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Joel Tarning - One of the best experts on this subject based on the ideXlab platform.
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Piperaquine concentration and malaria treatment outcomes in Ugandan children treated for severe malaria with intravenous Artesunate or quinine plus Dihydroartemisinin-Piperaquine.
BMC Infectious Diseases, 2019Co-Authors: Pauline Byakika-kibwika, Daniel Blessborn, Ronald Ssenyonga, Mohammed Lamorde, Joel TarningAbstract:Treatment for severe malaria must be prompt with effective parenteral antimalarial drugs for at least 24 h to achieve fast parasite clearance, and when the patient can tolerate oral therapy, treatment should be completed with effective artemisinin based combination therapy (ACT) for complete parasite clearance and to prevent recrudescence. We evaluated Piperaquine concentration and malaria treatment outcomes among Ugandan children treated for severe malaria with intravenous artesunate (AS) or quinine (QN) plus dihydroartemisinin-Piperaquine (DP), in Tororo District Hospital in Eastern Uganda. Capillary blood Piperaquine concentration data were obtained from a randomized clinical trial whose objective was to evaluate parasite clearance, 42-day parasitological treatment outcomes and safety, following treatment of severe malaria with intravenous AS or QN, plus artemether-lumefantrine or DP among children in Tororo District Hospital, in Eastern Uganda. Piperaquine concentration data from 150 participants who received DP were analyzed. Participants with unadjusted treatment failure had lower median day 7 capillary Piperaquine concentration than those with treatment success (34.7 (IQR) (17.9–49.1) vs 66.7 (IQR) (41.8–81.9), p 57 ng/mL). Considering the low day 7 concentrations of Piperaquine reported in the patients studied here, we suggest to adopt the recently recommended higher dose of DP in young children or a prolonged 5-day dosing in children living in malaria endemic areas who have suffered an initial episode of severe malaria in order to achieve adequate drug exposures for effective post-treatment prophylactic effects. The study was registered with the Pan African Clinical Trial Registry (PACTR201110000321348). Registered 7th October 2011.
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treatment failure of dihydroartemisinin Piperaquine for plasmodium falciparum malaria vietnam
Emerging Infectious Diseases, 2017Co-Authors: Bui Quang Phuc, Joel Tarning, Didier Menard, Pascal Ringwald, Charlotte Rasmussen, Tran Thanh Duong, Le Than Dong, Dorina G Bustos, Gawrie Loku Galappaththy, Nguyen Quang ThieuAbstract:: We conducted a study in Binh Phuoc, Vietnam, in 2015 on the therapeutic efficacy of dihydroartemisinin/Piperaquine for Plasmodium falciparum malaria. A high number of treatment failures (14/40) was found, and Piperaquine resistance in Vietnam was confirmed. A change in the malaria treatment policy for Vietnam is in process.
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Treatment Failure of Dihydroartemisinin/Piperaquine for Plasmodium falciparum Malaria, Vietnam.
Emerging Infectious Diseases, 2017Co-Authors: Bui Quang Phuc, Joel Tarning, Didier Menard, Pascal Ringwald, Charlotte Rasmussen, Tran Thanh Duong, Dorina G Bustos, Le Than Dong, Gawrie Loku GalappaththyAbstract:: We conducted a study in Binh Phuoc, Vietnam, in 2015 on the therapeutic efficacy of dihydroartemisinin/Piperaquine for Plasmodium falciparum malaria. A high number of treatment failures (14/40) was found, and Piperaquine resistance in Vietnam was confirmed. A change in the malaria treatment policy for Vietnam is in process.
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open label crossover study of primaquine and dihydroartemisinin Piperaquine pharmacokinetics in healthy adult thai subjects
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Borimas Hanboonkunupakarn, Warunee Hanpithakpong, Joel Tarning, Podjanee Jittamala, Sasithon Pukrittayakamee, Palang Chotsiri, Thanaporn Wattanakul, Salwaluk Panapipat, Elizabeth A. Ashley, Nicholas J. WhiteAbstract:Dihydroartemisinin-Piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-Piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-Piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-Piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and Piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-Piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0-last), and area under the concentration-time curve from 0 h to infinity (AUC0-∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.).
