 ART 模型，AUC(0-∞)的中位数为 1,652μg·h/L。有证据表明 ART 代谢自动诱导（第二剂量的相对生物利用度为 0.27）。这些数据以及之前发表的数据表明，应根据世界卫生组织对所有青蒿素联合疗法的建议，进一步评估 3 天的 ART-PQ 碱方案。
