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Semi-mechanistic pharmacokinetic and pharmacodynamic modelling of piperaquine in a volunteer infection study with Plasmodium falciparum blood-stage malaria

January 21, 2021 - 15:29 -- Open Access
Wattanakul T, Baker M, Mohrle J, McWhinney B, Hoglund RM, McCarthy JS, Tarning J
Antimicrob Agents Chemother. 2021 Jan 19:AAC.01583-20

Dihydroartemisinin-piperaquine is a recommended first-line artemisinin combination therapy for falciparum malaria. Piperaquine is also under consideration for other antimalarial combination therapies. The aim of this study was to develop a pharmacokinetic-pharmacodynamic model that could be used to optimize the use of piperaquine in new antimalarial combination therapies. The pharmacokinetic-pharmacodynamic model was developed using data from a previously reported dose-ranging study where 24 healthy volunteers were inoculated 1,800 blood-stage Plasmodium falciparum parasites.

Piperaquine pharmacokinetics during intermittent preventive treatment for malaria in pregnancy

December 29, 2020 - 15:37 -- Open Access
Chotsiri P, Gutman J, Tarning J, et al.
Antimicrob Agents Chemother. 2020 Dec 23:AAC.01150-20

Dihydroartemisinin-piperaquine (DP) is a long-acting artemisinin combination treatment that provides effective chemoprevention and has been proposed as an alternative antimalarial drug for intermittent-preventive therapy in pregnancy (IPTp). Several pharmacokinetic studies have shown that dose adjustment may not be needed for the treatment of malaria in pregnancy with DP. However, there are limited data on the optimal dosing for IPTp.

Mass Drug Administration With High-Dose Ivermectin and Dihydroartemisinin-Piperaquine for Malaria Elimination in an Area of Low Transmission With High Coverage of Malaria Control Interventions: Protocol for the MASSIV Cluster Randomized Clinical Trial

November 25, 2020 - 12:10 -- Open Access
Dabira ED, Soumare HM, D'Alessandro U, et al.
JMIR Res Protoc. 2020 Nov 19;9(11):e20904

With a decline in malaria burden, innovative interventions and tools are required to reduce malaria transmission further. Mass drug administration (MDA) of artemisinin-based combination therapy (ACT) has been identified as a potential tool to further reduce malaria transmission, where coverage of vector control interventions is already high. However, the impact is limited in time. Combining an ACT with an endectocide treatment that is able to reduce vector survival, such as ivermectin (IVM), could increase the impact of MDA and offer a new tool to reduce malaria transmission.

Defining the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood stage Plasmodium falciparum

November 18, 2020 - 12:18 -- Open Access
McCarthy JS, Abd-Rahman AN, Collins KA, Marquart L, Griffin P, Kümmel A, Fuchs A, Winnips C, Mishra V, Csermak-Renner K, Jain JP, Gandhi P
Antimicrob Agents Chemother. 2020 Nov 16:AAC.01423-20

The spiroindolone cipargamin, a new antimalarial compound that inhibits Plasmodium ATP4, is currently in clinical development. This study aimed to characterize the antimalarial activity of cipargamin in healthy volunteers experimentally infected with blood-stage Plasmodium falciparum Eight subjects were intravenously inoculated with parasite-infected erythrocytes and received a single oral dose of 10 mg cipargamin 7 days later. Blood samples were collected to monitor the development and clearance of parasitemia, and plasma cipargamin concentrations.

NOT Open Access | Piperaquine exposure is altered by pregnancy, HIV and nutritional status in Ugandan women

October 7, 2020 - 15:38 -- NOT Open Access
Hughes E, Imperial M, Savic RM, et al.
Antimicrob Agents Chemother. 2020 Oct 5:AAC.01013-20

Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations >10.3 ng/mL have been associated with reduced maternal parasitemia, placental malaria and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post-hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8 weeks.

Antimalarial drugs inhibit the replication of SARS-CoV-2: an in vitro evaluation

September 15, 2020 - 14:26 -- Open Access
Gendrot M, Andreani J, Pradines B, et al.
Travel Med Infect Dis. 2020 Sep 8:101873

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs.

