Day 7 concentration effects of partner drugs of artemisinin and derivatives on recurrent episodes of uncomplicated Plasmodium falciparum malaria after repetitive treatment with the same drug during two years in Mali

The recommendation of artemisinin-based combination therapy (ACT) as a first line treatment of malaria continues to be based only on data obtained from single episode treatment rather than repetitive treatment. However, malaria episodes are frequent and there is thus a need to understand the long-term impact of repeated use of ACT to treat consecutive episodes of malaria over successive seasons. My study aimed to define the risk of parasite recurrence as a function of the pharmacokinetic and pharmacodynamic characteristics of ACT partner drugs in patients re-treated for multiple malaria episodes. Participants from Mali were randomized into three treatment arms: dihydroartemisinin-piperaquine (DHA-PPQ), pyronaridine-artesunate (PA), and first-line ACT (either artemether-lumefantrine [AL] or artesunate-amodiaquine [ASAQ]). Participants received the same ACT for each new episode of malaria for two years. Clinical and parasitological data were collected at each visit. Plasma samples were collected at day 7 of follow-up for quantification of drugs using high-performance liquid chromatography methods. In total, study participants experienced 5,260 episodes of malaria during the two-year follow-up period. Major findings were: i) accumulation of desethylamodiaquine (DEAQ), the main and active metabolite of amodiaquine (AQ), in the study population after early (between 25 to 45 days) retreatment with ASAQ; ii) no association of DEAQ concentration on day 7 with treatment outcome; iii) an association between day 7 lumefantrine concentrations and a reduced risk of re-infections within day 28 follow-up (hazard ratio, HR = 0.605, CI (0.50 – 0.74), p < 0.001). This protection of lumefantrine was concentration dependent; a concentration below a threshold of 380 ng/ml did not protect against subsequent re-infection by day 28. Importantly, the majority of the children under five years (84 out of 140; 60%) had lumefantrine day 7 concentrations (median (interquartile range): 305 ng/ml (207 – 490 ng/ml)) below this threshold. In conclusion, my results demonstrated an accumulation of DEAQ in the study population after early re-treatment with ASAQ, and suggest a need of lumefantrine dose optimisation in under five years age group. My analyses also showcase the value of re-treatment studies for improving treatment recommendations

Efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria: revisiting molecular markers in an area of emerging AQ and SP resistance in Mali

<p>Abstract</p> <p>Background</p> <p>To update the National Malaria Control Programme of Mali on the efficacy of chloroquine, amodiaquine and sulphadoxine-pyrimethamine in the treatment of uncomplicated <it>falciparum </it>malaria.</p> <p>Methods</p> <p>During the malaria transmission seasons of 2002 and 2003, 455 children – between six and 59 months of age, with uncomplicated malaria in Kolle, Mali, were randomly assigned to one of three treatment arms. <it>In vivo </it>outcomes were assessed using WHO standard protocols. Genotyping of <it>msp1</it>, <it>msp2 </it>and CA1 polymorphisms were used to distinguish reinfection from recrudescent parasites (molecular correction).</p> <p>Results</p> <p>Day 28 adequate clinical and parasitological responses (ACPR) were 14.1%, 62.3% and 88.9% in 2002 and 18.2%, 60% and 85.2% in 2003 for chloroquine, amodiaquine and sulphadoxine-pyrimethamine, respectively. After molecular correction, ACPRs (cACPR) were 63.2%, 88.5% and 98.0% in 2002 and 75.5%, 85.2% and 96.6% in 2003 for CQ, AQ and SP, respectively. Amodiaquine was the most effective on fever. Amodiaquine therapy selected molecular markers for chloroquine resistance, while in the sulphadoxine-pyrimethamine arm the level of <it>dhfr </it>triple mutant and <it>dhfr</it>/<it>dhps </it>quadruple mutant increased from 31.5% and 3.8% in 2002 to 42.9% and 8.9% in 2003, respectively. No infection with <it>dhps </it>540E was found.</p> <p>Conclusion</p> <p>In this study, treatment with sulphadoxine-pyrimethamine emerged as the most efficacious on uncomplicated falciparum malaria followed by amodiaquine. The study demonstrated that sulphadoxine-pyrimethamine and amodiaquine were appropriate partner drugs that could be associated with artemisinin derivatives in an artemisinin-based combination therapy.</p

Effects of amodiaquine and artesunate on sulphadoxine-pyrimethamine pharmacokinetic parameters in children under five in Mali

