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Joel Tarning - One of the best experts on this subject based on the ideXlab platform.
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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, Elizabeth A Ashley, Podjanee Jittamala, Sasithon Pukrittayakamee, Palang Chotsiri, Thanaporn Wattanakul, Salwaluk Panapipat, 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.)
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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, Elizabeth A Ashley, Aung Pyae Phyo, Francois Nosten, Praiya ThanaAbstract: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 properties of artemether Dihydroartemisinin lumefantrine and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in uganda
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Joel Tarning, Nicholas J White, Francois Nosten, Frank Kloprogge, Mehul Dhorda, Vincent JullienAbstract:Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite Dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, Dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/Dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.
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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, Nicholas J White, Aung Pyae Phyo, 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.
Nicholas J White - One of the best experts on this subject based on the ideXlab platform.
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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, Josep Brugada, Nicholas J WhiteAbstract: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, Elizabeth A Ashley, Podjanee Jittamala, Sasithon Pukrittayakamee, Palang Chotsiri, Thanaporn Wattanakul, Salwaluk Panapipat, 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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pharmacokinetic properties of artemether Dihydroartemisinin lumefantrine and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in uganda
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Joel Tarning, Nicholas J White, Francois Nosten, Frank Kloprogge, Mehul Dhorda, Vincent JullienAbstract:Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite Dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, Dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/Dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.
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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, Nicholas J White, Aung Pyae Phyo, 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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Assessment of the neurotoxicity of oral Dihydroartemisinin in mice
Transactions of The Royal Society of Tropical Medicine and Hygiene, 2004Co-Authors: Apichart Nontprasert, Sasithon Pukrittayakamee, Sompol Prakongpan, Wichai Supanaranond, Sornchai Looareesuwan, Nicholas J WhiteAbstract:High doses of the oil-soluble antimalarial artemisinin derivatives artemether and arteether, given by intramuscular injection to experimental mammals, produce an unusual pattern of selective damage to brainstem centres predominantly involved in auditory processing and vestibular reflexes. We have shown recently, in adult Swiss albino mice, that constant exposure either from depot intramuscular injection of oil-based artemisinin derivatives, or constant oral intake carries relatively greater neurotoxic potential than other methods of drug administration. Using the same model, oral Dihydroartemisinin suspended in water was administered once or twice daily at different doses ranging from 50 to 300 mg/kg/day for 28 days. The neurotoxic potential of the oral Dihydroartemisinin was assessed and compared to that of oral artemether and artesunate. Oral artemether, artesunate, and Dihydroartemisinin had similar neurotoxic effects with no significant clinical or neuropathological evidence of toxicity at doses below 200 mg/kg/day. These data indicate that once and twice daily oral administration of artemether, artesunate and Dihydroartemisinin is relatively safe when compared to intramuscular administration of the oil-based compounds.
Francois Nosten - One of the best experts on this subject based on the ideXlab platform.
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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, Elizabeth A Ashley, Aung Pyae Phyo, Francois Nosten, Praiya ThanaAbstract: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 properties of artemether Dihydroartemisinin lumefantrine and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in uganda
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Joel Tarning, Nicholas J White, Francois Nosten, Frank Kloprogge, Mehul Dhorda, Vincent JullienAbstract:Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite Dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, Dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/Dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.
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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, Nicholas J White, Aung Pyae Phyo, 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.
Gillian M. Keating - One of the best experts on this subject based on the ideXlab platform.
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Dihydroartemisinin/Piperaquine: a review of its use in the treatment of uncomplicated Plasmodium falciparum malaria.
Drugs, 2012Co-Authors: Gillian M. KeatingAbstract:: Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative Dihydroartemisinin and the bisquinolone piperaquine. Eurartesim® is the only Dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of Dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of Dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria. A number of trials have shown Dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria. Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim® formulation of Dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, Dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving Dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens. The Eurartesim® formulation of Dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving Dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias. In conclusion, Dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria.
