Dataset Information

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

ABSTRACT: AIMS:The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. METHODS:Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55?years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100-800?mg and 160-1440?mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. RESULTS:A significant relation between plasma concentrations and placebo-corrected change from baseline QTc F (??QTc F) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047?ms per ng ml(-1) (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTc F effect of 14?ms (90% CI 10, 18?ms) and 18?ms (90% CI 14, 22?ms) was predicted at expected plasma concentrations of a single dose 800?mg OZ439 combined with PQP 960?mg (188?ng?ml(-1) ) and 1440?mg (281?ng?ml(-1) ), respectively, administered in the fasted state. CONCLUSIONS:Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800?mg OZ439 with 960?mg or 1440?mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3?day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.

SUBMITTER: Darpo B

PROVIDER: S-EPMC4594707 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

Darpo Borje B Ferber Georg G Siegl Peter P Laurijssens Bart B Macintyre Fiona F Toovey Stephen S Duparc Stephan S

British journal of clinical pharmacology 20150714 4

<h4>Aims</h4>The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment.<h4>Methods</h4>Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ...[more]

PMID: 25966781

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Project description:BackgroundDihydroartemisinin-piperaquine has been Indonesia's first-line anti-malarial treatment since 2008. Annual therapeutic efficacy studies (TES) done in the last 12 years showed continued high treatment efficacy in uncomplicated Plasmodium falciparum malaria. Although these studies did not show evidence for artemisinin resistance, a slight increase in Late Treatment Failure was observed over time. It is highlight to explore the evolution of genetic markers for ACT partner drug resistance since adopting DHA-PPQ.MethodsDry blood spots were identified from a mass blood survey of uncomplicated falciparum malaria patients (N = 50) in Sumba from 2010 to 2018. Analysis of genotypic profile (N = 51) and a Therapeutic Efficacy Study (TES) from Papua (N = 142) from 2020 to 2021, 42-day follow-up. PCR correction using msp1, msp2, and glurp was used to distinguish recrudescence and reinfection. Parasite DNA from DBSs was used for genotyping molecular markers for antimalaria drug resistance, including in Pfk13, pfcrt, and pfmdr1, as well as gene copy number variation in pfpm2/3 and pfmdr1.ResultsThe study revealed the absence of SNPs associated with ART resistance and several novel SNPs such as L396F, I526V, M579I and N537S (4.25%). In Sumba, the mutant haplotype SDD of pfmdr1 was found in one-third of the isolates, while only 8.9% in Papua. None of the pfcrt mutations linked to piperaquine resistance were observed, but 71% of isolates had pfcrt I356L. Amplification of the pfpm2/3 genes was in Sumba (17.02%) and Papua (13.7%), while pfmdr1 copy number prevalence was low (3.8%) in both areas. For the TES study, ten recurrences of infection were observed on days 28, 35, and 42. Late parasitological failure (LPF) was observed in 10/117 (8.5%) subjects by microscopy. PCR correction revealed that all nine cases were re-infections and one was confirmed as recrudescence.ConclusionThis study revealed that DHA-PPQ is still highly effective against P. falciparum. The genetic architecture of the parasite P. falciparum isolates during 2010-2021 revealed single copy of Pfpm2 and pfmdr1 were highly prevalent. The slight increase in DHA-PPQ LTF alerts researchers to start testing other ACTs as alternatives to DHA-PPQ for baseline data in order to get a chance of achieving malaria elimination wants by 2030.

