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Pharmacokinetics

NOT Open Access | Discovery of Potent and Fast-Acting Antimalarial Bis-1,2,4-triazines

March 26, 2021 - 16:11 -- NOT Open Access
Author(s): 
Priebbenow DL, Mathiew M, Baell JB, et al.
Reference: 
J Med Chem. 2021 Mar 24

Novel 3,3'-disubstituted-5,5'-bi(1,2,4-triazine) compounds with potent in vitro activity against Plasmodium falciparum parasites were recently discovered. To improve the pharmacokinetic properties of the triazine derivatives, a new structure-activity relationship (SAR) investigation was initiated with a focus on enhancing the metabolic stability of lead compounds.

Absence of gender influence on the pharmacokinetics of chloroquine combined with primaquine in malaria vivax patients

November 7, 2020 - 12:25 -- Open Access
Author(s): 
Vieira MVDF, Mello AGCN, Sena LWP, Vieira JLF
Reference: 
Rev Inst Med Trop Sao Paulo. 2020 Oct 30;62:e83

Chloroquine is the first-line therapy against the asexual stages of Plasmodium vivax . There is a high variation of chloroquine plasma levels after therapeutic doses, which can lead to inadequate exposure to the drug. The gender influence was low regarding the disposition of the drug, which is relevant as there are significant physiological variations between male and female patients.

NOT Open Access | Identification and Pharmacokinetics of Quinone Reductase 2 Inhibitors after Oral Administration of Garcinia mangostana L. Extract in Rat by LC-MS/MS

October 20, 2020 - 16:02 -- NOT Open Access
Author(s): 
Liang X, Hu Y, Li J, Chang AK, Tao X, Li Y, Liu W, Pi K, Yuan J, Jiang Z
Reference: 
J Agric Food Chem. 2020 Oct 15

Garcinia mangostana L. (mangosteen) is a famous tropical fruit that contains a large number of xanthones. Regular consumption of mangosteen may confer health benefits and prevent some diseases, such as malaria. Quinone reductase 2 (QR-2) is a cytosolic enzyme found in human red blood cells, and it is becoming a target for chemoprevention because it is involved in the mechanisms of several diseases, including malaria.

Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial

August 3, 2020 - 15:49 -- Open Access
Author(s): 
Gaur AH, McCarthy JS, Panetta JC, Dallas RH, Woodford J, Tang L, Smith AM, Stewart TB, Branum KC, Freeman BB 3rd, Patel ND, John E, Chalon S, Ost S, Heine RN, Richardson JL, Christensen R, Flynn PM, Van Gessel Y, Mitasev B, Möhrle JJ, Gusovsky F, Bebrevska L, Guy RK
Reference: 
Lancet Infect Dis. 2020 Aug; 20(8):964-975

(+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans.

NOT Open Access | Safety, pharmacokinetics and causal prophylactic efficacy of KAF156 in a Plasmodium falciparum human infection study

July 13, 2020 - 16:22 -- NOT Open Access
Author(s): 
Kublin JG, Murphy SC, Prince WT, et al.
Reference: 
Clin Infect Dis. 2020 Jul 9:ciaa952

KAF156 is a novel antimalarial drug that is active against both liver- and blood- stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model.

Population pharmacokinetics and pharmacodynamics of chloroquine in a Plasmodium vivax volunteer infection study

May 19, 2020 - 15:01 -- Open Access
Author(s): 
Abd-Rahman AN, Marquart L, Gobeau N, Kümmel A, Simpson JA, Chalon S, Möhrle JJ, McCarthy JS
Reference: 
Clin Pharmacol Ther. 2020 May 16

Chloroquine has been used for the treatment of malaria for more than 70 years; however, chloroquine pharmacokinetic (PK) and pharmacodynamic (PD) profile in Plasmodium vivax malaria is poorly understood. The objective of this study was to describe the PKPD relationship of chloroquine and its major metabolite, desethylchloroquine, in a P. vivax volunteer infection study.

Safety, Pharmacokinetics, and Mosquito-Lethal Effects of Ivermectin in Combination With Dihydroartemisinin-Piperaquine and Primaquine in Healthy Adult Thai Subjects

May 7, 2020 - 13:34 -- Open Access
Author(s): 
Kobylinski KC, Jittamala P, Tarning J, et al.
Reference: 
Clin Pharmacol Ther. 2020 May;107(5):1221-1230

Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics, and mosquito‐lethal effects of combinations of ivermectin, dihydroartemisinin‐piperaquine, and primaquine were evaluated. Coadministration of ivermectin and dihydroartemisinin‐piperaquine resulted in increased ivermectin concentrations with corresponding increases in mosquito‐lethal effect across all subjects.

A phase 1, placebo controlled, randomised, single ascending dose study and a volunteer infection study to characterize the safety, pharmacokinetics and antimalarial activity of the Plasmodium phosphatidylinositol 4-kinase inhibitor MMV390048

April 6, 2020 - 15:38 -- Open Access
Author(s): 
McCarthy JS, Donini C, Möhrle JJ, et al.
Reference: 
Clin Infect Dis. 2020 Apr 2. pii: ciaa368

MMV390048 is the first Plasmodium phosphatidylinositol 4-kinase inhibitor to reach clinical development as a new antimalarial. We aimed to characterize the safety, pharmacokinetics and antimalarial activity of a tablet formulation of MMV390048.

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers

March 30, 2020 - 10:47 -- Open Access
Author(s): 
Sinxadi P, Donini C, Johnstone H, Langdon G, Wiesner L, Allen E, Duparc S, Chalon S, McCarthy JS, Lorch U, Chibale K, Möhrle J, Barnes KI
Reference: 
Antimicrob Agents Chemother. 2020 Mar 24;64(4). pii: e01896-19

MMV390048 is a novel antimalarial compound that inhibits Plasmodium phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed. Additionally, a volunteer infection study investigated the antimalarial activity of MMV390048 using the Plasmodium falciparum induced blood-stage malaria (IBSM) model.

Differential Impact of Nevirapine on Artemether-Lumefantrine Pharmacokinetics in Individuals Stratified by CYP2B6 c.516G>T Genotypes

February 24, 2020 - 13:42 -- Open Access
Author(s): 
Abdullahi ST, Soyinka JO, Olagunju A, Bolarinwa RA, Olarewaju OJ, Bakare-Odunola MT, Winterberg M, Tarning J, Owen A, Khoo S
Reference: 
Antimicrob Agents Chemother. 2020 Feb 21;64(3). pii: e00947-19

There is an increased recognition of the need to identify and quantify the impact of genetic polymorphisms on drug-drug interactions. This study investigated the pharmacogenetics of the pharmacokinetic drug-drug interaction between nevirapine and artemether-lumefantrine in HIV-positive and HIV-negative adult Nigerian subjects. Thirty each of HIV-infected patients on nevirapine-based antiretroviral therapy and HIV-negative volunteers without clinical malaria, but with predetermined CYP2B6 c.516GG and TT genotypes, were administered a complete treatment dose of 3 days of artemether-lumefantrine. Rich pharmacokinetic sampling prior to and following the last dose was conducted, and the plasma concentrations of artemether/dihydroartemisinin and lumefantrine/desbutyl-lumefantrine were quantified using tandem mass spectrometry.

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