Lumefantrine

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Niklas Lindegardh - One of the best experts on this subject based on the ideXlab platform.

  • population pharmacokinetics of Lumefantrine in pregnant and nonpregnant women with uncomplicated plasmodium falciparum malaria in uganda
    CPT: Pharmacometrics & Systems Pharmacology, 2013
    Co-Authors: Frank Kloprogge, Niklas Lindegardh, Mehul Dhorda, Patrice Piola, Sulaiman Muwanga, Eleanor Turyakira, S Apinan
    Abstract:

    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 and pharmacodynamics of artemether and Lumefantrine during combination treatment in children with uncomplicated falciparum malaria in tanzania
    Antimicrobial Agents and Chemotherapy, 2010
    Co-Authors: Sofia Friberg Hietala, Anna Annerberg, Niklas Lindegardh, Andreas Martensson, Billy Ngasala, Sabina Dahlstrom, Zul Premji, Anna Farnert
    Abstract:

    The combination of artemether (ARM) and Lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to Lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and Lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and Lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of Lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.

  • population pharmacokinetics of Lumefantrine in pregnant women treated with artemether Lumefantrine for uncomplicated plasmodium falciparum malaria
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Niklas Lindegardh, Joel Tarning, Elizabeth A Ashley, Rose Mcgready, Mupawjay Pimanpanarak, Benjamas Kamanikom, Anna Annerberg
    Abstract:

    Artemether-Lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of Lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-Lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of Lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of Lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of Lumefantrine contribute to the high rates of failure of artemether-Lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

  • adherence and efficacy of supervised versus non supervised treatment with artemether Lumefantrine for the treatment of uncomplicated plasmodium falciparum malaria in bangladesh a randomised controlled trial
    Transactions of The Royal Society of Tropical Medicine and Hygiene, 2008
    Co-Authors: Md Mushfiqur Rahman, Niklas Lindegardh, Nicholas P J Day, Arjen M Dondorp, Mallika Imwong, M A Faiz, Mannan A Bangali
    Abstract:

    As artemether/Lumefantrine is now deployed as the first-line treatment for uncomplicated falciparum malaria in Bangladesh, information on its efficacy and adherence to its use is important. A randomised controlled non-inferiority trial comparing directly observed treatment (DOT) and non-directly observed treatment (NDOT) was conducted in 320 patients with uncomplicated falciparum malaria in Bandarban Hill Tract District, Bangladesh. Both regimens showed similar high levels of PCR-corrected 42-day parasitological and clinical cure rates (99.3% in the NDOT group and 100% in the DOT group; P=0.49). Survival analysis for the time to recurrence of infection showed no difference between treatment groups (log rank, P=0.98). Adherence, as assessed by counting remaining tablets and oral interviews, was 93% in the NDOT group and was confirmed by Day 7 Lumefantrine concentrations. Adherence was independent of educational level. Patients with plasma Lumefantrine concentrations < 280 ng/ml at Day 7 were at greater risk for re-infection (relative risk 5.62; P=0.027). The efficacy of artemether/Lumefantrine for the treatment of uncomplicated falciparum malaria in Bangladesh is high and is similar for DOT and NDOT. Adherence to therapy is high.

  • pharmacokinetic study of artemether Lumefantrine given once daily for the treatment of uncomplicated multidrug resistant falciparum malaria
    Tropical Medicine & International Health, 2007
    Co-Authors: Anna Annerberg, Niklas Lindegardh, Elizabeth A Ashley, Rose Mcgready, Kasia Stepniewska, Robert Hutagalung
    Abstract:

