Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.
Malar J. 2012 Aug 22;11:293. doi: 10.1186/1475-2875-11-293.
Malaria in pregnancy increases the risk of maternal anemia, abortion and low birth weight. Approximately 85.3 million pregnancies occur annually in areas with Plasmodium falciparum transmission. Pregnancy has been reported to alter the pharmacokinetic properties of many anti-malarial drugs. Reduced drug exposure increases the risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin in pregnant women with uncomplicated P. falciparum malaria in Uganda.
Twenty-one women with uncomplicated P. falciparum malaria in the second and third trimesters of pregnancy received the fixed oral combination of 80 mg artemether and 480 mg lumefantrine twice daily for three days. Artemether and dihydroartemisinin plasma concentrations after the last dose administration were quantified using liquid chromatography coupled to tandem mass-spectroscopy. A simultaneous drug-metabolite population pharmacokinetic model for artemether and dihydroartemisinin was developed taking into account different disposition, absorption, error and covariate models. A separate modeling approach and a non-compartmental analysis (NCA) were also performed to enable a comparison with literature values and different modeling strategies.
The treatment was well tolerated and there were no cases of recurrent malaria. A flexible absorption model with sequential zero-order and transit-compartment absorption followed by a simultaneous one-compartment disposition model for both artemether and dihydroartemisinin provided the best fit to the data. Artemether and dihydroartemisinin exposure was lower than that reported in non-pregnant populations. An approximately four-fold higher apparent volume of distribution for dihydroartemisinin was obtained by non-compartmental analysis and separate modeling compared to that from simultaneous modeling of the drug and metabolite. This highlights a potential pitfall when analyzing drug/metabolite data with traditional approaches.
The population pharmacokinetic properties of artemether and dihydroartemisinin, in pregnant women with uncomplicated P. falciparum malaria in Uganda, were described satisfactorily by a simultaneous drug-metabolite model without covariates. Concentrations of artemether and its metabolite dihydroartemisinin were relatively low in pregnancy compared to literature data. However, this should be interpreted with caution considered the limited literature available. Further studies in larger series are urgently needed for this vulnerable group.
妊娠期间的疟疾会增加母体贫血、流产和低出生体重的风险。在有恶性疟原虫传播的地区，每年约有 8530 万例妊娠。有报道称，妊娠会改变许多抗疟药物的药代动力学特性。药物暴露减少会增加治疗失败的风险。本研究的目的是评估乌干达妊娠合并无并发症恶性疟的妇女中，青蒿素及其活性代谢物双氢青蒿素的群体药代动力学特征。
21 例妊娠 2 至 3 个月合并无并发症恶性疟的妇女接受 80mg 青蒿素和 480mg 咯萘啶的固定口服合剂，每日两次，共 3 天。末次给药后，采用液相色谱-串联质谱法定量检测青蒿素和双氢青蒿素的血浆浓度。建立了青蒿素和双氢青蒿素的药物-代谢物群体药代动力学模型，考虑了不同的处置、吸收、误差和协变量模型。还进行了单独的建模方法和非房室分析（NCA），以实现与文献值和不同建模策略的比较。
该治疗方法耐受性良好，无疟疾复发病例。灵活的吸收模型，具有顺序零级和转运室吸收，随后是同时的一室处置模型，用于青蒿素和双氢青蒿素，为数据提供了最佳拟合。与非妊娠人群相比，青蒿素和双氢青蒿素的暴露量较低。非房室分析和单独建模得到的双氢青蒿素表观分布容积约为同时建模药物和代谢物的 4 倍。这突出了在使用传统方法分析药物/代谢物数据时的一个潜在陷阱。
在乌干达患有无并发症恶性疟的妊娠妇女中，青蒿素和双氢青蒿素的群体药代动力学特征可以通过没有协变量的同时药物-代谢物模型来很好地描述。与文献数据相比，妊娠期间青蒿素及其代谢物双氢青蒿素的浓度相对较低。然而，鉴于可用的文献有限，这应该谨慎解释。对于这个脆弱的群体，迫切需要在更大的系列中进行进一步的研究。