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randomized comparison of the efficacies and tolerabilities of three artemisinin based combination treatments for children with acute plasmodium falciparum malaria in the democratic republic of the congo
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Joel Tarning, M A Onyamboko, Caterina I Fanello, Klanarong Wongsaen, Phaik Yeong Cheah, K A TshefuAbstract:ABSTRACT An open-label, randomized controlled trial was carried out in 2011–2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-Piperaquine, amodiaquine-artesunate, and artemether-lumefantrine. Six hundred eighty-four children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm. Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms ( P = 0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-Piperaquine ( P = 0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-Piperaquine ( P = 0.78). The last provided a longer posttreatment prophylactic effect than did the other two treatments. The day 7 plasma concentration of Piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-Piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine. Thus, although cure rates were all satisfactory, they could be improved by increasing the dose. (This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no. ISRCTN20984426.)
Niklas Lindegardh - One of the best experts on this subject based on the ideXlab platform.
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efficacy and day 7 plasma Piperaquine concentrations in african children treated for uncomplicated malaria with dihydroartemisinin Piperaquine
PLOS ONE, 2014Co-Authors: Issaka Zongo, Joel Tarning, Niklas Lindegardh, Philip J Rosenthal, Fabrice A Some, Serge A M Somda, Sunil Parikh, Noel RouambaAbstract:Background: 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 characteri
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population pharmacokinetic assessment of the effect of food on Piperaquine bioavailability in patients with uncomplicated malaria
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Khin Maung Lwin, Joel Tarning, Niklas Lindegardh, Elizabeth A. Ashley, Anna Annerberg, Lily KiricharoenAbstract:ABSTRACT Previously published literature reports various impacts of food on the oral bioavailability of Piperaquine. The aim of this study was to use a population modeling approach to investigate the impact of concomitant intake of a small amount of food on Piperaquine pharmacokinetics. This was an open, randomized comparison of Piperaquine pharmacokinetics when administered as a fixed oral formulation once daily for 3 days with ( n = 15) and without ( n = 15) concomitant food to patients with uncomplicated Plasmodium falciparum malaria in Thailand. Nonlinear mixed-effects modeling was used to characterize the pharmacokinetics of Piperaquine and the influence of concomitant food intake. A modified Monte Carlo mapped power approach was applied to evaluate the relationship between statistical power and various degrees of covariate effect sizes of the given study design. Piperaquine population pharmacokinetics were described well in fasting and fed patients by a three-compartment distribution model with flexible absorption. The final model showed a 25% increase in relative bioavailability per dose occasion during recovery from malaria but demonstrated no clinical impact of concomitant intake of a low-fat meal. Body weight and age were both significant covariates in the final model. The novel power approach concluded that the study was adequately powered to detect a food effect of at least 35%. This modified Monte Carlo mapped power approach may be a useful tool for evaluating the power to detect true covariate effects in mixed-effects modeling and a given study design. A small amount of food does not affect Piperaquine absorption significantly in acute malaria.
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pharmacokinetic predictors for recurrent malaria after dihydroartemisinin Piperaquine treatment of uncomplicated malaria in ugandan infants
The Journal of Infectious Diseases, 2013Co-Authors: Abel Kakuru, Darren J Creek, Victor Bigira, Shelley A Mccormack, Emmanuel Arinaitwe, Humphrey Wanzira, Jordan W Tappero, Taylor Sandison, Niklas LindegardhAbstract:Background. Although dihydroartemisinin-Piperaquine (DP) is used primarily in children, pharmacokinetic/ pharmacodynamic (PK/PD) data on DP use in young children are lacking. Methods. We conducted a prospective PK/PD study of Piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. Results. The median capillary Piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low Piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low Piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable Piperaquine concentrations at the time of presentation with recurrent malaria. Conclusions. These Piperaquine PK/PD data represent the first in children <2 years of age. Piperaquine exposure on day 7 correlated with an increased risk of recurrent malaria after DP treatment in children receiving TMPSMX prophylaxis. Interestingly, despite strong associations, infants remained at risk for malaria, even if they had residual levels of Piperaquine.