    Summary Background  Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether–Lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. Methods  In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma Lumefantrine concentration–time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Results  Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC(0∞) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114–5781) μg/ml h, compared with 432 (308–992) μg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84–100) in the six-dose arm and 85% (70–100) in the three-dose arm (P = 0.3). Conclusion  Artemether–Lumefantrine efficacy is reduced by once-daily dosing, because absorption of Lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat. Donnees de base  La compliance aux traitements a base d'antimalariques est amelioree par des doses simples. Si la combinaison a dose fixe d'antimalariques artemether–Lumefantrine pouvait etre administree une fois par jour, cela devrait ameliorer la compliance et donc l'efficacite, et reduire le risque de selection de resistance. Methodes  dans une etude randomisee ouverte, 43 patients presentant une malaria falciparum non compliquee ont recu des doses equivalentes d'artemether–Lumefantrine avec 200 ml de lait aromatise, selon le regime conventionnel i.e: deux fois par jour ou selon un regime a une seule dose quotidienne pendant 3 jours. L'objectif final primaire etait la comparaison des aires sous la courbe (AUC) de la concentration plasmatique de Lumefantrine en fonction du temps. Les objectifs secondaires etaient la mesure des taux de guerison ajustes par les resultats de la reaction en chaine de la polymerase (PCR) au jour 42ieme et les profils de tolerance. Resultats  Les profils pharmacocinetiques de Lumefantrine ont ete obtenus pour 36 patients. Les AUC(0∞) dans le regime ‘‘une fois par jour’’etait 30% inferieur a celles dans le regime conventionnel (p = 0,011) avec une valeur mediane de 306 (114–5781) μg/ml h comparea 432 (308–992) μg/ml h. Il n'y avait aucune difference significative dans les concentrations plasmatiques maximales atteintes. Les taux de guerison ajustes par la PCR au 42ieme jour du suivi etaient de 94% (IC95%: 84–100) dans le groupe a 6 doses et 85% (IC95%: 70–100) dans le groupe a 3 doses (p = 0,3). Conclusion  L'efficacite de l'Artemether–Lumefantrine est reduite dans le regime ‘'une fois par jour‘’ parce que l'absorption du Lumefantrine est dose dependante. Aux doses recommandees actuellement, cet antimalarique devrait etre administre deux fois par jour dans un regime de trois jours, avec la nourriture contenant la matiere grasse. Antecedentes  La adherencia al tratamiento con antimalaricos mejora si se simplifica la dosificacion. Si se pudiese dar la combinacion fija de antimalaricos artemeter–lumefantrina (AL) en una dosis unica por dia, deberia mejorar la adherencia y por lo tanto la efectividad del tratamiento, habiendo un menor riesgo de seleccion de cepas resistentes. Metodos  En un ensayo abierto, aleatorizado, en el que 43 pacientes con malaria no complicada por falciparum recibieron durante tres dias dosis equivalentes de AL con 200ml de leche, bien bajo el regimen convencional de dos veces al dia o en una dosis unica cada dia. El criterio principal de valoracion fue una comparacion de las areas bajo las curvas de la concentracion de lumefantrina en plasma a lo largo del tiempo (ABC). Los criterios secundarios de valoracion fueron las PCR del dia 42, las tasas de curacion ajustadas y los perfiles de tolerabilidad. Resultados  Se obtuvieron los perfiles farmacocineticos de la lumefantrina para 36 pacientes. El ABC (0∞) del regimen unico al dia era un 30% mas bajo que el regimen convencional (p = 0.011) con una media (rango) de 306 (114–5781) μg/ml h comparado con 432 (308–992) μg/ml h. No habia una diferencia significativa entre las maximas concentraciones de plasma alcanzadas. Las tasas de curacion ajustadas por PCR a los 42 dias de seguimiento fueron 94% (95%CI 84–100) para el grupo con 6 dosis y 85% (70–100) para los que recibieron 3 dosis (p = 0.3). Conclusion  La eficacia de artemeter–lumefantrina se reduce al dar una dosis unica, puesto que la absorcion de la lumefantrina esta limitada por la dosis. En las dosis recomendadas en la actualidad, este antimalarico deberia darse dos veces al dia en un regimen de tres dias, acompa,nado con alimentos que contengan grasas.

Nicholas J. White - One of the best experts on this subject based on the ideXlab platform.

