• Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis

      Kloprogge, F; Workman, L; Borrmann, S; Tékété, M; Lefèvre, G; Hamed, K; Piola, P; Ursing, J; Kofoed, PE; Mårtensson, A; Ngasala, B; Björkman, A; Ashton, M; Friberg Hietala, S; Aweeka, F; Parikh, S; Mwai, L; Davis, T; Karunajeewa, H; Salman, S; Checchi, F; Fogg, C; Newton, PN; Mayxay, M; Deloron, P; Faucher, JF; Nosten, F; Ashley, EA; McGready, R; van Vugt, M; Proux, S; Price, RN; Karbwang, J; Ezzet, F; Bakshi, R; Stepniewska, K; White, NJ; Guerin, PJ; Barnes, KI; Tarning, J (Public Library of Science, 2018-06)
      The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.
    • Complex interactions between malaria and malnutrition: a systematic literature review

      Das, D; Grais, R F; Okiro, E A; Stepniewska, K; Mansoor, R; van der Kam, S; Terlouw, D J; Tarning, J; Barnes, K I; Guerin, P J (BMC, 2018-10-29)
      Despite substantial improvement in the control of malaria and decreased prevalence of malnutrition over the past two decades, both conditions remain heavy burdens that cause hundreds of thousands of deaths in children in resource-poor countries every year. Better understanding of the complex interactions between malaria and malnutrition is crucial for optimally targeting interventions where both conditions co-exist. This systematic review aimed to assess the evidence of the interplay between malaria and malnutrition.
    • Population Pharmacokinetics of Lumefantrine in Pregnant and Nonpregnant Women With Uncomplicated Plasmodium falciparum Malaria in Uganda

      Kloprogge, F; Piola, P; Dhorda, M; Muwanga, S; Turyakira, E; Apinan, S; Lindegårdh, N; Nosten, F; Day, N P J; White, N J; Guerin, P J; Tarning, J; 1] Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand [2] Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. (2013)
      Pregnancy alters the pharmacokinetic properties of many antimalarial compounds. The objective of this study was to evaluate the pharmacokinetic properties of lumefantrine in pregnant and nonpregnant women with uncomplicated Plasmodium falciparum malaria in Uganda after a standard fixed oral artemether-lumefantrine treatment. Dense venous (n = 26) and sparse capillary (n = 90) lumefantrine samples were drawn from pregnant patients. A total of 17 nonpregnant women contributed with dense venous lumefantrine samples. Lumefantrine pharmacokinetics was best described by a flexible absorption model with multiphasic disposition. Pregnancy and body temperature had a significant impact on the pharmacokinetic properties of lumefantrine. Simulations from the final model indicated 27% lower day 7 concentrations in pregnant women compared with nonpregnant women and a decreased median time of 0.92 and 0.42 days above previously defined critical concentration cutoff values (280 and 175 ng/ml, respectively). The standard artemether-lumefantrine dose regimen in P. falciparum malaria may need reevaluation in nonimmune pregnant women.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e83; doi:10.1038/psp.2013.59; advance online publication 13 November 2013.
    • Population Pharmacokinetics of Piperaquine after Two Different Treatment Regimens with Dihydroartemisinin-Piperaquine in Patients with Plasmodium falciparum Malaria in Thailand.

      Tarning, J; Ashley, E A; Lindegardh, N; Stepniewska, K; Phaiphun, L; Day, N P J; McGready, R; Ashton, M; Nosten, F; White, N J; Mahidol - Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. nickw@tropmedres.ac. (American Society for Microbiology, 2008-03)
      The population pharmacokinetics of piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria treated with two different dosage regimens of dihydroartemisinin-piperaquine were characterized. Piperaquine pharmacokinetics in 98 Burmese and Karen patients aged 3 to 55 years were described by a two-compartment disposition model with first-order absorption and interindividual random variability on all parameters and were similar with the three- and four-dose regimens. Children had a lower body weight-normalized oral clearance than adults, resulting in longer terminal elimination half-lives and higher total exposure to piperaquine (area under the concentration-time curve from 0 to 63 days [AUC(day 0-63)]). However, children had lower plasma concentrations in the therapeutically relevant posttreatment prophylactic period (AUC(day 3-20)) because of smaller body weight-normalized central volumes of distribution and shorter distribution half-lives. Our data lend further support to a simplified once-daily treatment regimen to improve treatment adherence and efficacy and indicate that weight-adjusted piperaquine doses in children may need to be higher than in adults.
    • Severe acute malnutrition results in lower lumefantrine exposure in children treated with artemether-lumefantrine for uncomplicated malaria

      Chotsiri, P; Denoeud-Ndam, L; Baudin, E; Guindo, O; Diawara, H; Attaher, O; Smit, M; Guerin, PJ; Duombo, OK; Weisner, L; Barnes, KI; Hoglund, RM; Dicko, A; Etard, JF; Tarning, J (American Society for Clinical Pharmacology and Therapeutics, 2019-06-01)
      Severe acute malnutrition (SAM) has been reported to be associated with increased malaria morbidity in Sub‐Saharan African children and may affect the pharmacology of antimalarial drugs. This population pharmacokinetic‐pharmacodynamic study included 131 SAM and 266 non‐SAM children administered artemether‐lumefantrine twice daily for 3 days. Lumefantrine capillary plasma concentrations were adequately described by two transit‐absorption compartments followed by two distribution compartments. Allometrically scaled body weight and an enzymatic maturation effect were included in the pharmacokinetic model. Mid‐upper arm circumference (MUAC) was associated with decreased absorption of lumefantrine (25.4% decrease per 1 cm reduction). Risk of recurrent malaria episodes (i.e. reinfection) were characterised by an interval‐censored time‐to‐event model with a sigmoid EMAX‐model describing the effect of lumefantrine. SAM children were at risk of under‐exposure to lumefantrine and an increased risk of malaria reinfection compared to well‐nourished children. Research on optimised regimens should be considered for malaria treatment in malnourished children.