Piperaquine is a synthetic antiparasitic drug, classified as a bisquinoline, that was initially developed in the 1960s. It was widely used in China and Indochina for both preventing and treating malaria over the subsequent two decades. However, its use as a single therapy diminished in the 1980s due to the emergence of drug-resistant strains of Plasmodium falciparum, the parasite responsible for the most severe forms of malaria. Piperaquine has since been repurposed and is now primarily used in combination with other antimalarial agents to enhance effectiveness and combat resistance.
Primary Uses of Piperaquine
Piperaquine is predominantly used as an antimalarial drug, particularly in artemisinin-based combination therapies (ACTs). One widely adopted combination is dihydroartemisinin-piperaquine (DHA-PPQ), which is effective against both Plasmodium falciparum and Plasmodium vivax malaria. This combination is recognized as a treatment for uncomplicated malaria and is also recommended for severe malaria after initial artesunate administration.
The combination therapy is particularly beneficial because piperaquine has a slow absorption rate and a long biological half-life, making it a suitable partner for fast-acting, short-half-life artemisinin derivatives like dihydroartemisinin. This pairing helps clear the parasites rapidly while also providing a sustained effect to eliminate any remaining parasites, thereby reducing the likelihood of drug resistance. DHA-PPQ has demonstrated high cure rates against multidrug-resistant P. falciparum and chloroquine-resistant P. vivax infections. In certain regions, such as Southeast Asia, where resistance to both artemisinin and piperaquine has emerged, the combination is being investigated with a third drug, mefloquine, to maintain efficacy.
How Piperaquine Combats Malaria
Piperaquine works by disrupting the malaria parasite’s ability to detoxify heme, a byproduct of hemoglobin digestion within the parasite’s food vacuole. Plasmodium parasites consume hemoglobin from the host’s red blood cells, which releases toxic heme. Normally, the parasite converts this toxic heme into a non-toxic crystalline form called hemozoin.
Piperaquine is believed to interfere with this critical conversion process. By inhibiting the formation of hemozoin, piperaquine causes toxic heme to accumulate within the parasite, ultimately leading to its death. Piperaquine accumulates in the parasite’s digestive vacuole, binding to heme monomers and dimers, which prevents their crystallization into hemozoin.
Dosing and Potential Side Effects
Piperaquine is administered orally, usually as part of a fixed-dose combination medication. This combination is well-tolerated and has a simple dosing schedule. For uncomplicated Plasmodium falciparum infection, it is used in adults, children, and infants aged six months and older, weighing over 5 kg.
Concerns exist regarding piperaquine’s potential to prolong the corrected QT (QTc) interval, an electrical measurement of heart activity. QTc prolongation can lead to serious heart rhythm problems such as Torsades de Pointes. The risk of QTc prolongation with piperaquine is concentration-dependent. Some drugs, including certain antiarrhythmics, can increase the risk or severity of QTc prolongation when combined with piperaquine. Contraindications for piperaquine use include a history of heart rhythm problems or uncorrected electrolyte imbalances like low potassium or magnesium.
Piperaquine’s Role in Public Health
Piperaquine plays a role in global public health strategies, particularly in regions where malaria is widespread. Its inclusion in artemisinin-based combination therapies (ACTs) is important for malaria treatment guidelines recommended by organizations like the World Health Organization (WHO). The long post-treatment prophylactic period offered by piperaquine makes it suitable for sustained antimalarial effects, which is important for preventing reinfection and reducing disease transmission.
This drug is also being explored in mass drug administration (MDA) programs, where a full course of antimalarial treatment is given to an entire population or a specific segment, regardless of symptoms. Such programs aim to reduce malaria transmission in areas nearing elimination. Studies have shown that MDA with artemisinin-piperaquine can lower the burden of malaria and reduce the incidence of infection and clinical disease. For instance, in São Tomé Island, artemisinin-piperaquine MDA led to a substantial decrease in P. falciparum malaria cases and eliminated gametocyte carriage. The drug’s effectiveness against drug-resistant strains also helps to preserve the efficacy of other antimalarial treatments.