Project description:BackgroundAnti-malarial drugs play a critical role in reducing malaria morbidity and mortality, but their role is mediated by their effectiveness. Effectiveness is defined as the probability that an anti-malarial drug will successfully treat an individual infected with malaria parasites under routine health care delivery system. Anti-malarial drug effectiveness (AmE) is influenced by drug resistance, drug quality, health system quality, and patient adherence to drug use; its influence on malaria burden varies through space and time.MethodsThis study uses data from 232 efficacy trials comprised of 86,776 infected individuals to estimate the artemisinin-based and non-artemisinin-based AmE for treating falciparum malaria between 1991 and 2019. Bayesian spatiotemporal models were fitted and used to predict effectiveness at the pixel-level (5 km × 5 km). The median and interquartile ranges (IQR) of AmE are presented for all malaria-endemic countries.ResultsThe global effectiveness of artemisinin-based drugs was 67.4% (IQR: 33.3-75.8), 70.1% (43.6-76.0) and 71.8% (46.9-76.4) for the 1991-2000, 2006-2010, and 2016-2019 periods, respectively. Countries in central Africa, a few in South America, and in the Asian region faced the challenge of lower effectiveness of artemisinin-based anti-malarials. However, improvements were seen after 2016, leaving only a few hotspots in Southeast Asia where resistance to artemisinin and partner drugs is currently problematic and in the central Africa where socio-demographic challenges limit effectiveness. The use of artemisinin-based combination therapy (ACT) with a competent partner drug and having multiple ACT as first-line treatment choice sustained high levels of effectiveness. High levels of access to healthcare, human resource capacity, education, and proximity to cities were associated with increased effectiveness. Effectiveness of non-artemisinin-based drugs was much lower than that of artemisinin-based with no improvement over time: 52.3% (17.9-74.9) for 1991-2000 and 55.5% (27.1-73.4) for 2011-2015. Overall, AmE for artemisinin-based and non-artemisinin-based drugs were, respectively, 29.6 and 36% below clinical efficacy as measured in anti-malarial drug trials.ConclusionsThis study provides evidence that health system performance, drug quality and patient adherence influence the effectiveness of anti-malarials used in treating uncomplicated falciparum malaria. These results provide guidance to countries' treatment practises and are critical inputs for malaria prevalence and incidence models used to estimate national level malaria burden.

Project description:One promising new Artemisinin-based combination therapies (ACTs) is dihydroartemisinin-piperaquine (DHA-PQ). However, the pharmacokinetics of piperaquine and the relationship between drug levels and clinical efficacy are incompletely characterized, particularly in children.We performed a single-arm open-label trial in Bobo-Dioulasso, Burkina Faso. A total of 379 participants aged 6 months or more with uncomplicated falciparum malaria were enrolled. Each participant received daily dose of DHA-PQ for three days and followed for 42 days. Parasitological efficacy was analyzed, considering rates of recrudescence and overall recurrence. PK was an exploratory endpoint and a priori, no sample size had been determined. Day 7 capillary and venous plasma concentrations of piperaquine were measured in children aged 2-10 years.Of the 379 participants, 365 (96.3%) completed 42 days of follow-up. The median daily dose of PQ was 18.5 mg/kg [6.5-24]. Treatment with DHA-PQ was well tolerated with fever and parasitemia resolution within 48 hours in nearly all children. Recurrent malaria within 42 days of follow-up occurred in 31.3% (10/34) of children less than 2 years old, 16.0% (16/106) of those aged 2-5 years, 9.4% (15/160) of those aged 5-10 years, and none (0/68) of those over 10 years old. After genotyping, 3 of 41 recurrent episodes were recrudescence. An exploratory analysis shows that children with successful treatment outcomes had significantly higher median plasma concentrations of PQ compared to those with recurrent malaria within 42 days after therapy, considering either capillary samples (68 ng/ml [50-85] compared to 48 ng/ml [36-55], p<0.001) or venous samples (42 ng/ml [29-59] compared to 25 ng/ml [19-44], p<0.001).DHA-PQ was effective for uncomplicated P. falciparum malaria treatment and offers an alternative to other ACTs. Recurrent malaria was mainly due to new infections after treatment and was correlated with low day 7 PQ concentration in the youngest patients.Controlled-Trials.com ISRCTN59761234.

Dataset Information

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

Publications

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

Similar Datasets

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