<p>Abstract</p> <p>Background</p> <p>Sulphadoxine-pyrimethamine, in combination with artesunate or amodiaquine, is recommended for the treatment of uncomplicated malaria and is being evaluated for intermittent preventive treatment. Yet, limited data is available on pharmacokinetic interactions between these drugs.</p> <p>Methods</p> <p>In a randomized controlled trial, children aged 6-59 months with uncomplicated <it>falciparum </it>malaria, received either one dose of sulphadoxine-pyrimethamine alone (SP), one dose of SP plus three daily doses of amodiaquine (SP+AQ) or one dose of SP plus 3 daily doses of artesunate (SP+AS). Exactly 100 μl of capillary blood was collected onto filter paper before drug administration at day 0 and at days 1, 3, 7, 14, 21 and 28 after drug administration for analysis of sulphadoxine and pyrimethamine pharmacokinetic parameters.</p> <p>Results</p> <p>Fourty, 38 and 31 patients in the SP, SP+AQ and SP+AS arms, respectively were included in this study. The concentrations on day 7 (that are associated with therapeutic efficacy) were similar between the SP, SP+AQ and SP+AS treatment arms for sulphadoxine (median [IQR] 35.25 [27.38-41.70], 34.95 [28.60-40.85] and 33.40 [24.63-44.05] μg/mL) and for pyrimethamine (56.75 [46.40-92.95], 58.75 [43.60-98.60] and 59.60 [42.45-86.63] ng/mL). There were statistically significant differences between the pyrimethamine volumes of distribution (4.65 [3.93-6.40], 4.00 [3.03-5.43] and 5.60 [4.40-7.20] L/kg; <it>p = 0.001</it>) and thus elimination half-life (3.26 [2.74 -3.82], 2.78 [2.24-3.65] and 4.02 [3.05-4.85] days; <it>p < 0.001</it>). This study confirmed the lower SP concentrations previously reported for young children when compared with adult malaria patients.</p> <p>Conclusion</p> <p>Despite slight differences in pyrimethamine volumes of distribution and elimination half-life, these data show similar exposure to SP over the critical initial seven days of treatment and support the current use of SP in combination with either AQ or AS for uncomplicated <it>falciparum </it>malaria treatment in young Malian children.</p

Quinine Treatment Selects the pfnhe-1 ms4760-1 Polymorphism in Malian Patients with Falciparum Malaria

Background. The mechanism of Plasmodium falciparum resistance to quinine is not known. In vitro quantitative trait loci mapping suggests involvement of a predicted P. falciparum sodium-hydrogen exchanger (pfnhe-1) on chromosome 13. Methods. We conducted prospective quinine efficacy studies in 2 villages, Kolle and Faladie, Mali. Cases of clinical malaria requiring intravenous therapy were treated with standard doses of quinine and followed for 28 days. Treatment outcomes were classified using modified World Health Organization protocols. Molecular markers of parasite polymorphisms were used to distinguish recrudescent parasites from new infections. The prevalence of pfnhe-1 ms4760-1 among parasites before versus after quinine treatment was determined by direct sequencing. Results. Overall, 163 patients were enrolled and successfully followed. Without molecular correction, the mean adequate clinical and parasitological response (ACPR) was 50.3% (n = 163). After polymerase chain reaction correction to account for new infections, the corrected ACPR was 100%. The prevalence of ms4760-1 increased significantly, from 26.2% (n = 107) before quinine treatment to 46.3% (n = 54) after therapy (P = .01). In a control sulfadoxine-pyrimethamine study, the prevalence of ms4760-1 was similar before and after treatment. Conclusions. This study supports a role for pfnhe-1 in decreased susceptibility of P. falciparum to quinine in the field.Howard Hughes Medical Institute [55005502]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; European and Developing Countries Clinical Trials Partnership [EDCTP IP_07_31060_002]info:eu-repo/semantics/publishedVersio

Overall and Gender-Specific Effects of Intermittent Preventive Treatment of Malaria with Artemisinin-Based Combination Therapies among Schoolchildren in Mali: A Three-Group Open Label Randomized Controlled Trial.

Intermittent preventive treatment of malaria among schoolchildren (IPTsc) reduces clinical malaria, asymptomatic parasitemia, and anemia. The effects of IPTsc by gender have not been studied longitudinally. We investigated overall IPTsc efficacy and conducted a secondary analysis to explore gender-specific differences. We enrolled schoolchildren aged 6-13 years in an open-label, rolling-cohort randomized controlled trial between September 2007 and February 2013 in Kolle, Mali. Annually, schoolchildren received two full-treatment courses of sulfadoxine-pyrimethamine (SP) plus artesunate, or amodiaquine (AQ) plus artesunate, or no malaria treatment as control. We used mixed-effects generalized linear models to estimate differences in treatment outcomes across groups with interaction terms to explore gender-specific differences associated with Plasmodium falciparum infection, hemoglobin, and grade point averages (GPA) based on standardized testing. Overall, 305 students contributed 4,564 observations. Compared with the control, SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection (odds ratio [OR]: 0.33, 95% CI: 0.26-0.43; OR: 0.46, 95% CI: 0.36-0.59). We found strong evidence of increased mean hemoglobin concentrations (g/dL) in the SP plus artesunate group versus control (difference +0.37, 95% CI: 0.13-0.58). Collectively, schoolchildren given AQ plus artesunate had higher mean GPA (difference +0.36, 95% CI: 0.02-0.69) relative to control. Schoolgirls, compared with schoolboys, given SP plus artesunate had greater improvement in GPA (+0.50, 95% CI: -0.02 to 1.02 versus -0.27, 95% CI: -0.71 to 0.16); interaction P = 0.048, respectively. The IPTsc decreases P. falciparum infections in schoolchildren. Treatment regimens that include longer-acting drugs may be more effective at decreasing malaria-related anemia and improving educational outcomes as observed among girls in this setting