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Dihydroartemisinin piperaquine a review of its use in the treatment of uncomplicated plasmodium falciparum malaria
Drugs, 2012Co-Authors: Gillian M. KeatingAbstract:: Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative Dihydroartemisinin and the bisquinolone piperaquine. Eurartesim® is the only Dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of Dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of Dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria. A number of trials have shown Dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria. Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim® formulation of Dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, Dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving Dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens. The Eurartesim® formulation of Dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving Dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias. In conclusion, Dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria.
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Dihydroartemisinin/Piperaquine
Drugs, 2012Co-Authors: Gillian M. KeatingAbstract:Artemisinin-based combination regimens are recommended by WHO for the treatment of uncomplicated Plasmodium falciparum malaria. One such combination comprises the artemisinin derivative Dihydroartemisinin and the bisquinolone piperaquine. Eurartesim® is the only Dihydroartemisinin/piperaquine formulation that meets international good manufacturing practice standards. This article reviews the pharmacological properties of Dihydroartemisinin and piperaquine, and the therapeutic efficacy and tolerability of Dihydroartemisinin/piperaquine in the treatment of uncomplicated P. falciparum malaria. A number of trials have shown Dihydroartemisinin/piperaquine to be highly effective in the treatment of uncomplicated P. falciparum malaria . Two pivotal, randomized, open-label, multicentre trials demonstrated the Eurartesim® formulation of Dihydroartemisinin/piperaquine to be noninferior to artesunate plus mefloquine in children and adults in Asia and noninferior to artemether/lumefantrine in children in Africa, in terms of polymerase chain reaction-corrected cure rates. In both trials, Dihydroartemisinin/piperaquine recipients were significantly less likely than artesunate plus mefloquine recipients or artemether/lumefantrine recipients to experience reinfection. Gametocyte carriage was greater in patients receiving Dihydroartemisinin/piperaquine than in those receiving comparator antimalarial regimens. The Eurartesim® formulation of Dihydroartemisinin/piperaquine was generally well tolerated in the treatment of uncomplicated P. falciparum malaria, and was associated with significantly less nausea, vomiting and dizziness than artesunate plus mefloquine. Although prolongation of the corrected QT interval has been reported in patients receiving Dihydroartemisinin/piperaquine, there are currently no clinical data signalling that it is associated with clinically significant arrhythmias. In conclusion, Dihydroartemisinin/piperaquine is a valuable option for use in the first-line treatment of uncomplicated P. falciparum malaria.
Aung Pyae Phyo - One of the best experts on this subject based on the ideXlab platform.
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triple artemisinin based combination therapies versus artemisinin based combination therapies for uncomplicated plasmodium falciparum malaria a multicentre open label randomised clinical trial
The Lancet, 2020Co-Authors: Richard M Hoglund, Rob W Van Der Pluijm, Rupam Tripura, Aung Pyae Phyo, Akhter Ul Islam, Anupkumar R AnvikarAbstract:Summary Background Artemisinin and partner-drug resistance in Plasmodium falciparum are major threats to malaria control and elimination. Triple artemisinin-based combination therapies (TACTs), which combine existing co-formulated ACTs with a second partner drug that is slowly eliminated, might provide effective treatment and delay emergence of antimalarial drug resistance. Methods In this multicentre, open-label, randomised trial, we recruited patients with uncomplicated P falciparum malaria at 18 hospitals and health clinics in eight countries. Eligible patients were aged 2–65 years, with acute, uncomplicated P falciparum malaria alone or mixed with non-falciparum species, and a temperature of 37·5°C or higher, or a history of fever in the past 24 h. Patients were randomly assigned (1:1) to one of two treatments using block randomisation, depending on their location: in Thailand, Cambodia, Vietnam, and Myanmar