  • Lumefantrine attenuates plasmodium falciparum artemisinin resistance during the early ring stage
    International Journal for Parasitology-Drugs and Drug Resistance, 2021
    Co-Authors: Krittikorn Kumpornsin, Nicholas J. White, Duangkamon Loesbanluechai, Cristina De Cozar, Namfon Kotanan, Kesinee Chotivanich, Prapon Wilairat, Maria G Gomezlorenzo, Franciscojavier Gamo, Laura M Sanz
    Abstract:

    Emerging artemisinin resistance in Plasmodium falciparum malaria has the potential to become a global public health crisis. In Southeast Asia, this phenomenon clinically manifests in the form of delayed parasite clearance following artemisinin treatment. Reduced artemisinin susceptibility is limited to the early ring stage window, which is sufficient to allow parasites to survive the short half-life of artemisinin exposure. A screen of known clinically-implemented antimalarial drugs was performed to identify a drug capable of enhancing the killing activity of artemisinins during this critical resistance window. As a result, Lumefantrine was found to increase the killing activity of artemisinin against an artemisinin-resistant clinical isolate harboring the C580Y kelch13 mutation. Isobologram analysis revealed synergism during the early ring stage resistance window, when Lumefantrine was combined with artemether, an artemisinin derivative clinically partnered with Lumefantrine. These findings suggest that Lumefantrine should be clinically explored as a partner drug in artemisinin-based combination therapies to control emerging artemisinin resistance.

  • Lumefantrine and desbutyl Lumefantrine population pharmacokinetic pharmacodynamic relationships in pregnant women with uncomplicated plasmodium falciparum malaria on the thailand myanmar border
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Frank Kloprogge, Daniel Blessborn, Nicholas J. White, Rose Mcgready, Warunee Hanpithakpong, Nicholas P J Day
    Abstract:

    Artemether-Lumefantrine is the most widely used antimalarial artemisinin-based combination treatment. Recent studies have suggested that day 7 plasma concentrations of the potent metabolite desbutyl-Lumefantrine correlate better with treatment outcomes than those of Lumefantrine. Low cure rates have been reported in pregnant women with uncomplicated falciparum malaria treated with artemether-Lumefantrine in northwest Thailand. A simultaneous pharmacokinetic drug-metabolite model was developed based on dense venous and sparse capillary Lumefantrine and desbutyl-Lumefantrine plasma samples from 116 pregnant patients on the Thailand-Myanmar border. The best model was used to evaluate therapeutic outcomes with a time-to-event approach. Lumefantrine and desbutyl-Lumefantrine concentrations, implemented in an Emax model, both predicted treatment outcomes, but Lumefantrine provided better predictive power. A combined model including both Lumefantrine and desbutyl-Lumefantrine did not improve the model further. Simulations suggested that cure rates in pregnant women with falciparum malaria could be increased by prolonging the treatment course. (These trials were registered at controlled-trials.com [ISRCTN 86353884].).

  • artemether Lumefantrine co administration with antiretrovirals population pharmacokinetics and dosing implications
    British Journal of Clinical Pharmacology, 2015
    Co-Authors: Richard M Hoglund, Pauline Byakikakibwika, Mohammed Lamorde, Nicholas J. White, Warunee Hanpithakpong, Nicholas P J Day, Concepta Merry, Michael Ashton
    Abstract:

    AIM Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, Lumefantrine, artemether and their respective metabolites desbutyl-Lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

  • pharmacokinetic properties of artemether dihydroartemisinin Lumefantrine and quinine in pregnant women with uncomplicated plasmodium falciparum malaria in uganda
    Antimicrobial Agents and Chemotherapy, 2013
    Co-Authors: Frank Kloprogge, Vincent Jullien, Joel Tarning, Mehul Dhorda, Francois Nosten, Nicholas J. White
    Abstract:

    Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and Lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, Lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 Lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total Lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens.