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Pharmacokinetic Predictors for Recurrent Malaria After Dihydroartemisinin-Piperaquine Treatment of Uncomplicated Malaria in Ugandan Infants
The Journal of Infectious Diseases, 2013Co-Authors: Darren J Creek, Niklas Lindegardh, Abel Kakuru, Victor Bigira, Shelley A Mccormack, Emmanuel Arinaitwe, Humphrey Wanzira, Jordan W Tappero, Taylor Sandison, Francois NostenAbstract:Background. Although dihydroartemisinin-Piperaquine (DP) is used primarily in children, pharmacokinetic/ pharmacodynamic (PK/PD) data on DP use in young children are lacking. Methods. We conducted a prospective PK/PD study of Piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. Results. The median capillary Piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low Piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low Piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable Piperaquine concentrations at the time of presentation with recurrent malaria. Conclusions. These Piperaquine PK/PD data represent the first in children
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a population pharmacokinetic model of Piperaquine in pregnant and non pregnant women with uncomplicated plasmodium falciparum malaria in sudan
Malaria Journal, 2012Co-Authors: Richard M Hoglund, Warunee Hanpithakpong, Niklas Lindegardh, Nicholas J. White, Francois Nosten, Michael Ashton, Ishag AdamAbstract:Background Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of Piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.
Francois Nosten - One of the best experts on this subject based on the ideXlab platform.
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optimal dosing of dihydroartemisinin Piperaquine for seasonal malaria chemoprevention in young children
Nature Communications, 2019Co-Authors: Palang Chotsiri, Warunee Hanpithakpong, Francois Nosten, Issaka Zongo, Paul Milligan, Yves Daniel Compaore, Anyirekun Fabrice Some, Daniel Chandramohan, B M GreenwoodAbstract:Young children are the population most severely affected by Plasmodium falciparum malaria. Seasonal malaria chemoprevention (SMC) with amodiaquine and sulfadoxine-pyrimethamine provides substantial benefit to this vulnerable population, but resistance to the drugs will develop. Here, we evaluate the use of dihydroartemisinin-Piperaquine as an alternative regimen in 179 children (aged 2.33–58.1 months). Allometrically scaled body weight on pharmacokinetic parameters of Piperaquine result in lower drug exposures in small children after a standard mg per kg dosage. A covariate-free sigmoidal EMAX-model describes the interval to malaria re-infections satisfactorily. Population-based simulations suggest that small children would benefit from a higher dosage according to the WHO 2015 guideline. Increasing the dihydroartemisinin-Piperaquine dosage and extending the dose schedule to four monthly doses result in a predicted relative reduction in malaria incidence of up to 58% during the high transmission season. The higher and extended dosing schedule to cover the high transmission period for SMC could improve the preventive efficacy substantially. Seasonal malaria chemoprevention provides substantial benefit for young children, but resistance to used drugs will likely develop. Here, Chotsiri et al. evaluate the use of dihydroartemisinin-Piperaquine as a regimen in 179 children, and population-based simulations suggest that small children would benefit from a higher and extended dosage.
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population pharmacokinetics and antimalarial pharmacodynamics of Piperaquine in patients with plasmodium vivax malaria in thailand
CPT Pharmacometrics Syst. Pharmacol., 2014Co-Authors: Warunee Hanpithakpong, Khin Maung Lwin, Joel Tarning, Aung Pyae Phyo, Praiya Thana, Francois Nosten, Elizabeth A. AshleyAbstract:Dihydroartemisinin-Piperaquine is an effective drug in the treatment of Plasmodium falciparum and P. vivax malaria. The objective of this study was to evaluate the population pharmacokinetics and pharmacodynamics of Piperaquine in patients with P. vivax malaria in Thailand after a standard regimen of dihydroartemisinin-Piperaquine to determine whether residual Piperaquine prevents or delays the emergence of P. vivax relapse. Sparse blood samples were collected from 116 patients. Piperaquine pharmacokinetics were described well by a three-compartment distribution model. Relapsing P. vivax malaria was accommodated by a constant baseline hazard (8.94 relapses/year) with the addition of a surge function in a fixed 3-week interval and a protective Piperaquine effect. The results suggest that a large proportion of the first relapses were suppressed completely by residual Piperaquine concentrations and that recurrences resulted mainly from emergence of the second or third relapse or from reinfection. This suggests a significant reduction in P. vivax morbidity when using dihydroartemisinin-Piperaquine compared with other antimalarial drugs with shorter terminal postprophylactic effects.
