Malaria in Pregnancy. Photo: LSTMH

Piperaquine Pharmacokinetics in Pregnancy Study Group

Determining the effects of pregnancy on piperaquine pharmacokinetics. The analysis aims to contribute evidence needed to inform recommendations on the use and optimal dosing of piperaquine in pregnant women.

Update and overview

This Study Group’s population pharmacokinetic (PK) analysis on Piperaquine in Pregnancy is currently ongoing. In an extensive systematic literature review, data from a total of 45 published [1-45] and several unpublished clinical trials have been identified. We are now in the process of contacting potential data contributors to share these data. The outcomes will be circulated among participating investigators for feedback and approval and a draft publication is expected by Q2 2021.


Pregnant women are particularly vulnerable to malaria, and malaria in pregnancy is an important cause of maternal and neonatal morbidity and mortality [46]. Physiological changes during pregnancy can affect the pharmacokinetics (PK) of most medicines, often resulting in lower drug concentrations and thus increased risk of therapeutic failure. Artemisinin-based combination therapy (ACT) is the recommended first-line treatment for uncomplicated Plasmodium falciparum malaria in pregnant women in the second and third trimester according to WHO guidelines [47]. The 3-day fixed-dose combination of dihydroartemisinin piperaquine (DP) is one of five ACTs currently recommended by the WHO [47]. DP has excellent efficacy and an acceptable safety profile in pregnant women according to a recently published large clinical trial [49]. DP also appears to be well tolerated and effective as intermittent preventive therapy (IPT) [49,50], the exception being pregnant women on efavirenz-based antiretroviral therapy. However, the reported PK properties of piperaquine in pregnant women are contradictory; some studies report unchanged piperaquine exposures [1,6,28,36], and others report elevated piperaquine clearance resulting in decreased total exposure [21,29] in pregnant women with malaria. A large-scale individual patient data (IPD) meta-analysis is needed to characterise the PK properties of piperaquine in pregnant women and to provide evidence whether dosage adjustments should be considered during pregnancy.


  1. To investigate the impact of pregnancy on the PK parameters of piperaquine using individual patient data from published and unpublished clinical trials.
  2. If needed, modelling and simulations to define optimal dosage regimens of piperaquine in pregnant women.

Essential inclusion criteria

  1. Study of piperaquine (in any formulation) with the purpose of treating patients with uncomplicated malaria mono- and/or mixedinfection or preventing malaria in healthy subjects (IPT).
  2. Pregnant and/or non-pregnant women. 
  3. Drug concentration(s) of piperaquine.

Desirable criteria

  1. Therapeutic outcome, such as time to recurrent malaria.
  2. Safety data, and in particular ECG measurements.

Data standardisation and analysis

After upload to the WWARN Data Repository, WWARN will standardise data sets according to the WWARN Clinical Data Management and Statistical Analysis Plan and pool into a single database of quality-assured individual patient data. 

The pooled piperaquine PK database includes the following:

  1. Demographic variables (e.g. bodyweight, age, ethnicity, pregnancy status, trimester, estimated gestational age and how measured)
  2. Baseline patient characteristics (e.g. baseline parasite density, fever)
  3. Dosing and dosing time(s), and whether or not does were supervised
  4. Co-morbidities (e.g. HIV)
  5. Concomitant medication/s
  6. Capillary and/or venous plasma and/or whole blood piperaquine concentration(s) and sampling times
  7.  Sensitivity of the bioanalytical method (i.e. lower limit of quantification of piperaquine concentration measurements)
  8. Therapeutic outcome data (both efficacy and safety, such as vomiting and ECG)


Study group governance

The Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the investigator. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy. The Study Group is led by Professor Joel Tarning, Head of the Pharmacometric Modelling Scientific Group of WWARN. thanaporn [at] tropmedres [dot] ac (Dr Thanaporn Wattanakul) is leading the pharmacometric analysis. These individuals coordinate activities including the completion of data collation, plans for analysis, and drafting of publications and reports for group review.

