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 In an extensive systematic literature review, data from a total of 45 published [1-45] and several unpublished clinical trials have been identified.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the impact of pregnancy on the PK parameters of piperaquine using individual patient data from published and unpublished clinical trials.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.

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.

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

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)

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 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 Tarning and/or 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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