Review of artemisinin derivatives: An artful approach to malaria treatment
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The mosquito is one of the world’s most impactful forces. The breadth of transmissible diseases caused by a mosquito bite, including malaria, has helped shape human history.
Malaria is caused by infection of erythrocytes with protozoan parasites of the genus Plasmodium that are transmitted through the bites of infected female Anopheles mosquitoes. In 2020, there were an estimated 241 million cases and 627,000 deaths from malaria globally, most in tropical and subtropical regions, where malaria is often endemic, including most of Africa and parts of South America and Asia. Of the five Plasmodium species known to infect humans, P. falciparum is the predominant species, with P. vivax being the second most common threat.
Prompt treatment of malaria can be challenging. People are typically asymptomatic for the first few weeks following the bite. Infection is classified as either “uncomplicated” or “severe” based on the severity of symptoms and end organ dysfunction, the infecting Plasmodium species and the parasitemia level. It is important to distinguish between the two forms of malaria infection because that decision influences what treatment is chosen. Artemisinin derivatives are the mainstay of treatment of malaria, with IV artesunate being the preferred antimalarial for severe disease.
A brief history of artemisinin
Artemisinin is derived from leaves of the Chinese sweet wormwood plant (Artemisia annua). Extracts from these leaves have been used in China dating back more than 1,500 years for their reported antipyretic effects. However, the artemisinin molecule was not discovered until more recently.
Quinine and its derivative, chloroquine, had been successfully used to treat malaria for several years before the discovery of artemisinin. However, efficacy of these agents decreased as resistance developed, in part due to the extensive use during the Vietnam War. In search of new antimalarial medications, Vietnam turned to China for help, where an organized research program was initiated by the Chinese government in 1967 to aid in these efforts. In 1971, the active ingredient of the Chinese sweet wormwood plant was discovered and identified as artemisinin. Since then, several derivatives of artemisinin have been developed and used in modern malaria treatments.
Artemisinin derivatives share a similar mechanism of action against Plasmodium species. They interact with heme iron within the parasite, causing the breakdown of peroxide bridges within the artemisinin molecule, leading to free radical production that damages parasitic proteins. Artemisinin derivatives have the fastest parasite clearance times of any antimalarials because of their preferred place in therapy. Oral options of artemisinin derivatives are coformulated with other antimalarial medications and are available as what is known as “artemisinin-based combination therapy” (ACT). Artesunate is the only IV artemisinin derivative to treat malaria.
IV artesunate
Before the discovery of artemisinin and the development of its derivatives, IV quinidine was the main treatment for severe malaria. In 2019, Eli Lilly stopped producing quinidine, and IV artesunate became the first-line therapy for severe malaria. Several studies have demonstrated improved mortality rates with IV artesunate compared with IV quinidine. An open-label randomized controlled trial (RCT) of 1,461 patients with severe malaria showed a 15% mortality rate among patients treated with IV artesunate vs. 22% among patients treated with IV quinine. Another open-label RCT of 5,425 African children with severe malaria demonstrated similar outcomes, with an 8.5% mortality rate among those treated with IV artesunate vs. 10.9% in the IV quinine cohort. These data, in addition to better tolerability and ease of administration, have led to artesunate becoming first-line therapy for severe malaria.
The initial recommended dosing for IV artesunate for severe malaria is 2.4 mg/kg given at 0 hours, 12 hours, and 24 hours. After the first three doses of IV therapy, a patient may be transitioned to a follow-on oral regimen to complete a treatment course if their parasitemia level is 1% or less and is able to take oral medications. If both criteria are not met, a patient can continue daily dosing of IV artesunate for up to 6 more days. Artesunate does not require any dose adjustments for renal or hepatic dysfunction. A significant adverse drug reaction that can occur is artesunate-induced hemolytic anemia. This reaction is typically delayed and occurs in approximately 15% of patients after parasite clearance is achieved. The average hemoglobin nadir observed is 6.2 g/dL. It is recommended that every patient treated with IV artesunate have weekly hemolysis labs checked for 4 weeks after treatment initiation. Otherwise, artesunate is generally well tolerated.