patients were assigned to either Dihydroartemisinin–piperaquine or Dihydroartemisinin–piperaquine plus mefloquine; at three sites in Cambodia they were assigned to either artesunate–mefloquine or Dihydroartemisinin–piperaquine plus mefloquine; and in Laos, Myanmar, Bangladesh, India, and the Democratic Republic of the Congo they were assigned to either artemether–lumefantrine or artemether–lumefantrine plus amodiaquine. All drugs were administered orally and doses varied by drug combination and site. Patients were followed-up weekly for 42 days. The primary endpoint was efficacy, defined by 42-day PCR-corrected adequate clinical and parasitological response. Primary analysis was by intention to treat. A detailed assessment of safety and tolerability of the study drugs was done in all patients randomly assigned to treatment. This study is registered at ClinicalTrials.gov, NCT02453308, and is complete. Findings Between Aug 7, 2015, and Feb 8, 2018, 1100 patients were given either Dihydroartemisinin–piperaquine (183 [17%]), Dihydroartemisinin–piperaquine plus mefloquine (269 [25%]), artesunate–mefloquine (73 [7%]), artemether–lumefantrine (289 [26%]), or artemether–lumefantrine plus amodiaquine (286 [26%]). The median age was 23 years (IQR 13 to 34) and 854 (78%) of 1100 patients were male. In Cambodia, Thailand, and Vietnam the 42-day PCR-corrected efficacy after Dihydroartemisinin–piperaquine plus mefloquine was 98% (149 of 152; 95% CI 94 to 100) and after Dihydroartemisinin–piperaquine was 48% (67 of 141; 95% CI 39 to 56; risk difference 51%, 95% CI 42 to 59; p Interpretation Dihydroartemisinin–piperaquine plus mefloquine and artemether–lumefantrine plus amodiaquine TACTs are efficacious, well tolerated, and safe treatments of uncomplicated P falciparum malaria, including in areas with artemisinin and ACT partner-drug resistance. Funding UK Department for International Development, Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and US National Institutes of Health.
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chloroquine versus Dihydroartemisinin piperaquine with standard high dose primaquine given either for 7 days or 14 days in plasmodium vivax malaria
Clinical Infectious Diseases, 2019Co-Authors: Aung Pyae Phyo, Claudia Turner, Widi Yotyingaphiram, Suradet Thinraow, Pornpimon Wilairisak, Rattanaporn Raksapraidee, Verena I Carrara, Jacher Wiladphaingern, Stephane ProuxAbstract:BACKGROUND Primaquine is necessary for the radical cure of Plasmodium vivax malaria, but the optimum duration of treatment and best partner drug are uncertain. A randomized controlled trial was performed to compare the tolerability and radical curative efficacy of 7-day versus 14-day high-dose primaquine regimens (total dose 7mg/kg) with either chloroquine or Dihydroartemisinin-piperaquine. METHODS Patients with uncomplicated P. vivax malaria on the Thailand-Myanmar border were randomized to either chloroquine (25mg base/kg) or Dihydroartemisinin-piperaquine (Dihydroartemisinin 7mg/kg and piperaquine 55mg/kg) plus primaquine, either 0.5 mg/kg/day for 14 days or 1 mg/kg/day for 7 days. Adverse events within 42 days and 1-year recurrence rates were compared and their relationship with day 6 drug concentrations assessed. RESULTS Between February 2012 and July 2014, 680 patients were enrolled. P. vivax recurrences (all after day 35) occurred in 80/654 (12%) patients; there was no difference between treatments. Compared to the 7-day primaquine groups the pooled relative risk of recurrence in the 14-day groups was 1.15 (95% confidence interval 0.7 to 1.8). Hematocrit reductions were clinically insignificant except in G6PD female heterozygotes, 2 of whom had hematocrit reductions to <23% requiring blood transfusion. CONCLUSION Radical cure should be deployed more widely. The radical curative efficacy in vivax malaria of 7-day high-dose primaquine is similar to the standard 14-day high-dose regimen. Chloroquine and Dihydroartemisinin-piperaquine are both highly effective treatments of the blood stage infection. Quantitative point of care G6PD testing would ensure safe use of the 7-day high-dose primaquine regimen in G6PD heterozygous females. CLINICAL TRIALS REGISTRATION NCT01640574.
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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, Elizabeth A Ashley, Aung Pyae Phyo, Francois Nosten, Praiya ThanaAbstract: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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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, Nicholas J White, Aung Pyae Phyo, 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.