Date Published: June 12, 2018
Publisher: Public Library of Science
Author(s): Frank Kloprogge, Lesley Workman, Steffen Borrmann, Mamadou Tékété, Gilbert Lefèvre, Kamal Hamed, Patrice Piola, Johan Ursing, Poul Erik Kofoed, Andreas Mårtensson, Billy Ngasala, Anders Björkman, Michael Ashton, Sofia Friberg Hietala, Francesca Aweeka, Sunil Parikh, Leah Mwai, Timothy M. E. Davis, Harin Karunajeewa, Sam Salman, Francesco Checchi, Carole Fogg, Paul N. Newton, Mayfong Mayxay, Philippe Deloron, Jean François Faucher, François Nosten, Elizabeth A. Ashley, Rose McGready, Michele van Vugt, Stephane Proux, Ric N. Price, Juntra Karbwang, Farkad Ezzet, Rajesh Bakshi, Kasia Stepniewska, Nicholas J. White, Philippe J. Guerin, Karen I. Barnes, Joel Tarning, James G. Beeson
Abstract: BackgroundThe 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.Methods and findingsA search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15–25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.ConclusionsOur findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.
Partial Text: Malaria is a major infectious disease in tropical countries, with an estimated 212 (range 148–304) million infections and 429,000 (range 235,000–639,000) deaths in 2015 . Over 90% of the global malaria mortality is reported in sub-Saharan Africa. Children under 5 years of age are the most vulnerable, accounting for 70% of all malaria-related deaths . The World Health Organization recommends that uncomplicated Plasmodium falciparum malaria should be treated with an artemisinin-based combination therapy (ACT) . Artemether-lumefantrine (AL) is the most widely used ACT, accounting for 73% of global ACT procurement in 2013 , which makes it one of the most widely used anti-infective agents in the world today. Furthermore, AL is well tolerated and safe for the treatment of uncomplicated P. falciparum (and other malaria species) infections in all age groups. This includes young children and pregnant women in their second and third trimesters, groups with increased morbidity and mortality from falciparum malaria . Sub-optimal drug exposures have been reported following currently recommended doses of AL both in young children and pregnant women in their second and third trimesters [4–12]. On the other hand, similar exposure in pregnant women during their second and third trimester compared to non-pregnant women has also been observed, although the non-pregnant women in this study might not have been as symptomatic as the pregnant women . Moreover, the numbers of patients recruited to these clinical trials were generally small, and differences in study design including selection of comparator therapies and dose regimens and co-administration with fat [14,15] all limit the generalisability of the findings. A meta-analysis could potentially overcome this by pooling individual patient level data from several different studies and characterising both pharmacological properties and the influence of differences in study design, study size, comparator therapies, dose regimens, and inconsistent co-administration with fat. Lumefantrine exposure at day 7 has been evaluated in a meta-analysis previously, but not using a dynamic modelling approach to characterise and quantify pharmacological properties, the influence of covariates, and the relationship between drug concentrations and study outcome .
Lumefantrine concentration-time data from 4,122 patients from 26 studies were uploaded to the WWARN pharmacology database (Fig 1; S1 Table). These data were categorised into 3 different geographic areas (Africa, Oceania, and Southeast Asia) comprising 12 countries (Benin, Guinea-Bissau, Tanzania, Uganda, Kenya, Mali, Mozambique, Liberia, Papua New Guinea, Lao People’s Democratic Republic [Laos], Thailand, and Cambodia). Lumefantrine concentrations were available for analysis in 4 different matrices: 2,312 patients contributed venous plasma samples, 595 patients contributed venous whole blood samples, 191 patients contributed capillary plasma samples, and 840 patients contributed capillary whole blood samples. In total, 154 patients were excluded from the analysis, 71 because of missing dosing information and 83 who took repeated dosing (i.e., retreatment). A further 30 patients were excluded from the evaluation of pre-treatment parasitaemia as a covariate because relevant parasitological data were missing. Venous plasma data from 1,347 out of 2,312 patients who contributed at least 2 samples was used for the development of the lumefantrine population pharmacokinetic model. The remaining 400, 278, and 287 patients contributed only 1 venous plasma sample per patient after treatment with intact, crushed, and dispersible tables, respectively, and were therefore only used for external validation and evaluation of formulation effects in a separate analysis (Table 1). Approximately 37% of the patients were children below 10 years of age and 3.12% were pregnant women (median [range: interquartile range] 23.0 [13.1–38.0: 19.1–30.0] weeks gestational age). Data from 3,486 patients were available for the development of the pharmacokinetic-pharmacodynamic time-to-event model. Approximately 59% of the patients were below 10 years of age and 4.7% were pregnant women (median [range: interquartile range] 22.0 [13.1–39.0: 18.5–28.0] weeks gestational age). Venous plasma data from 159 patients were used for the development of the simultaneous lumefantrine/desbutyl-lumefantrine population pharmacokinetic model. Approximately 57% of the patients were below 10 years of age and 8.81% were pregnant women (median [range: interquartile range] 23.4 [16.2–38.0: 20.8–30.4] weeks gestational age).
The population pharmacokinetic model based on this covariate-rich dataset from nearly 4,000 patients provides an improved understanding of how body weight, pregnancy, dosage, and admission parasitaemia affect the absorption, distribution, and elimination of the most important and widely used anti-malarial therapy in current use. By applying a pharmacokinetic-pharmacodynamic time-to-event model to this dataset, we have made, to the best of our knowledge, the first comprehensive attempt to evaluate the relationship between pharmacokinetic factors and AL treatment outcome (PCR-corrected recrudescent malaria infections) across different geographical areas and populations. The lumefantrine/desbutyl-lumefantrine population pharmacokinetic model provides an improved understanding of the disposition effect of lumefantrine’s main active metabolite, which had hitherto remained poorly characterised. Young children and pregnant women have lower lumefantrine exposures compared with non-pregnant adults. The reason that young children have relatively low lumefantrine exposure is that currently recommended AL dosage regimens do not adjust adequately for the non-linear relationship between body weight and systemic exposure. Pregnant women were underexposed due to changes in the distribution kinetics of lumefantrine. Underexposure in these vulnerable populations contributes to lower cure rates and the selection of parasite resistance. In silico dose optimisations utilising the lumefantrine population pharmacokinetic model provide a sound basis for proposing improved dosing regimens for these 2 vulnerable groups.