Host candidate gene polymorphisms and clearance of drug-resistant Plasmodium falciparum parasites

Resistance to anti-malarial drugs is a widespread problem for control programmes for this devastating disease. Molecular tests are available for many anti-malarial drugs and are useful tools for the surveillance of drug resistance. However, the correlation of treatment outcome and molecular tests with particular parasite markers is not perfect, due in part to individuals who are able to clear genotypically drug-resistant parasites. This study aimed to identify molecular markers in the human genome that correlate with the clearance of malaria parasites after drug treatment, despite the drug resistance profile of the protozoan as predicted by molecular approaches

SNPs on ABC Transporters and in vivo Malaria Parasite Non Clearance after Chloroquine Treatment in Malian Children

Background: pfcrt K76T mutation was demonstrated to play a central role in the P. falciparum resistance to chloroquine. Aim: To find any association between mutant alleles of pfcrt K76T, pfmdr1 N86Y, pfG30 and pfG47 and the in vivo parasite non clearance after chloroquine treatment in Mali. Methodology: We carried out a chloroquine efficacy study in 196 children suffering from uncomplicated malaria in a rural village of Kollé, Mali, using WHO protocol. Subjects were treated with standard dose of chloroquine and followed for 14 days. Parasite DNA was extracted from finger prick blood blotted onto filter paper and genotypes were analyzed by different PCR methods. Results: The mutant alleles pfcrt 76T and pfmdr1 86Y were associated with parasite non clearance with p=0.00001 and 0.03 respectively. However, the association of SNPs on pfG30 and pfG47 genes with parasite non clearance was not statistically significant, p =0.43 and 0.57 respectively. The logistic regression analysis showed that the mutant allele pfmdr186Y contributed positively to the pfcrt 76T parasites non clearance (p=0.02). Conclusion: These findings have shown that pfcrt76T and pfmdr1 86Y alleles are associated with the in vivo parasite non clearance, but not SNPs on the new putative transporters genes

Pharmacokinetic and pharmacodynamic characteristics of a new pediatric formulation of artemether-lumefantrine in African children with uncomplicated Plasmodium falciparum malaria.

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria

Population Pharmacokinetic properties of Sulfadoxine and Pyrimethamine: A pooled analysis to Inform Optimal Dosing in African Children with Uncomplicated Malaria.

Sulfadoxine/pyrimethamine with amodiaquine is recommended by the World Health Organization as seasonal malaria chemoprevention for children between 3 to 59 months in the sub-Sahel regions of Africa. Sub-optimal dosing in children may lead to treatment failure and increased resistance. Pooled individual patient data from four previously published trials on the pharmacokinetics of sulfadoxine and pyrimethamine in 415 paediatric and 386 adult patients were analysed using nonlinear mixed effects modelling to evaluate the current dosing regimen and, if needed, propose an optimised dosing regimen in children under five years old. The population pharmacokinetics of sulfadoxine and pyrimethamine were both best described by a one-compartment disposition model, with first-order absorption and elimination. Body weight, age and nutrition status (measured as weight-for-age z-scores) were found to be significant covariates. Allometric scaling with total body weight and maturation of clearance in children using post-gestational age improved the model fit. Underweight-for-age children were found to have 15.3% and 26.7% lower bioavailability of sulfadoxine and pyrimethamine, respectively, for each z-score unit below minus 2. Under current dosing recommendations, simulation predicted that the median day 7 concentration was below the 25 percentile of a typical adult patient (50 kg) for sulfadoxine for patients in 8-9, 19-24, 46-49 and 74-79 kg weight bands, and for pyrimethamine for the weight-bands 8-9, 14-24 and 42-49 kg. An evidence-based dosing regimen was constructed that would achieve sulfadoxine and pyrimethamine exposure in young children and underweight-for-age young children that was similar to that currently seen in a typical adult. [Abstract copyright: Copyright © 2018 de Kock et al.

Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria▿

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to <15 kg, 15 and <25 kg, and 25 to <35 kg). Treatment was administered twice daily over 3 days. Plasma concentrations of artemether and its active metabolite, dihydroartemisinin (DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (Cmax) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population Cmax were 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA Cmax and parasite clearance time or between the lumefantrine Cmax and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria