A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.
A pharmacokinetic-pharmacodynamic model for chemoprotective agents against malaria.
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DOI：
10.1002/psp4.12875
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发表时间：
2023-01
影响因子：
3.5
通讯作者：
Gobeau, Nathalie
中科院分区：
文献类型：
--
作者：
Cherkaoui-Rbati, Mohammed H.;Andenmatten, Nicole;Burgert, Lydia;Egbelowo, Oluwaseun F.;Fendel, Rolf;Fornari, Chiara;Gabel, Michael;Ward, John;Mohrle, Jorg J.;Gobeau, Nathalie
化学预防药物是防治疟疾的重要工具。它们可用于保护面临风险的人群，例如季节性疟疾传播地区的5岁以下儿童或孕妇。目前批准的化学预防药物都存在挑战。人们要么担心不可接受的副作用，如神经精神后遗症（甲氟喹），要么担心G6PD缺乏症患者的溶血风险（8 -氨基喹啉类药物，如他非诺喹），要么担心成本和每日剂量（阿托伐醌-原胍）。因此，有必要开发新的化学预防药物，通过改善药代动力学等特性，使每周（最好是每月）给药，提供更实惠的治疗方法和更好的依从性。在这里，我们提出了一个药代动力学-药效学（PKPD）模型构建使用DSM265（二氢酸脱氢酶抑制剂，具有抗疟疾肝分裂活性，因此，预防候选）。PKPD模型通过描述肝脏和血液阶段的寄生虫动力学和药物活性来模拟寄生虫的生命周期。一个主要的挑战是模型参数的估计，因为一旦达到阈值，就只能观察到血期寄生虫。通过结合来自各种来源的关于寄生虫的定性和定量知识，已经表明有可能推断出有关肝期生长及其初始感染水平的信息。此外，通过整合临床数据，可以将药物对肝期和血期寄生虫的杀伤作用纳入PKPD模型，并可以预测临床结果。尽管存在诸多挑战，但所提出的模型有可能帮助从临床前到新的化学预防候选药物的后期开发。
Chemoprophylactics are a vital tool in the fight against malaria. They can be used to protect populations at risk, such as children younger than the age of 5 in areas of seasonal malaria transmission or pregnant women. Currently approved chemoprophylactics all present challenges. There are either concerns about unacceptable adverse effects such as neuropsychiatric sequalae (mefloquine), risks of hemolysis in patients with G6PD deficiency (8‐aminoquinolines such as tafenoquine), or cost and daily dosing (atovaquone–proguanil). Therefore, there is a need to develop new chemoprophylactic agents to provide more affordable therapies with better compliance through improving properties such as pharmacokinetics to allow weekly, preferably monthly, dosing. Here we present a pharmacokinetic–pharmacodynamic (PKPD) model constructed using DSM265 (a dihydroorotate dehydrogenase inhibitor with activity against the liver schizonts of malaria, therefore, a prophylaxis candidate). The PKPD model mimics the parasite lifecycle by describing parasite dynamics and drug activity during the liver and blood stages. A major challenge is the estimation of model parameters, as only blood‐stage parasites can be observed once they have reached a threshold. By combining qualitative and quantitative knowledge about the parasite from various sources, it has been shown that it is possible to infer information about liver‐stage growth and its initial infection level. Furthermore, by integrating clinical data, the killing effect of the drug on liver‐ and blood‐stage parasites can be included in the PKPD model, and a clinical outcome can be predicted. Despite multiple challenges, the presented model has the potential to help translation from preclinical to late development for new chemoprophylactic candidates.
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DOI：
10.1016/0035-9203(90)90258-g
发表时间：
1990-03-01
影响因子：
2.2
作者：
ROSENBERG, R;WIRTZ, RA;BURGE, R
通讯作者：
BURGE, R
影响因子：
168.9
作者：
White, Nicholas J.;Pukrittayakamee, Sasithon;Dondorp, Arjen M.
通讯作者：
Dondorp, Arjen M.
影响因子：
7.3
作者：
Foquet, Lander;Schafer, Carola;Kappe, Stefan H. I.
通讯作者：
Kappe, Stefan H. I.
影响因子：
17.1
作者：
Phillips MA;Lotharius J;Marsh K;White J;Dayan A;White KL;Njoroge JW;El Mazouni F;Lao Y;Kokkonda S;Tomchick DR;Deng X;Laird T;Bhatia SN;March S;Ng CL;Fidock DA;Wittlin S;Lafuente-Monasterio M;Benito FJ;Alonso LM;Martinez MS;Jimenez-Diaz MB;Bazaga SF;Angulo-Barturen I;Haselden JN;Louttit J;Cui Y;Sridhar A;Zeeman AM;Kocken C;Sauerwein R;Dechering K;Avery VM;Duffy S;Delves M;Sinden R;Ruecker A;Wickham KS;Rochford R;Gahagen J;Iyer L;Riccio E;Mirsalis J;Bathhurst I;Rueckle T;Ding X;Campo B;Leroy D;Rogers MJ;Rathod PK;Burrows JN;Charman SA
通讯作者：
Charman SA
DOI：
10.1016/s1473-3099(17)30171-8
发表时间：
2017-06
期刊：
The Lancet. Infectious diseases
影响因子：
--
作者：
McCarthy JS;Lotharius J;Rückle T;Chalon S;Phillips MA;Elliott S;Sekuloski S;Griffin P;Ng CL;Fidock DA;Marquart L;Williams NS;Gobeau N;Bebrevska L;Rosario M;Marsh K;Möhrle JJ
通讯作者：
Möhrle JJ