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      Population pharmacokinetics of mefloquine, piperaquine and artemether-lumefantrine in Cambodian and Tanzanian malaria patients

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          Abstract

          Background

          Inter-individual variability in plasma concentration-time profiles might contribute to differences in anti-malarial treatment response. This study investigated the pharmacokinetics of three different forms of artemisinin combination therapy (ACT) in Tanzania and Cambodia to quantify and identify potential sources of variability.

          Methods

          Drug concentrations were measured in 143 patients in Tanzania (artemether, dihydroartemisinin, lumefantrine and desbutyl-lumefantrine), and in 63 (artesunate, dihydroartemisinin and mefloquine) and 60 (dihydroartemisinin and piperaquine) patients in Cambodia. Inter- and intra-individual variabilities in the pharmacokinetic parameters were assessed and the contribution of demographic and other covariates was quantified using a nonlinear mixed-effects modelling approach (NONMEM ®).

          Results

          A one-compartment model with first-order absorption from the gastrointestinal tract fitted the data for all drugs except piperaquine (two-compartment). Inter-individual variability in concentration exposure was about 40% and 12% for mefloquine. From all the covariates tested, only body weight (for all antimalarials) and concomitant treatment (for artemether only) showed a significant influence on these drugs’ pharmacokinetic profiles. Artesunate and dihydroartemisinin could not be studied in the Cambodian patients due to insufficient data-points. Modeled lumefantrine kinetics showed that the target day 7 concentrations may not be achieved in a substantial proportion of patients.

          Conclusion

          The marked variability in the disposition of different forms of ACT remained largely unexplained by the available covariates. Dosing on body weight appears justified. The concomitance of unregulated drug use (residual levels found on admission) and sub-optimal exposure (variability) could generate low plasma levels that contribute to selecting for drug-resistant parasites.

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          Most cited references46

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          Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria.

          The objective of this study was to conduct a prospective population pharmacokinetic and pharmacodynamic evaluation of lumefantrine during blinded comparisons of artemether-lumefantrine treatment regimens in uncomplicated multidrug-resistant falciparum malaria. Three combination regimens containing an average adult lumefantrine dose of 1,920 mg over 3 days (four doses) (regimen A) or 2,780 mg over 3 or 5 days (six doses) (regimen B or C, respectively) were given to 266 Thai patients. Detailed observations were obtained for 51 hospitalized adults, and sparse data were collected for 215 patients of all ages in a community setting. The population absorption half-life of lumefantrine was 4.5 h. The model-based median (5th and 95th percentiles) peak plasma lumefantrine concentrations were 6.2 (0.25 and 14.8) microgram/ml after regimen A, 9. 0 (1.1 and 19.8) microgram/ml after regimen B, and 8 (1.4 and 17.4) microgram/ml after regimen C. During acute malaria, there was marked variability in the fraction of drug absorbed by patients (coefficient of variation, 150%). The fraction increased considerably and variability fell with clinical recovery, largely because food intake was resumed; taking a normal meal close to drug administration increased oral bioavailability by 108% (90% confidence interval, 64 to 164) (P, 0.0001). The higher-dose regimens (B and C) gave 60 and 100% higher areas under the concentration-time curves (AUC), respectively, and thus longer durations for which plasma lumefantrine concentrations exceeded the putative in vivo MIC of 280 microgram/ml (median for regimen B, 252 h; that for regimen C, 298 h; that for regimen A, 204 h [P, 0.0001]) and higher cure rates. Lumefantrine oral bioavailability is very dependent on food and is consequently poor in acute malaria but improves markedly with recovery. The high cure rates with the two six-dose regimens resulted from increased AUC and increased time at which lumefantrine concentrations were above the in vivo MIC.
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            Molecular and pharmacological determinants of the therapeutic response to artemether-lumefantrine in multidrug-resistant Plasmodium falciparum malaria.

            Our study examined the relative contributions of host, pharmacokinetic, and parasitological factors in determining the therapeutic response to artemether-lumefantrine (AL). On the northwest border of Thailand, patients with uncomplicated Plasmodium falciparum malaria were enrolled in prospective studies of AL treatment (4- or 6-dose regimens) and followed up for 42 days. Plasma lumefantrine concentrations were measured by high performance liquid chromatography; malaria parasite pfmdr1 copy number was quantified using a real-time polymerase chain reaction assay (PCR), and in vitro drug susceptibility was tested. All treatments resulted in a rapid clinical response and were well tolerated. PCR-corrected failure rates at day 42 were 13% (95% confidence interval [CI], 9.6%-17%) for the 4-dose regimen and 3.2% (95% CI, 1.8%-4.6%) for the 6-dose regimen. Increased pfmdr1 copy number was associated with a 2-fold (95% CI, 1.8-2.4-fold) increase in lumefantrine inhibitory concentration(50) (P=.001) and an adjusted hazard ratio for risk of treatment failure following completion of a 4-dose regimen, but not a 6-dose regimen, of 4.0 (95% CI, 1.4-11; P=.008). Patients who had lumefantrine levels below 175 ng/mL on day 7 were more likely to experience recrudescence by day 42 (adjusted hazard ratio, 17; 95% CI, 5.5-53), allowing prediction of treatment failure with 75% sensitivity and 84% specificity. The 6-dose regimen ensured that therapeutic levels were achieved in 91% of treated patients. The lumefantrine plasma concentration profile is the main determinant of efficacy of artemether-lumefantrine. Amplification in pfmdr1 determines lumefantrine susceptibility and, therefore, treatment responses when plasma lumefantrine levels are subtherapeutic.
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              The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia

              Background Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. Methods A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. Results The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32–3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. Conclusion Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved.
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                Author and article information

                Journal
                Malar J
                Malar. J
                Malaria Journal
                BioMed Central
                1475-2875
                2013
                10 July 2013
                : 12
                : 235
                Affiliations
                [1 ]Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland
                [2 ]School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
                [3 ]Division of Clinical Pharmacology and Toxicology, Department of Laboratories, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
                [4 ]National Center for Parasitology, Entomology and Malaria Control, Phnom Penh, Cambodia
                [5 ]Ifakara Health Institute, Dar es Salaam, Tanzania
                [6 ]Institut Pasteur in Cambodia, Molecular Epidemiology UnitInstitut Pasteur in Cambodia, Molecular Epidemiology Unit, Phnom Penh, Cambodia
                [7 ]UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland
                [8 ]Department of Ambulatory Care and Community Medicine & Division of Infectious Diseases, University Hospital, Lausanne, Switzerland
                Article
                1475-2875-12-235
                10.1186/1475-2875-12-235
                3720542
                23841950
                9970af34-48e6-43c8-9279-bddd4388e501
                Copyright ©2013 Staehli Hodel et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 March 2013
                : 28 June 2013
                Categories
                Research

                Infectious disease & Microbiology
                lumefantrine,malaria,population pharmacokinetics,artemisinin-based combination therapy,tanzania,cambodia,piperaquine,mefloquine,artemether,nonlinear mixed-effects modelling

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