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Artemether–Lumefantrine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Robert J. Commons, Julie A. Simpson, Ric N. Price
The principal pharmacokinetic determinant of lumefantrine for therapeutic efficacy in patients with P. falciparum malaria is the AUC. Doubling the AUC0–∞ was predicted to halve the risk of failure (Ezzet et al., 1998); this was confirmed in a small clinical study describing four patients failing treatment with a median AUCobserved of 386 μmol/l/h compared with 788 μmol/l/h in the 32 patients who were cured (Ashley et al., 2007b). Plasma lumefantrine concentrations on day 7 have also been shown to correlate with therapeutic efficacy. Ezzet et al. (1998) found that 75% of patients with a plasma lumefantrine concentration above 280 ng/ml (0.53 μmol/l) on day 7 were cured, compared with only 51% of patients with concentrations below this level (Ezzet et al., 1998). The importance of day 7 concentrations was reconfirmed using PCR-corrected failure data for the same patient group. Overall, 24% (95% CI: 12–36%) of patients with concentrations <175 ng/ml (0.33 μmol/l) experienced treatment failure, compared with 1.1% (0–2.3%) of patients with concentrations above 175 ng/ml (0.33 μmol/l) (Price et al., 2006).
Antimalarial treatment in infants
Published in Expert Opinion on Pharmacotherapy, 2022
Laura C. Kalkman, Thomas Hanscheid, Sanjeev Krishna, Peter G. Kremsner, Martin P. Grobusch
First, lumefantrine plasma levels on day seven are repeatedly found to be lower in young children and infants (generally <15 kg; six months to two years) when compared to older patients [72–74]. Lumefantrine doses of <60 mg/kg were associated with an augmented risk of recrudescence in Asian infants and young African children with malnutrition [75]. Some trials reported no correlation between PK and PD parameters such as cure rates [71,72,74,76]. At the same time, Kloprogge et al. and Tchaparian et al. found that lower lumefantrine day seven concentrations increased the recrudescence risk [72,73]. Dose-limited absorption preclude the possibility of simply increasing the lumefantrine dose in infants to achieve adequate plasma lumefantrine levels. An extended treatment regimen (A-L bi-daily for five days) or an intensified regimen (A-L three times daily for three days) is one proposed solution. Testing the efficacy and safety of an extended or intensified A-L regimen in infants, who have limited immunity as well as possible suboptimal lumefantrine levels, is advisable. Similarly, measuring day seven lumefantrine concentrations in the context of clinical trials will provide valuable information on efficacy.
Enantioselective in vitro ADME, absolute oral bioavailability, and pharmacokinetics of (−)-lumefantrine and (+)-lumefantrine in mice
Published in Xenobiotica, 2021
Bhavesh Babulal Gabani, Abhishek Dixit, Vinay Kiran, Ram Murthi Bestha, Balaji Narayanan, Nuggehally R. Srinivas, Ramesh Mullangi
Lumefantrine (LFN) or benflumetol (Figure 1) is a chiral long-acting antimalarial drug commonly co-administered with artemether to obtain an improved efficacy as compared with artemether alone (Tse et al., 2019). The combination of artemether and LFN is recommended to as a first-line therapy for uncomplicated malaria. Artemether by its rapid action will reduce the parasite load and the long-acting LFN will eliminate the residual parasites (White et al., 1999). Karle et al. (1993) reported that (+)-mefloquine exhibited two-fold higher in vivo activity over (−)-mefloquine, however, the enantiomers of LFN have shown similar in vivo potency against 29 isolates of Plasmodium falciparum (Wernsdorfer et al., 1998). Post oral administration of LFN (120 mg) to humans, peak plasma concentration (Cmax) was attained between 6 and 8 h. Due to its poor absorption, LFN exhibits high inter-individual variability in pharmacokinetics. LFN is highly bound to plasma proteins (99.7%) with a long half-life ranging between 3 and 6 days. LFN is majorly metabolized by CYP3A4 into the active metabolite, desbutyllumefantrine. Following LFN oral administration, the active metabolite concentrations were 100-fold lower than LFN (Coartem®, 2009).
Characterization of solid lipid dispersions prepared by hot fusion containing a double-fixed dose combination of artemether and lumefantrine
Published in Drug Development and Industrial Pharmacy, 2020
Christi A. Wilkins, Lissinda H. du Plessis, Joe M. Viljoen
Malaria remains one of the most prevalent and life-threatening vector-borne diseases of our time [1,2]. The World Health Organization (WHO) encourages the development of artemisinin-based combination therapy to combat this disease [3], however, the primary challenge when working with anti-malarial drugs is their high lipophilicity [4] and, thus, there is a need to design a dosage form that is able to augment the solubility of these active pharmaceutical ingredients (APIs). One of the artemisinin-based combination therapies for the treatment of uncomplicated Plasmodium falciparum malaria is artemether and lumefantrine. Current treatment regimens recommend that artemether (ART) and lumefantrine (LUM) be administered after meals, preferably one rich in fat(s) to invoke the food effect (the associated rate and extent of drug absorption based on the fed state and meal composition compared to the fasted state) [5–9]. This proves problematic due to nausea presenting as a predominant symptom in malarial patients as well as the economic factor associated with low-income regions most often being the highest burdened with this disease [3].