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Pharmacokinetics

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.

The gender-related variability in the pharmacokinetics and antiplasmodial activity of naphthoquine in rodents

February 17, 2020 - 14:31 -- Open Access
Author(s): 
Yuewu Xie, Huixiang Liu, Yanhong Sun and Jie Xing
Reference: 
Malaria Journal 2020 19:71, 13 February 2020

Naphthoquine (NQ) is a suitable partner anti-malarial for the artemisinin-based combination therapy (ACT), which is recommended to be taken orally as a single-dose regimen. The metabolism of NQ was mainly mediated by CYP2D6, which is well-known to show gender-specific differences in its expression. In spite of its clinical use, there is limited information on the pharmacokinetics of NQ, and no data are available for females. In this study, the effect of gender on the pharmacokinetics and antiplasmodial efficacy of NQ in rodents was evaluated. The underlying factors leading to the potential gender difference, i.e., plasma protein binding and metabolic clearance, were also evaluated.

NOT Open Access | Pharmacokinetics and Ex vivo Antimalarial Activity of Artesunate-Amodiaquine plus Methylene Blue in Healthy Volunteers

January 27, 2020 - 13:47 -- NOT Open Access
Author(s): 
Anh CX, Chavchich M, Birrell GW, Van Breda K, Travers T, Rowcliffe K, Lord AR, Shanks GD, Edstein MD
Reference: 
Antimicrob Agents Chemother. 2020 Jan 6. pii: AAC.01441-19

High artesunate combination therapy (ACT) treatment failures of Plasmodium falciparum malaria in Southeast Asia has led to triple drug strategies to extend the useful life of ACTs. In this study, we determined whether methylene blue (MB) alters the pharmacokinetics of artesunate-amodiaquine (ASAQ) and enhances the ex vivo antimalarial activity of ASAQ. In an open labelled, randomized cross-over design, a single oral dose of either ASAQ (200 mg AS/540 mg AQ) alone or with MB (325 mg MB) was administered to 15 healthy Vietnamese volunteers. Serial blood samples were collected up to 28 days after dosing.


NOT Open Access | First-in-human clinical trial to assess safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection

January 14, 2020 - 09:44 -- NOT Open Access
Author(s): 
Chughlay MF, Rossignol E, Donini C, El Gaaloul M, Lorch U, Coates S, Langdon G, Hammond T, Möhrle J, Chalon S
Reference: 
Br J Clin Pharmacol. 2020 Jan 11

This first‐in‐human clinical trial of P218, a novel dihydrofolate reductase inhibitor antimalarial candidate, assessed safety, tolerability, pharmacokinetics and food effect in healthy subjects.

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