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Pharmacokinetic Predictors for Recurrent Malaria After Dihydroartemisinin-Piperaquine Treatment of Uncomplicated Malaria in Ugandan Infants
The Journal of Infectious Diseases, 2013Co-Authors: Darren J Creek, Niklas Lindegardh, Abel Kakuru, Victor Bigira, Shelley A Mccormack, Emmanuel Arinaitwe, Humphrey Wanzira, Jordan W Tappero, Taylor Sandison, Francois NostenAbstract:Background. Although dihydroartemisinin-Piperaquine (DP) is used primarily in children, pharmacokinetic/ pharmacodynamic (PK/PD) data on DP use in young children are lacking. Methods. We conducted a prospective PK/PD study of Piperaquine in 107 young children in Uganda. Samples were collected up to 28 days after 218 episodes of malaria treatment, which occurred during follow-up periods of up to 5 months. Malaria follow-up was conducted actively to day 28 and passively to day 63. Results. The median capillary Piperaquine concentration on day 7 after treatment was 41.9 ng/mL. Low Piperaquine concentrations were associated with an increased risk of recurrent malaria for up to 42 days, primarily in those receiving trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis. In children not receiving TMP-SMX, low Piperaquine concentrations were only modestly associated with an increased risk of recurrent malaria. However, for children receiving TMP-SMX, associations were strong and evident for all sampling days, with PQ concentrations of ≤27.3 ng/mL on day 7 associated with a greatly increased risk of recurrent malaria. Notably, of 132 cases of recurrent malaria, 119 had detectable Piperaquine concentrations at the time of presentation with recurrent malaria. Conclusions. These Piperaquine PK/PD data represent the first in children
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a population pharmacokinetic model of Piperaquine in pregnant and non pregnant women with uncomplicated plasmodium falciparum malaria in sudan
Malaria Journal, 2012Co-Authors: Richard M Hoglund, Warunee Hanpithakpong, Niklas Lindegardh, Nicholas J. White, Francois Nosten, Michael Ashton, Ishag AdamAbstract:Background Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of Piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.
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Pharmacokinetics of Piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria.
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Ishag Adam, Joel Tarning, Rose Mcgready, Niklas Lindegardh, Hyder M. Mahgoub, Francois NostenAbstract:The pharmacokinetic properties of Piperaquine were investigated in 12 pregnant and 12 well-matched, non- pregnant women receiving a three-day oral fixed dose combination regimen of dihydroartemisinin and Piperaquine for treatment of uncomplicated Plasmodium falciparum at New Halfa Hospital in eastern Sudan. Frequent venous plasma samples were drawn from the patients over a 63-day period and a complete concentration-time profile was collected for 7 pregnant and 11 non-pregnant patients. Piperaquine was quantified using a liquid chromatography-mass spectrometry/ mass spectrometry method. Pregnant women had a significantly higher total drug exposure (median area under the curve (range) = 1,770 (1,200-5,600) hr +ng/mL versus 858 (325-2,370) hr +ng/mL; P = 0.018) and longer time to maximal concentration (4.00 (1.50-4.03) hr versus 1.50 (0.500-8.00) hr; P = 0.02) after the first dose compared with non-pregnant women. There was no other significant difference observed in Piperaquine pharmacokinetics between pregnant and non- pregnant women, including no difference in total drug exposure or maximum concentration. The overall pharmacokinetic properties of Piperaquine in this study were consistent with previously published reports in non-pregnant patients.
Nicholas J. White - One of the best experts on this subject based on the ideXlab platform.