No evidence of amplified Plasmodium falciparum plasmepsin II gene copy number in an area with artemisinin-resistant malaria along the China–Myanmar border

September 15, 2020 - 10:38 -- Open Access
Fang Huang, Biraj Shrestha, Hui Liu, Lin-Hua Tang, Shui-Sen Zhou, Xiao-Nong Zhou, Shannon Takala-Harrison, Pascal Ringwald, Myaing M. Nyunt and Christopher V. Plowe
Malaria Journal 2020 19:334, 14 September 2020

The emergence and spread of artemisinin resistance in Plasmodium falciparum poses a threat to malaria eradication, including China’s plan to eliminate malaria by 2020. Piperaquine (PPQ) resistance has emerged in Cambodia, compromising an important partner drug that is widely used in China in the form of dihydroartemisinin (DHA)-PPQ. Several mutations in a P. falciparum gene encoding a kelch protein on chromosome 13 (k13) are associated with artemisinin resistance and have arisen spread in the Great Mekong subregion, including the China–Myanmar border. Multiple copies of the plasmepsin II/III (pm2/3) genes, located on chromosome 14, have been shown to be associated with PPQ resistance.

Plasmodium falciparum genetic factors rather than host factors are likely to drive resistance to ACT in Ghana

July 20, 2020 - 14:50 -- Open Access
Peter Hodoameda, Nancy Odurowah Duah-Quashie, Charles Oheneba Hagan, Sena Matrevi, Benjamin Abuaku, Kwadwo Koram and Neils Ben Quashie
Malaria Journal 2020 19:255, 15 July 2020

Artemisinin-based combination therapy (ACT) partner drugs, currently used in Ghana are lumefantrine, amodiaquine and piperaquine. Plasmodium falciparum isolates with reduced susceptibility to these partner drugs may affect treatment outcome. Mutations in pfmdr1 gene is linked to reduced parasite susceptibility to amodiaquine and lumefantrine. In addition, the potency of the partner drugs in vivo depends on the metabolism by the cytochrome P450 (CYP) enzyme in the host. Mutations in the CYP2C8 and CYP3A4 genes are linked to reduced metabolism of amodiaquine and lumefantrine in vitro, respectively. This study investigated the host and parasite genetic factors affecting the susceptibility of the malaria parasite to ACT partner drugs.

Prevalence of mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, and association with ex vivo susceptibility to common anti-malarial drugs against African Plasmodium falciparum isolates

June 8, 2020 - 15:27 -- Open Access
Francis Tsombeng Foguim, Hervé Bogreau, Mathieu Gendrot, Joel Mosnier, Isabelle Fonta, Nicolas Benoit, Rémy Amalvict, Marylin Madamet, Sharon Wein and Bruno Pradines
Malaria Journal 2020 19:201, 5 June 2020

The Plasmodium falciparum chloroquine transporter gene (pfcrt) is known to be involved in chloroquine and amodiaquine resistance, and more particularly the mutations on the loci 72 to 76 localized within the second exon. Additionally, new mutations (T93S, H97Y, C101F, F145I, M343L, C350R and G353V) were recently shown to be associated with in vitro reduced susceptibility to piperaquine in Asian or South American P. falciparum strains. However, very few data are available on the prevalence of these mutations and their effect on parasite susceptibility to anti-malarial drugs, and more particularly piperaquine in Africa.

Cardiovascular safety and population pharmacokinetic properties of piperaquine in African patients with uncomplicated falciparum malaria - a pooled multicentre analysis

April 23, 2020 - 09:50 -- Open Access
Wattanakul T, Ogutu B, Tarning J, et al.
Antimicrob Agents Chemother. 2020 Apr 20. pii: AAC.01848-19

Dihydroartemisinin-piperaquine has shown excellent efficacy and tolerability in malaria treatment. However, concerns have been raised of potentially harmful cardiotoxic effects associated with piperaquine. The population pharmacokinetics and cardiac effects of piperaquine were evaluated in 1,000 patients, mostly children enrolled in a multicentre trial from 10 sites in Africa.


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