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In a preliminary analysis, data from a total of 1,291 pregnant and 220 non-pregnant women from 5 published [1-6] and 3 unpublished clinical trials [7] were included. The outcomes will be circulated among participating investigators for feedback and approval and a draft publication is expected by Q4 2019.


Pregnant women are particularly vulnerable to malaria, and malaria in pregnancy is an important cause of maternal and neonatal morbidity and mortality [8]. 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 [9]. The 3-day fixed-dose combination of dihydroartemisinin piperaquine (DP) is one of five ACTs currently recommended by the WHO [9]. DP has excellent efficacy and an acceptable safety profile in pregnant women according to a recently published large clinical trial [10]. DP also appears to be well tolerated and effective as intermittent preventive therapy (IPT) [11,12], 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 [2-6], and others report elevated piperaquine clearance resulting in decreased total exposure [1,13] 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the impact of pregnancy on the PK parameters of piperaquine using individual patient data from published and unpublished clinical trials.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, simulations to define optimal dosage regimen of piperaquine in pregnant women.

Essential inclusion criteria

  1. Study of piperaquine (in any formulation) with the purpose of treating patients with uncomplicated P. falciparum 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. Demographics (e.g. bodyweight, age, race, 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), whether or not supervised, any post-dose vomiting.
  4. Any co-morbidities (e.g. HIV)?
  5. Any concomitant medication/s?
  6. Capillary and/or venous plasma and/or whole blood piperaquine concentration(s) and sample times
  7. The reported range of piperaquine concentration measurements (i.e. range of bioanalytical method, defined by the lower and upper limits of quantification).
  8. Any therapeutic outcome data (both safety and efficacy)

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. Dr. Junjie Ding 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 junjie [dot] ding [at] wwarn [dot] org (Junjie Ding).


Data collation started in March 2018 and the pharmacometric modelling should be completed by end of 2019.


[1] Moore BR, et al. Safety, tolerability and pharmacokinetic properties of co-administered azithromycin and piperaquine in pregnant Papua New Guinean women. Br J Clin Pharmacol, 2016.

[2] Benjamin JM, et al. Population pharmacokinetics, tolerability, and safety of dihydroartemisinin-piperaquine and sulfadoxine-pyrimethamine-piperaquine in pregnant and nonpregnant Papua New Guinean women. Antimicrob Agents Chemother 2015;59:4260–71

[3] Tarning J, et al. Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and non-pregnant women with uncomplicated malaria. Antimicrob Agents Chemother 2012;65:1997–2225

[4] Rijken MJ, et al. Pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated falciparum malaria. Antimicrob Agents Chemother 2011;55:5500

[5] Adam I, et al. Pharmacokinetics of piperaquine in pregnant women in Sudan with uncomplicated Plasmodium falciparum malaria. Am J Trop Med Hyg 2012;87:35–40.

[6] Hoglund RM, et al. A population pharmacokinetic model of piperaquine in pregnant and non-pregnant women with uncomplicated Plasmodium falciparum malaria in Sudan. Malar J 2012;11:398

[7] Tarning J, et al. Pharmacokinetics and accumulation of piperaquine when used for intermittent preventive treatment in pregnancy (IPTp). In: American Journal of Tropical Medicine and Hygiene. 65th annual meeting ASTMH, November. 

[8] Dellicour S, et al. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med 2010;7:e1000221

[9] World Health Organization. Guidelines for the treatment of malaria. - 3rd edition. Geneva: World Health Organization; 2015

[10] The PREGACT Study Group. Four Artemisinin-Based Treatments in African Pregnant Women with Malaria. N Engl J Med 2016;374:913–27

[11] Kakuru A, et al. Dihydroartemisinin-Piperaquine for the Prevention of Malaria in Pregnancy. N Engl J Med. 2016 Mar 10;374(10):928-39

[12] Gutman J, et al. Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis. Lancet Infect Dis. 2017 Feb;17(2):184-193

[13] Savic R, et al. Prevention of malaria in pregnancy: quantification of target concentrations of dihydroartemisinin-piperaquine. In: American Journal of Tropical Medicine and Hygiene. University of California San Francisco, San Francisco, CA, United States: 2016. 471–2 XX – 65th annual meeting ASTMH, November.