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sequential open label study of the safety tolerability and pharmacokinetic interactions between dihydroartemisinin Piperaquine and mefloquine in healthy thai adults
Antimicrobial Agents and Chemotherapy, 2019Co-Authors: Borimas Hanboonkunupakarn, Markus Winterberg, Sasithon Pukrittayakamee, Richard M Hoglund, Rob W Van Der Pluijm, Kesinee Chotivanich, Mavuto Mukaka, Naomi Waithira, Pratap Singhasivanon, Nicholas J. WhiteAbstract:Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon. Combining three existing antimalarials in the form of triple ACTs, including dihydroartemisinin (DHA)-Piperaquine + mefloquine, is a potential treatment option for multidrug-resistant Plasmodium falciparum malaria. In a sequential open-label study, healthy Thai volunteers were treated with DHA-Piperaquine (120 to 960 mg), mefloquine (500 mg), and DHA-Piperaquine + mefloquine (120 to 960 mg + 500 mg), and serial symptom questionnaires, biochemistry, full blood counts, pharmacokinetic profiles, and electrocardiographic measurements were performed. Fifteen healthy subjects were enrolled. There was no difference in the incidence or severity of adverse events between the three treatment arms. The slight prolongation in QTc (QT interval corrected for heart rate) associated with DHA-Piperaquine administration did not increase after administration of DHA-Piperaquine + mefloquine. The addition of mefloquine had no significant effect on the pharmacokinetic properties of Piperaquine. However, coadministration of mefloquine significantly reduced the exposures to dihydroartemisinin for area under the concentration-time curve (-22.6%; 90% confidence interval [CI], -33.1, -10.4; P = 0.0039) and maximum concentration of drug in serum (-29.0%; 90% CI, -40.6, -15.1; P = 0.0079). Mefloquine can be added safely to dihydroartemisinin-Piperaquine in malaria treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT02324738.).
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overexpression of plasmepsin ii and plasmepsin iii does not directly cause reduction in plasmodium falciparum sensitivity to artesunate chloroquine and Piperaquine
International Journal for Parasitology-Drugs and Drug Resistance, 2019Co-Authors: Duangkamon Loesbanluechai, Nicholas J. White, Prapon Wilairat, Namfon Kotanan, Cristina De Cozar, Theerarat Kochakarn, Megan R Ansbro, Kesinee Chotivanich, Francisco Javier Gamo, Laura M SanzAbstract:Artemisinin derivatives and their partner drugs in artemisinin combination therapies (ACTs) have played a pivotal role in global malaria mortality reduction during the last two decades. The loss of artemisinin efficacy due to evolving drug-resistant parasites could become a serious global health threat. Dihydroartemisinin-Piperaquine is a well tolerated and generally highly effective ACT. The implementation of a partner drug in ACTs is critical in the control of emerging artemisinin resistance. Even though artemisinin is highly effective in parasite clearance, it is labile in the human body. A partner drug is necessary for killing the remaining parasites when the pulses of artemisinin have ceased. A population of Plasmodium falciparum parasites in Cambodia and adjacent countries has become resistant to Piperaquine. Increased copy number of the genes encoding the haemoglobinases Plasmepsin II and Plasmepsin III has been linked with Piperaquine resistance by genome-wide association studies and in clinical trials, leading to the use of increased plasmepsin II/plasmepsin III copy number as a molecular marker for Piperaquine resistance. Here we demonstrate that overexpression of plasmepsin II and plasmepsin III in the 3D7 genetic background failed to change the susceptibility of P. falciparum to artemisinin, chloroquine and Piperaquine by both a standard dose-response analysis and a Piperaquine survival assay. Whilst plasmepsin copy number polymorphism is currently implemented as a molecular surveillance resistance marker, further studies to discover the molecular basis of Piperaquine resistance and potential epistatic interactions are needed.
