Sangana Ramachandra, Ogutu Bernhards, Yeka Adoke, Kusemererwa Sylvia, Tinto Halidou, Toure Andre Offianan, Kibuuka Afizi, Lingani Moussa, Lourenço Carlos, Mombo-Ngoma Ghyslain, Nduba Videlis, Landry N'Guessan Tiacoh, Nassa Guétawendé Job Wilfried, Nyantaro Mary, Tina Lucas Otieno, Anvikar Anup, Sinha Abhinav, Kaguthi Grace, Fofana Bakary, Grobusch Martin Peter, Gaaloul Myriam El, Marrast Anne Claire, Pathan Rashidkhan, Chikoto Havana, Csermak Katalin, Risterucci Celine, Su Guoqin, Winnips Cornelis, Zhang Jie, Zack Julia
PK Sciences, Biomedical Research, Novartis, Cambridge, MA, USA.
Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya and CREATES, Strathmore University, Nairobi, Kenya.
J Clin Pharmacol. 2025 Feb;65(2):179-189. doi: 10.1002/jcph.6138. Epub 2024 Sep 29.
The novel antimalarial ganaplacide combined with lumefantrine solid dispersion formulation (LUM-SDF) was effective and well tolerated in the treatment of uncomplicated falciparum malaria in adults, adolescents, and children in a multinational, prospective, randomized, active-controlled Phase II study conducted between August 2017 and June 2021 (EudraCT 2020-003284-25, Clinicaltrials.gov NCT03167242). Pharmacokinetic data from that study are reported here. The trial comprised three parts: a run-in part in 12 adult/adolescent patients treated with a single dose of ganaplacide 200 mg plus LUM-SDF 960 mg assessed potential pharmacokinetic (PK) interactions between ganaplacide and lumefantrine; in Part A, adult/adolescent patients received one of the six ganaplacide-LUM-SDF regimens or artemether-lumefantrine; and in Part B, three dose regimens identified in Part A, and artemether-lumefantrine, were assessed in children aged 2 to <12 years, with body weight ≥10 kg. A rich blood sampling schedule was used for all 12 patients in the PK run-in part and a subset of patients (N = 32) in Part A, with sparse sampling for remaining patients in Parts A (N = 275) and B (N = 159). Drug concentrations were determined by a validated protein precipitation and reverse phase liquid chromatography with tandem mass spectrometry detection method. Parameters including AUC, AUC, AUC, C and t were reported where possible, using non-compartmental analysis. In the PK run-in part, there was no notable increase in ganaplacide or lumefantrine exposure when co-administered. In Parts A and B, ganaplacide exposures increased with dose, but lumefantrine exposure was numerically under dose-proportional. Lumefantrine exposure was higher with ganaplacide-LUM-SDF than with artemether-lumefantrine, although high variability was observed. Ganaplacide and lumefantrine exposures (C and AUC) were comparable across age and body weight groups. Drug exposures needed for efficacy were achieved using the dose regimen 400 mg ganaplacide plus lumefantrine 960 mg once daily for 3 days under fasted conditions.
在2017年8月至2021年6月期间进行的一项多国、前瞻性、随机、活性对照II期研究（EudraCT 2020-003284-25，Clinicaltrials.gov NCT03167242）中，新型抗疟药甘氨苯双胍与本芴醇固体分散体制剂（LUM-SDF）联合使用，在治疗成人、青少年和儿童的非复杂性恶性疟方面有效且耐受性良好。本文报告了该研究的药代动力学数据。该试验包括三个部分：在12名成年/青少年患者中进行的导入期部分，这些患者接受单剂量200 mg甘氨苯双胍加960 mg LUM-SDF治疗，评估甘氨苯双胍和本芴醇之间潜在的药代动力学（PK）相互作用；在A部分，成年/青少年患者接受六种甘氨苯双胍-LUM-SDF方案之一或蒿甲醚-本芴醇治疗；在B部分，对2至<12岁、体重≥10 kg的儿童评估在A部分确定的三种剂量方案以及蒿甲醚-本芴醇。对PK导入期部分的所有12名患者以及A部分的一部分患者（N = 32）采用密集采血计划，对A部分（N = 275）和B部分（N = 159）的其余患者采用稀疏采血。通过经过验证的蛋白沉淀和反相液相色谱-串联质谱检测方法测定药物浓度。在可能的情况下，使用非房室分析报告包括AUC、AUC、AUC、C和t等参数。在PK导入期部分，联合给药时甘氨苯双胍或本芴醇的暴露量没有显著增加。在A部分和B部分，甘氨苯双胍的暴露量随剂量增加而增加，但本芴醇的暴露量在数值上低于剂量比例关系。尽管观察到高变异性，但甘氨苯双胍-LUM-SDF组的本芴醇暴露量高于蒿甲醚-本芴醇组。甘氨苯双胍和本芴醇的暴露量（C和AUC）在不同年龄和体重组中具有可比性。在禁食条件下，采用400 mg甘氨苯双胍加960 mg本芴醇每日一次、共3天的剂量方案可达到疗效所需的药物暴露量。
