Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.
<h4>Background</h4>Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS Medicine |
| Online Access: | https://doi.org/10.1371/journal.pmed.1002212 |
| _version_ | 1811177216438960128 |
|---|---|
| author | Richard M Hoglund Lesley Workman Michael D Edstein Nguyen Xuan Thanh Nguyen Ngoc Quang Issaka Zongo Jean Bosco Ouedraogo Steffen Borrmann Leah Mwai Christian Nsanzabana Ric N Price Prabin Dahal Nancy C Sambol Sunil Parikh Francois Nosten Elizabeth A Ashley Aung Pyae Phyo Khin Maung Lwin Rose McGready Nicholas P J Day Philippe J Guerin Nicholas J White Karen I Barnes Joel Tarning |
| author_facet | Richard M Hoglund Lesley Workman Michael D Edstein Nguyen Xuan Thanh Nguyen Ngoc Quang Issaka Zongo Jean Bosco Ouedraogo Steffen Borrmann Leah Mwai Christian Nsanzabana Ric N Price Prabin Dahal Nancy C Sambol Sunil Parikh Francois Nosten Elizabeth A Ashley Aung Pyae Phyo Khin Maung Lwin Rose McGready Nicholas P J Day Philippe J Guerin Nicholas J White Karen I Barnes Joel Tarning |
| author_sort | Richard M Hoglund |
| collection | DOAJ |
| description | <h4>Background</h4>Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.<h4>Methods and findings</h4>Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals.<h4>Conclusions</h4>The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015). |
| first_indexed | 2024-04-10T22:59:01Z |
| format | Article |
| id | doaj.art-64549cda3d864c179ebe2ab8a7073ef4 |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-04-10T22:59:01Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-64549cda3d864c179ebe2ab8a7073ef42023-01-14T05:30:58ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762017-01-01141e100221210.1371/journal.pmed.1002212Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.Richard M HoglundLesley WorkmanMichael D EdsteinNguyen Xuan ThanhNguyen Ngoc QuangIssaka ZongoJean Bosco OuedraogoSteffen BorrmannLeah MwaiChristian NsanzabanaRic N PricePrabin DahalNancy C SambolSunil ParikhFrancois NostenElizabeth A AshleyAung Pyae PhyoKhin Maung LwinRose McGreadyNicholas P J DayPhilippe J GuerinNicholas J WhiteKaren I BarnesJoel Tarning<h4>Background</h4>Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine.<h4>Methods and findings</h4>Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals.<h4>Conclusions</h4>The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015).https://doi.org/10.1371/journal.pmed.1002212 |
| spellingShingle | Richard M Hoglund Lesley Workman Michael D Edstein Nguyen Xuan Thanh Nguyen Ngoc Quang Issaka Zongo Jean Bosco Ouedraogo Steffen Borrmann Leah Mwai Christian Nsanzabana Ric N Price Prabin Dahal Nancy C Sambol Sunil Parikh Francois Nosten Elizabeth A Ashley Aung Pyae Phyo Khin Maung Lwin Rose McGready Nicholas P J Day Philippe J Guerin Nicholas J White Karen I Barnes Joel Tarning Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. PLoS Medicine |
| title | Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. |
| title_full | Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. |
| title_fullStr | Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. |
| title_full_unstemmed | Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. |
| title_short | Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis. |
| title_sort | population pharmacokinetic properties of piperaquine in falciparum malaria an individual participant data meta analysis |
| url | https://doi.org/10.1371/journal.pmed.1002212 |
| work_keys_str_mv | AT richardmhoglund populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT lesleyworkman populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT michaeldedstein populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT nguyenxuanthanh populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT nguyenngocquang populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT issakazongo populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT jeanboscoouedraogo populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT steffenborrmann populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT leahmwai populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT christiannsanzabana populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT ricnprice populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT prabindahal populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT nancycsambol populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT sunilparikh populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT francoisnosten populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT elizabethaashley populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT aungpyaephyo populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT khinmaunglwin populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT rosemcgready populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT nicholaspjday populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT philippejguerin populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT nicholasjwhite populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT karenibarnes populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis AT joeltarning populationpharmacokineticpropertiesofpiperaquineinfalciparummalariaanindividualparticipantdatametaanalysis |