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risk of sudden unexplained death after use of dihydroartemisinin Piperaquine for malaria a systematic review and bayesian meta analysis
Lancet Infectious Diseases, 2018Co-Authors: Xin Hui S Chan, Laura J Mawer, Nicholas J. White, Josep BrugadaAbstract:Summary Background Dihydroartemisinin–Piperaquine is an effective and well tolerated artemisinin-based combination therapy that has been assessed extensively for the prevention and treatment of malaria. Piperaquine, similar to several structurally related antimalarials currently used, can prolong cardiac ventricular repolarisation duration and the electrocardiographic QT interval, leading to concerns about its proarrhythmic potential. We aimed to assess the risk of potentially lethal iatrogenic ventricular arrhythmias in individuals receiving dihydroartemisinin–Piperaquine. Methods We did a systematic review and Bayesian meta-analysis. We searched clinical bibliographic databases (last on May 24, 2017) for studies of dihydroartemisinin–Piperaquine in human beings. Further unpublished studies were identified with the WHO Evidence Review Group on the Cardiotoxicity of Antimalarials. We searched for articles containing "dihydroartemisinin-Piperaquine" as title, abstract, or subject heading keywords, with synonyms and variant spellings as additional search terms. We excluded animal studies, but did not apply limits on language or publication date. Eligible studies were prospective, randomised, controlled trials or cohort studies in which individuals received at least one 3-day treatment course of dihydroartemisinin–Piperaquine for mass drug administration, preventive therapy, or case management of uncomplicated malaria, with follow-up over at least 3 days. At least two independent reviewers screened titles, abstracts, and full texts, agreed study eligibility, and extracted information about study and participant characteristics, adverse event surveillance methodology, dihydroartemisinin–Piperaquine exposures, loss-to-follow up, and any deaths after dihydroartemisinin–Piperaquine treatment into a standardised database. The risk of sudden unexplained death after dihydroartemisinin–Piperaquine with 95% credible intervals (CI) generated by Bayesian meta-analysis was compared with the baseline rate of sudden cardiac death. Findings Our search identified 94 eligible primary studies including data for 197 867 individuals who had received dihydroartemisinin–Piperaquine: 154 505 in mass drug administration programmes; 15 188 in 14 studies of repeated courses in preventive therapies and case management of uncomplicated malaria; and 28 174 as single-course treatments of uncomplicated malaria in 76 case-management studies. There was one potentially drug-related sudden unexplained death: a healthy woman aged 16 in Mozambique who developed heart palpitations several hours after the second dose of dihydroartemisinin–Piperaquine and collapsed and died on the way to hospital (no autopsy or ECG was done). The median pooled risk estimate of sudden unexplained death after dihydroartemisinin–Piperaquine was 1 in 757 950 (95% CI 1 in 2 854 490 to 1 in 209 114). This risk estimate was not higher than the baseline rate of sudden cardiac death (0·7–11·9 per 100 000 person-years or 1 in 1 714 280 to 1 in 100 835 over a 30-day risk period). The risk of bias was low in most studies and unclear in a few. Interpretation Dihydroartemisinin–Piperaquine was associated with a low risk of sudden unexplained death that was not higher than the baseline rate of sudden cardiac death. Concerns about repolarisation-related cardiotoxicity need not limit its current use for the prevention and treatment of malaria. Funding Wellcome Trust, UK Medical Research Council, WHO, Bill & Melinda Gates Foundation, and University of Oxford.
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open label crossover study of primaquine and dihydroartemisinin Piperaquine pharmacokinetics in healthy adult thai subjects
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Borimas Hanboonkunupakarn, Warunee Hanpithakpong, Joel Tarning, Podjanee Jittamala, Sasithon Pukrittayakamee, Palang Chotsiri, Thanaporn Wattanakul, Salwaluk Panapipat, Elizabeth A. Ashley, Nicholas J. WhiteAbstract:Dihydroartemisinin-Piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicated Plasmodium falciparum malaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduce P. falciparum transmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-Piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-Piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-Piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and Piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-Piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0-last), and area under the concentration-time curve from 0 h to infinity (AUC0-∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.).
