Novartis Institutes for BioMedical Research, Postfach, CH-4002, Basel, Switzerland.
Malar J. 2013 Sep 8;12:312. doi: 10.1186/1475-2875-12-312.
Artemether-lumefantrine (Coartem; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets.
A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses.
Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 μg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 μg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 μg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1.25). In addition, secondary PK parameters also met bioequivalence criterion.
Both of the novel artemether-lumefantrine tablet formulations evaluated are bioequivalent to their respective standard Coartem tablet doses. These novel formulations are easy to administer and may improve adherence in the treatment of uncomplicated malaria caused by Plasmodium falciparum.
CTRI/2011/12/002256.
青蒿琥酯-咯萘啶（科泰新；AL）是治疗疟疾的标准疗法，作为一种口服六剂量方案，每天两次给药，持续三天，每次剂量为一至四片（20/120 毫克），具体取决于患者的体重。为了减少每次剂量的药丸负担并可能提高依从性，两种新型固定剂量片剂制剂（80/480 毫克和 60/360 毫克）已被开发并在这项研究中进行了测试，以与各自数量的标准片剂进行生物等效性比较。
一项随机、开放标签、两期、单剂量、制剂内交叉生物等效性研究，在 120 名健康受试者中进行，在进食条件下比较新型 80/480 毫克片剂与四片标准片剂，以及新型 60/360 毫克片剂与三片标准片剂之间的青蒿琥酯和咯萘啶的暴露情况。青蒿琥酯、二氢青蒿素和咯萘啶通过 HPLC/UPLC-MS/MS 在血浆中进行测量。通过非房室分析确定药代动力学（PK）参数。
调整后的青蒿琥酯 AUClast 的几何平均值分别为 345 和 364ng·h/mL（几何均数比（GMR）0.95；90%置信区间（CI）0.89-1.01）和咯萘啶分别为 219 和 218μg·h/mL（GMR 1.00；90%CI 0.93-1.08），80/480 毫克片剂与四片标准片剂相比，相应的 Cmax 为 96.8 和 99.7ng/mL（GMR 0.97；90%CI 0.89-1.06）和咯萘啶分别为 8.42 和 8.71μg/mL（GMR 0.97；90%CI 0.89-1.05）。对于 60/360 毫克片剂与三片标准片剂相比，调整后的青蒿琥酯 AUClast 的几何平均值分别为 235 和 231ng·h/mL（GMR 1.02；90%CI 0.94-1.10）和咯萘啶分别为 160 和 180μg·h/mL（GMR 0.89；90%CI 0.83-0.96）。相应的 Cmax 为 75.5 和 71.5ng/mL（GMR 1.06；90%CI 0.95-1.18）和咯萘啶分别为 6.64 和 7.61μg/mL（GMR 0.87；90%CI 0.81-0.94）。所有主要比较的青蒿琥酯和咯萘啶的 Cmax 和 AUClast 的 GMR 均在生物等效性接受标准（0.80-1.25）范围内。此外，次要 PK 参数也符合生物等效性标准。
评估的两种新型青蒿琥酯-咯萘啶片剂制剂均与各自的标准科泰新片剂剂量具有生物等效性。这些新型制剂易于给药，可能会提高治疗由恶性疟原虫引起的无并发症疟疾的依从性。
CTRI/2011/12/002256。
