Artemether Lumefantrine

Authored by Dr. Enola Okonkwo

 
Introduction
Artemether Lumefantrine is an oral medication which is used in treatment of chloroquine resistant uncomplicated malaria.  Artemether Lumefantrine falls within the drug class of Artemisinin-based combination therapies which have been found to be highly effective in treating malaria and are substantially less toxic than quinoline antimalarials.  Artemisins are derived from a Chinese medicinal herb which comes from the sweet wormwood plant (1).   Artemether Lumefantrine, known by the brand name Coartem, is the most widely used artemisinin based combination therapy used in Africa and is one of three medications recommended by the CDC as first line oral treatment for uncomplicated falciparum malaria within the United States (2). 

Structure

​1 tablet = 20mg artemether and 120 mg lumefantrine. 
Dosing is weight based.  For patients > 35 kg they are taking 4 tablets per dose twice daily for 3 days. 
 
Pharmacology/Pharmacokinetics:
Absorption/Distribution/Metabolism/Excretion
 
Artemeter is rapidly absorbed.  Peak plasma level of artemeter is approximately 2 hours. The half-life after ingestion is 2 hours (4-5). 95% of artemether is protein bound but quickly undergoes metabolism to dihydroartemisin which is approximately 50% protein bound.  Half life of dihydroartemisin is also around 2 hours (5). Bioavailability increased 2-3 fold when consumed with food (4).
 
Lumefantrine – Initial absorption at approximately 2 hours. Peak plasma level approximately 6-8 hours.    Half life is 4-5 days.  It is highly protein bound and has a large volume of distribution.  High fat meals significantly increase absorption 16 fold (4). 
   
 
Significant Drug/Drug interactions
Numerous theoretic drug interactions have been reported.  However, there is scant data available reporting clinical effects of drug interactions.
-May enhance QTc prolonging effects
-May enhance toxic effects of other antimalarial or HIV medications
-May increase serum concentration of antipsychotics
-May decrease serum concentration of estrogen related contraceptives
-May decrease serum concentration of CYP3A4 Substrates
 
Metabolic Pathways and active metabolites
 
Arthemeter is metabolized by the liver to the active metabolite dihydroartemisinin primarily by CYP3A4/5. 
 
Lumefantrine is metabolized by the liver to desbutyl-lumefantrine by CYP3A4. 
 
Studies suggest that artemisins inhibit the sarco/endoplasmic reticulum Ca ATPases of the malaria parasite causing rapid reduction in the parasite (6-7).  The mechanism of lumefantrine is unknown but both agents inhibit nucleic acid and protein synthesis.  Artemether rapidly kills the majority of the parasite and lumefantrine goes on to kill the residual remaining parasite (4-5). 
 
Mechanism of Toxicity
 
Artemether Lumefantrine has been extensively used for the treatment of malaria and appears to have an excellent safety profile.  There are no reported overdoses or intentional ingestions.  There has been no evidence of significant systemic or local toxicity reported in any large human study (1, 20-21).  However, there is animal data and a few small human studies and case reports which suggest neurotoxicity and QT prolongation are possible toxic effects of artimisinins (14). 
 
Neurotoxicity was especially common in animal studies both clinically and histologically (8-10, 14).  In vitro studies have postulated that neurotoxicity results secondary to ATP depletion of neurons and free radical generation created by the breakdown of artemisins (Schmuck 2002, Smith 1998) . Toover et. el wrote a review article cautioning that neurotoxic effects may also occur in humans more frequently than previously thought, though many critics viewed their review as bias (8, 13).  There are a small number of case reports within humans suggesting that artemisins contributed to neurologic symptoms such as anxiety, tremor, and ataxia (8, 15-16).  A small study looking at construction workers treated with arthemeter suggested that individuals had hearing loss following the administration of artemether (17).  Obviously, this study is limited by a serious potential confounder and attempts to reproduce these results have failed (18). 
 
One case report of delayed hemolytic anemia, not thought to be related to malaria was reported (19).
 
Clinical Toxicity
 
Given patients taking artemether lumefantrine have malaria, it is difficult to distinguish between symptoms caused by the disease state of malaria versus symptoms which may be attributed to medication toxicity.  Clinical toxicity appears to be very rare or possibly underreported.  A large review of 188 studies including over 9,000 patients found no serious clinical toxicity (21). This review article used methodology similar to Cochrane review and reported transient neutropenia in 1.3%, reticulocytopenia (0.6%), elevated liver enzymes (0.9%), and transient bradycardia and prolonged QT (1.1%).  The most common side effects reported were gastrointestinal.  The authors conclude that Artemether Lumefantrine is a safe and efficacious drug. 
 