  • the pharmacokinetics of artemether and Lumefantrine in pregnant women with uncomplicated falciparum malaria
    European Journal of Clinical Pharmacology, 2006
    Co-Authors: Rose Mcgready, Niklas Lindegardh, Nicholas J. White, Elizabeth A Ashley, Kasia Stepniewska, Pratap Singhasivanon
    Abstract:

    To determine the pharmacokinetic properties of artemether and Lumefantrine (AL) in pregnant women with recrudescent uncomplicated multi-drug resistant falciparum malaria. Pregnant women who had recurrence of parasitaemia following 7 days supervised quinine treatment were treated with AL. Serial blood samples were taken over a 7-day period, and pharmacokinetic parameters were estimated. For Lumefantrine, these data were compared in a population pharmacokinetic model with data from non-pregnant, mainly male adults with acute malaria. The pregnant women (five in the second trimester and eight in the third trimester) had lower concentrations of artemether, dihydroartemisinin and Lumefantrine, and the elimination of Lumefantrine in pregnant women was more rapid than reported previously in non-pregnant adults. Pregnancy is associated with reduced plasma concentrations of both artemether and Lumefantrine. This is likely to be of therapeutic significance as plasma concentrations of Lumefantrine, after elimination of artemether, are an important determinant of cure. Further studies are needed to determine the optimum dose regimen of artemether-Lumefantrine in pregnancy.

Pauline Byakikakibwika - One of the best experts on this subject based on the ideXlab platform.

  • an individual participant data population pharmacokinetic meta analysis of drug drug interactions between Lumefantrine and commonly used antiretroviral treatment
    Antimicrobial Agents and Chemotherapy, 2020
    Co-Authors: Jose Francis, Karen I Barnes, Tamara Kredo, Lesley Workman, Richard M Hoglund, Lasse S Vestergaard, Pauline Byakikakibwika
    Abstract:

    Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-Lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 Lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-Lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

  • drug interactions between dolutegravir and artemether Lumefantrine or artesunate amodiaquine
    bioRxiv, 2018
    Co-Authors: Stephen Walimbwa, Alieu Amara, Pauline Byakikakibwika, Laura Else, Catriona Waitt, Julian Kaboggoza, Joshua Gini, Mohammed Lamorde, Markus Winterberg, Justin Chiong
    Abstract:

    ABSTRACT Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artmether-Lumefantrine (AL) or artesunate-amodiaquine (AS-AQ) given with 50mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artmether-Lumefantrine or artesunate-amodiaquine and DTG. The DTG/artmether-Lumefantrine interaction was evaluated in a two-way cross-over study and measured artemether (ARM), dihydroartemisinin (DHA), Lumefantrine (LF), desbutyl-Lumefantrine (DBL) over 264h. The DTG/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine (DEAQ) and measured artesunate (ARS), amodiaquine (AQ), DEAQ over 624h. Non-compartmental analysis was performed, and geometric mean ratios and 90% confidence intervals generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, time to maximum concentration and area under the concentration-time curve (AUC) for ARM, DHA, LF and DBL nor significantly alter AUC for ARS, DHA, AQ and DEAQ. Co-administration of dolutegravir with AL resulted in a 37% decrease in DTG trough concentrations. Co-administration of dolutegravir with AS-AQ resulted in a decrease of approximately 42% and 24% in DTG trough concentrations and AUC respectively. Study drugs were well-tolerated with no serious adverse events. Standard doses of artmether-Lumefantrine and artesunate-amodiaquine should be used in patients receiving DTG. The significant decreases in DTG trough concentrations with artemether-Lumefantrine and artesunate-amodiaquine and DTG exposure with artesunate-amodiaquine are unlikely to be of clinical significance as DTG trough concentrations were above DTG target concentrations of 64ng/mL.

  • artemether Lumefantrine co administration with antiretrovirals population pharmacokinetics and dosing implications
    British Journal of Clinical Pharmacology, 2015
    Co-Authors: Richard M Hoglund, Pauline Byakikakibwika, Mohammed Lamorde, Nicholas J. White, Warunee Hanpithakpong, Nicholas P J Day, Concepta Merry, Michael Ashton
    Abstract:

    AIM Drug–drug interactions between antimalarial and antiretroviral drugs may influence antimalarial treatment outcomes. The aim of this study was to investigate the potential drug–drug interactions between the antimalarial drugs, Lumefantrine, artemether and their respective metabolites desbutyl-Lumefantrine and dihydroartemisinin, and the HIV drugs efavirenz, nevirapine and lopinavir/ritonavir.