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a population pharmacokinetic model of Piperaquine in pregnant and non pregnant women with uncomplicated plasmodium falciparum malaria in sudan
Malaria Journal, 2012Co-Authors: Richard M Hoglund, Warunee Hanpithakpong, Niklas Lindegardh, Nicholas J. White, Francois Nosten, Michael Ashton, Ishag AdamAbstract:Background Pregnancy is associated with an increased risk of developing a malaria infection and a higher risk of developing severe malaria. The pharmacokinetic properties of many anti-malarials are also altered during pregnancy, often resulting in a decreased drug exposure. Piperaquine is a promising anti-malarial partner drug used in a fixed-dose combination with dihydroartemisinin. The aim of this study was to investigate the population pharmacokinetics of Piperaquine in pregnant and non-pregnant Sudanese women with uncomplicated Plasmodium falciparum malaria.
Rose Mcgready - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of Piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria.
American Journal of Tropical Medicine and Hygiene, 2012Co-Authors: Ishag Adam, Joel Tarning, Rose Mcgready, Niklas Lindegardh, Hyder M. Mahgoub, Francois NostenAbstract:The pharmacokinetic properties of Piperaquine were investigated in 12 pregnant and 12 well-matched, non- pregnant women receiving a three-day oral fixed dose combination regimen of dihydroartemisinin and Piperaquine for treatment of uncomplicated Plasmodium falciparum at New Halfa Hospital in eastern Sudan. Frequent venous plasma samples were drawn from the patients over a 63-day period and a complete concentration-time profile was collected for 7 pregnant and 11 non-pregnant patients. Piperaquine was quantified using a liquid chromatography-mass spectrometry/ mass spectrometry method. Pregnant women had a significantly higher total drug exposure (median area under the curve (range) = 1,770 (1,200-5,600) hr +ng/mL versus 858 (325-2,370) hr +ng/mL; P = 0.018) and longer time to maximal concentration (4.00 (1.50-4.03) hr versus 1.50 (0.500-8.00) hr; P = 0.02) after the first dose compared with non-pregnant women. There was no other significant difference observed in Piperaquine pharmacokinetics between pregnant and non- pregnant women, including no difference in total drug exposure or maximum concentration. The overall pharmacokinetic properties of Piperaquine in this study were consistent with previously published reports in non-pregnant patients.
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population pharmacokinetics of dihydroartemisinin and Piperaquine in pregnant and nonpregnant women with uncomplicated malaria
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Warunee Hanpithakpong, Joel Tarning, Rose Mcgready, Marcus J Rijken, Aung Pyae Phyo, Nicholas J. White, Francois NostenAbstract:Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of Piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to Piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to Piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of Piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.
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pharmacokinetics of dihydroartemisinin and Piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria
Antimicrobial Agents and Chemotherapy, 2011Co-Authors: Marcus J Rijken, Aung Phae Phyo, Joel Tarning, Rose Mcgready, Niklas Lindegardh, Natthapon Laochan, Hla Hla ThanAbstract:Dihydroartemisinin-Piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg Piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and Piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total Piperaquine exposure (P = 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P = 0.64) between the two groups. The apparent volume of distribution of Piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P = 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P = 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P = 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or Piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.
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comparison of plasma venous and capillary blood levels of Piperaquine in patients with uncomplicated falciparum malaria
European Journal of Clinical Pharmacology, 2010Co-Authors: Elizabeth A. Ashley, Joel Tarning, Rose Mcgready, Niklas Lindegardh, Kasia Stepniewska, Anna AnnerbergAbstract:Purpose Dihydroartemisinin-Piperaquine (DP) is a fixed-dose artemisinin-based combination treatment. Field pharmacokinetic studies would be simplified and facilitated by being able to use small volume capillary assays rather than venous blood. The aim of this study was to describe the relationship between Piperaquine concentrations measured in capillary blood, venous blood and venous plasma.
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population pharmacokinetics of Piperaquine after two different treatment regimens with dihydroartemisinin Piperaquine in patients with plasmodium falciparum malaria in thailand
Antimicrobial Agents and Chemotherapy, 2008Co-Authors: Joel Tarning, Rose Mcgready, Niklas Lindegardh, Kasia Stepniewska, Elizabeth A. Ashley, Lucy PhaiphunAbstract:The population pharmacokinetics of Piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-Piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to Piperaquine (area under the concentration-time curve from 0 to 63 days [AUCday 0-63]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUCday 3-20) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted Piperaquine doses in children may need to be higher than in adults.