Common adverse events (4, 20-21)
Abdominal pain
Anorexia
Vomiting
Diarrhea
Headache
dizziness.
Pruritis and Rash < 2%
 
Laboratories
No specific toxicology labs are available
 
Management of Toxicity
No accepted recommendations regarding toxicity given the scarcity of data suggesting toxicity.
Below are general recommendations based off of literature review:
Avoid concurrent use of additional antimalarial medications
Use caution administering additional drugs which can prolong QT
Use caution in hypokalemia and replete electrolytes as needed
Use caution in patients with prolonged QT
Obtain EKG as screening for arrhythmia
 
References:
 
1.  Hien, T. T., White, N. J., & White. (1993). Qinghaosu. The Lancet, 341(8845), 603–608. https://doi.org/10.1016/0140-6736(93)90362-K
 
2. Center for Disease Control. (2009). Guidelines for treatment of malaria in the United States. Treatment Table Update, May, (770), 855–857. Retrieved from http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Guidelines+for+Treatment+of+Malaria+in+the+United+States#1
 
3.  Amin, N. C., Fabre, H., Blanchin, M.-D., Montels, J., & Aké, M. (2013). Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure. Malaria Journal, 12, 202. https://doi.org/10.1186/1475-2875-12-202
 
4.  Waning, B., & Montange, M. (2015). Access Pharmacy. Retrieved from http://accesspharmacy.mhmedical.com/content.aspx?bookid=438&sectionid=40428529
 
5.  White, N. J., Van Vugt, M., & Ezzet, F. (1999). Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clinical Pharmacokinetics. Adis International Ltd. https://doi.org/10.2165/00003088-199937020-00002
 
6.  Krishna, S., Pulcini, S., Moore, C. M., Teo, B. H. Y., & Staines, H. M. (2014, January). Pumped up: Reflections on PfATP6 as the target for artemisinins. Trends in Pharmacological Sciences. https://doi.org/10.1016/j.tips.2013.10.007
 
7.  Eckstein-Ludwig, U., Webb, R. J., Van Goethem, I. D. A., East, J. M., Lee, A. G., Kimura, M., … Krishna, S. (2003). Artemisinins target the SERCA of Plasmodium falciparum. Nature, 424(6951), 957–961. https://doi.org/10.1038/nature01813
 
8.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
9.  Genovese, R. F., Newman, D. B., Li, Q., Peggins, J. O., & Brewer, T. G. (1998). Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Research Bulletin, 45(2), 199–202. https://doi.org/10.1016/S0361-9230(97)00339-0
 
10.  Petras, J. M., Young, G. D., Bauman, R. A., Kyle, D. E., Gettayacamin, M., Webster, H. K., … Brewer, T. G. (2000). Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: The lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anatomy and Embryology, 201(5), 383–397. https://doi.org/10.1007/s004290050326
11.  Schmuck, G., Roehrdanz, E., Haynes, R. K., & Kahl, R. (2002). Neurotoxic mode of action of artemisinin. Antimicrobial Agents and Chemotherapy, 46(3), 821–827. https://doi.org/10.1128/AAC.46.3.821-827.2002
 
12.  Smith, S. L., Maggs, J. L., Edwards, G., Ward, S. A., Park, B. K., & McLean, W. G. (1998). The role of iron in neurotoxicity: a study of novel antimalarial drugs. Neurotoxicology, 19(4–5), 557–559.
 
13.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
14.  Brewer, T. G., Peggins, J. O., Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., … Schuster, B. G. (1994). Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 33–36. https://doi.org/10.1016/0035-9203(94)90469-3
 
15.  Miller, L. G., & Panosian, C. B. (1997). Ataxia and slurred speech after artesunate treatment for falciparum malaria. New England Journal of Medicine, 336(18), 1328. https://doi.org/10.1056/NEJM199705013361818
 
16.  Franco-Paredes, C., Dismukes, R., Nicolls, D., & Kozarsky, P. E. . (2005). Neurotoxicity Due to Antimalarial Therapy Associated with Misdiagnosis of Malaria. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 40(11), 1710–1711. https://doi.org/10.1086/430180
 
17.  Toovey, S. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygeine 74, 939-940. 
 
18.  Hutagalung, R., Htoo, H., Nwee, P., Arunkamomkiri, J., Zwang, J., Carrara, V. I., … Nosten, F. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene, 74(2), 211–214. https://doi.org/74/2/211 [pii]
 
19.  Hasegawa, C., Kudo, M., Maruyama, H., Kimura, M. (2017). Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveler. Journal of Infection and Chemotherapy.  In press.  https://doi.org/10.1016/j.jiac.2017.10.008
 
20.  Alkadi, H. O. (2007, November). Antimalarial drug toxicity: A review. Chemotherapy. https://doi.org/10.1159/000109767
 
21.  Ribeiro, I. R., & Olliaro, P. (1998). Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Medecine Tropicale : Revue Du Corps de Sante Colonial, 58(3 Suppl), 50–53. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=10212898