For further information, email joel [dot] tarning [at] wwarn [dot] org (Joel Tarning) and/or thanaporn [at] tropmedres [dot] ac (Dr Thanaporn Wattanakul).


A systematic literature review was conducted in mid-2020 and data collation started in November 2020. The pharmacometric modelling is expected to be completed by mid-2021.


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[2] Amaratunga C, et al. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study. Lancet Infectious Diseases. 2016;16(3):357-65.

[3] Anirudh G, et al. Pharmacokinetics and pharmacodynamics of arterolane maleate following multiple oral doses in adult patients with P. falciparum malaria. Journal of Clinical Pharmacology. 2011;51(11):1519-28.

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[22]  Mytton OT, et al. Electrocardiographic safety evaluation of dihydroartemisinin-piperaquine in the treatment of uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene. 2007;77(3):447-50.

[23]  Neena V, et al. Comparison of the safety and efficacy of fixed-dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax malaria: a phase III, multicentric, open-label study. Malaria Journal. 2016;15(42).

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[25]  Pekyi D, et al. Four artemisinin-based treatments in African pregnant women with malaria. New England Journal of Medicine. 2016;374(10):913 - 27 PMID PM:26962727.

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[27]  Price RN, et al. Clinical and pharmacological determinants of the therapeutic response to dihydroartemisinin-piperaquine for drug-resistant malaria. Antimicrobial agents and chemotherapy. 2007;51(11):4090‐7.

[28]  Rijken MJ, et al. Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria. Antimicrobial Agents and Chemotherapy. 2011;55(12):5500-6.

[29]  Savic RM, et al. Intermittent preventive treatment for malaria in pregnancy: optimization of target concentrations of dihydroartemisinin-piperaquine. Clinical Infectious Diseases. 2018;67(7):1079-88.

[30]  Sevene E, et al. Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: An open label non-randomized interventional trial. Malaria Journal. 2019;18(1).

[31]  Sim IK, et al. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrobial Agents and Chemotherapy. 2005;49(6):2407-11.

[32]  Smithuis F, et al. Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison. Lancet (london, england). 2006;367(9528):2075‐85.

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[35] Tarning J, et al. Population pharmacokinetics and antimalarial pharmacodynamics of piperaquine in patients with Plasmodium vivax Malaria in Thailand. CPT: Pharmacometrics and Systems Pharmacology. 2014;3 (8):(e132).

[36]  Trinh Ngoc H, et al. The influence of food on the pharmacokinetics of piperaquine in healthy Vietnamese volunteers. Acta Tropica. 2008;107(2):145-9.

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[39]  von Seidlein L, et al. Combining antimalarial drugs and vaccine for malaria elimination campaigns: a randomized safety and immunogenicity trial of RTS,S/AS01 administered with dihydroartemisinin, piperaquine, and primaquine in healthy Thai adult volunteers. Human Vaccines Immunother. 2020;16(1):33-41.

[40]  Wallender E, et al. Predicting optimal dihydroartemisinin-piperaquine regimens to prevent malaria during pregnancy for human immunodeficiency virus-infected women receiving efavirenz. Journal of Infectious Diseases. 2018;217(6):964-73.

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[42]  Wattanakul T, et al. Cardiovascular safety and population pharmacokinetic properties of piperaquine in African patients with uncomplicated falciparum malaria - a pooled multicentre analysis. Antimicrob Agents Chemother. 2020.

[43]  Yamin Ko K, et al. Pharmacokinetics of piperaquine in Myanmar healthy volunteers after oral administration of two fixed-dose dihydroartemisinin-piperaquine combinations. Myanmar Health Sciences Research Journal. 2013;25(3):219-24.

[44] Ahmed R, et al. Efficacy and safety of intermittent preventive treatment and intermittent screening and treatment versus single screening and treatment with dihydroartemisinin–piperaquine for the control of malaria in pregnancy in Indonesia: a cluster-randomised, open-label, superiority trial. The Lancet Infectious Diseases. 2019;19(9):973-87.

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