Department of Clinical Pharmacy and Pharmacology, School of Pharmacy (R.F.M., O.O.M.S.M., A.A.R.K.), and Department of Obstetrics and Gynecology, School of Medicine (S.N.M.), Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (M.A., A.F.); Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden (A.F.); and Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden (E.A.)
Department of Clinical Pharmacy and Pharmacology, School of Pharmacy (R.F.M., O.O.M.S.M., A.A.R.K.), and Department of Obstetrics and Gynecology, School of Medicine (S.N.M.), Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania; Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden (M.A., A.F.); Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden (A.F.); and Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden (E.A.).
Drug Metab Dispos. 2019 Dec;47(12):1415-1424. doi: 10.1124/dmd.119.088062.
Pregnancy and pharmacogenetics variation alter drug disposition and treatment outcome. The objective of this study was to investigate the effect of pregnancy and pharmacogenetics variation on day 7 lumefantrine (LF) plasma concentration and therapeutic responses in malaria-infected women treated with artemether-lumefantrine (ALu) in Tanzania. A total of 277 (205 pregnant and 72 nonpregnant) women with uncomplicated malaria were enrolled. Patients were treated with ALu and followed up for 28 days. , , and genotyping were done. Day 7 plasma LF concentration and the polymerase chain reaction (PCR) - corrected adequate clinical and parasitological response (ACPR) at day 28 were determined. The mean day 7 plasma LF concentrations were significantly lower in pregnant women than nonpregnant women [geometric mean ratio = 1.40; 95% confidence interval (CI) of geometric mean ratio (1.119-1.1745), < 0.003]. Pregnancy, low body weight, and genotype were significantly associated with low day 7 LF plasma concentration ( < 0.01). PCR-corrected ACPR was 93% (95% CI = 89.4-96.6) in pregnant women and 95.7% (95% CI = 90.7-100) in nonpregnant women. Patients with lower day 7 LF concentration had a high risk of treatment failure (mean 652 vs. 232 ng/ml, < 0.001). In conclusion, pregnancy, low body weight, and allele are significant predictors of low day 7 LF plasma exposure. In turn, lower day 7 LF concentration is associated with a higher risk of recrudescence. SIGNIFICANCE STATEMENT: This study reports a number of factors contributing to the lower day 7 lumefantrine (LF) concentration in women, which includes pregnancy, body weight, and genotype. It also shows that day 7 LF concentration is a main predictor of malaria treatment. These findings highlight the need to look into artemether-LF dosage adjustment in pregnant women so as to be able to maintain adequate drug concentration, which is required to reduce treatment failure rates in pregnant women.
妊娠和药物遗传学变异会改变药物的分布和治疗效果。本研究旨在探讨妊娠和药物遗传学变异对坦桑尼亚接受青蒿琥酯-咯萘啶（ALu）治疗的疟疾感染妇女第 7 天青蒿琥酯（LF）血浆浓度和治疗反应的影响。共纳入 277 例（205 例妊娠和 72 例非妊娠）无并发症的疟疾患者。患者接受 ALu 治疗，并随访 28 天。进行了基因分型，测定了第 7 天血浆 LF 浓度和第 28 天聚合酶链反应（PCR）校正的充分临床和寄生虫学反应（ACPR）。与非妊娠妇女相比，妊娠妇女第 7 天血浆 LF 浓度明显较低[几何均数比=1.40；95%置信区间（CI）的几何均数比（1.119-1.1745），<0.003]。妊娠、低体重和 基因型与第 7 天 LF 低血浆浓度显著相关（<0.01）。PCR 校正后的 ACPR 在妊娠妇女中为 93%（95%CI=89.4-96.6），在非妊娠妇女中为 95.7%（95%CI=90.7-100）。第 7 天 LF 浓度较低的患者治疗失败风险较高（平均 652 与 232ng/ml，<0.001）。结论：妊娠、低体重和 等位基因是第 7 天 LF 低血浆暴露的重要预测因素。反过来，第 7 天 LF 浓度较低与复发风险增加相关。意义声明：本研究报告了一些导致妇女第 7 天青蒿琥酯（LF）浓度降低的因素，包括妊娠、体重和 基因型。它还表明，第 7 天 LF 浓度是疟疾治疗的主要预测因素。这些发现强调需要研究青蒿琥酯-LF 剂量调整在孕妇中的应用，以便能够维持足够的药物浓度，从而降低孕妇的治疗失败率。