On May 26, 2020, the FDA approved IV artesunate for the treatment of severe malaria in adults and children. Before FDA approval and commercial availability, IV artesunate was available in the United States only through an expanded access investigational new drug (IND) program managed by the CDC. Artesunate is now available for purchase from the drug distributors Amerisource Bergen, Cardinal and McKesson. Despite these recent changes, there may still be some delays in obtaining product and starting therapy because malaria is still relatively uncommon in the U.S. and not all hospitals may stock artesunate given its high cost (approximately $5,000 per 110 mg vial). If a hospital does not have IV artesunate in stock and it is needed to treat a patient with severe malaria, the hospital pharmacy should contact its drug distributor to request an emergency procurement of the product. If unable to obtain artesunate quickly from a distributor or borrow product from a nearby hospital, the hospital pharmacy can still obtain IV artesunate from the CDC under an IND protocol. Given the importance of prompt initiation of antimalarial therapy for severe malaria, it is recommended to start oral antimalarials while awaiting IV artesunate supply, if able.
Artemisinin-based combination therapy
Several oral antimalarial options exist for uncomplicated disease and for follow-on therapy after IV artesunate for severe disease. However, ACT is the preferred therapy in most countries because of the high efficacy, fast onset of action and tolerability of artemisinin derivatives.
ACT is a combination of a shorter acting artemisinin derivative and a different longer acting antimalarial medication. This combination helps to prevent the development of resistance to the artemisinin derivatives, which should not be used as monotherapy for this reason. There are currently five WHO-approved, first-line ACT options that countries can use. They have all been shown to achieve a PCR-adjusted treatment failure rate of less than 5% in many trials. Artemether-lumefantrine is the ACT that is used in the U.S.
The FDA approved artemether-lumefantrine in 2009 for the treatment of uncomplicated P. falciparum malaria, but it has more recently been recommended for severe malaria infection as a follow-on regimen after IV therapy or as a bridge to artesunate while awaiting supply. It is supplied as a fixed-dose oral tablet and is given as a six-dose regimen over 3 days. Tablets should be taken with food and can be crushed for administration, if needed. There are no recommended dose adjustments for renal or hepatic dysfunction. Similar to IV artesunate, artemether-lumefantrine is generally well tolerated.
Mosquitoes and malaria are here for the long haul. Artemisinin derivatives have become the first-line treatments for uncomplicated and severe malaria with improved mortality, side effect profiles and accessibility. Yet, these mainstay treatments remain only part of the solution to defeating mosquitoes. Pharmacological — including vaccination — and nonpharmacological methods must be sustained.
- References:
- Artesunate (artesunate for injection) [package insert]. Wilmington, DE: Amivas, LLC; 2020.
- CDC. Malaria. https://www.cdc.gov/parasites/malaria/index.html. Accessed June 1, 2022.
- Coartem (artemether/lumefantrine) tablets [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2009.
- Dondorp A, et al. Lancet. 2005;doi:10.1016/S0140-6736(05)67176-0.
- Dondorp AM, et al. Lancet. 2010;doi:10.1016/S0140-6736(10)61924-1.
- Faurant C. Parasite. 2011;doi:10.1051/parasite/2011183215.
- Meshnick SR. Med Trop (Mars). 1998;doi:10.1016/S0020-7519(02)00194-7.
- WHO guidelines for malaria. https://www.who.int/publications/i/item/guidelines-for-malaria. Published March 31, 2022.
- Woodrow CJ, at al. Postgrad Med J. 2005;doi:10.1136/pgmj.2004.028399.
- For more information:
- Rachel Urbas, PharmD, is a PGY-2 infectious diseases pharmacy resident at M Health Fairview – University of Minnesota Medical Center.
- Jennifer Ross, PharmD, BCIDP, is an infectious diseases clinical pharmacist at M Health Fairview – University of Minnesota Medical Center. Ross can be reached at jross13@fairview.org.
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