  • significant pharmacokinetic interactions between artemether Lumefantrine and efavirenz or nevirapine in hiv infected ugandan adults
    Journal of Antimicrobial Chemotherapy, 2012
    Co-Authors: Rhoda Namakula, Harriet Mayanjakizza, Pauline Byakikakibwika, Lillian Nabukeera, Jonathan Mayito, Mohammed Lamorde, Elly Katabira, Muhammad Ntale
    Abstract:

    Results: Efavirenz significantly reduced artemether maximum concentration (Cmax) and plasma AUC (median 29 versus 12 ng/mL, P,0.01, and 119 versus 25 ng .h/mL, P,0.01), dihydroartemisinin Cmax and AUC (median 120 versus 26 ng/mL, P,0.01, and 341 versus 84 ng. h/mL, P,0.01), and Lumefantrine Cmax and AUC (median 8737 versus 6331 ng/mL, P ¼ 0.03, and 280370 versus 124 381 ng .h/mL, P,0.01). Nevirapine significantly reduced artemether Cmax and AUC (median 28 versus 11 ng/mL, P, 0.01, and 123 versus 34 ng. h/mL, P,0.01) and dihydroartemisinin Cmax and AUC (median 107 versus 59 ng/mL, P,0.01, and 364 versus 228 ng . h/mL, P,0.01). Lumefantrine Cmax and AUC were non-significantly reduced by nevirapine. Artemether/Lumefantrine reduced nevirapine Cmax and AUC (median 8620 versus 4958 ng/mL, P,0.01, and 66 329 versus 35728 ng. h/mL, P,0.01), but did not affect efavirenz exposure. Conclusions: Co-administration of artemether/Lumefantrine with efavirenz or nevirapine resulted in a reduction in artemether, dihydroartemisinin, Lumefantrine and nevirapine exposure. These drug interactions may increase the risk of malaria treatment failure and development of resistance to artemether/Lumefantrine and nevirapine. Clinical data from population pharmacokinetic and pharmacodynamic trials evaluating the impact of these drug interactions are urgently needed.

  • lopinavir ritonavir significantly influences pharmacokinetic exposure of artemether Lumefantrine in hiv infected ugandan adults
    Journal of Antimicrobial Chemotherapy, 2012
    Co-Authors: Harriet Mayanjakizza, Pauline Byakikakibwika, Mohammed Lamorde, Elly Katabira, Warunee Hanpithakpong, Violet Okabakayom, Nadine Pakker, Thomas P C Dorlo
    Abstract:

    BACKGROUND Treatment of HIV/malaria-coinfected patients with antiretroviral therapy (ART) and artemisinin-based combination therapy has potential for drug interactions. We investigated the pharmacokinetics of artemether, dihydroartemisinin and Lumefantrine after administration of a single dose of 80/480 mg of artemether/Lumefantrine to HIV-infected adults, taken with and without lopinavir/ritonavir. METHODS A two-arm parallel study of 13 HIV-infected ART-naive adults and 16 HIV-infected adults stable on 400/100 mg of lopinavir/ritonavir plus two nucleoside reverse transcriptase inhibitors (ClinicalTrials.gov, NCT 00619944). Each participant received a single dose of 80/480 mg of artemether/Lumefantrine under continuous cardiac function monitoring. Plasma concentrations of artemether, dihydroartemisinin and Lumefantrine were measured. RESULTS Co-administration of artemether/Lumefantrine with lopinavir/ritonavir significantly reduced artemether maximum concentration (C(max)) and area under the concentration-time curve (AUC) [median (range): 112 (20-362) versus 56 (17-236) ng/mL, P = 0.03; and 264 (92-1129) versus 151 (38-606) ng · h/mL, P < 0.01]. Dihydroartemisinin C(max) and AUC were not affected [66 (10-111) versus 73 (31-224) ng/mL, P = 0.55; and 213 (68-343) versus 175 (118-262) ng · h/mL P = 0.27]. Lumefantrine C(max) and AUC increased during co-administration [2532 (1071-5957) versus 7097 (2396-9462) ng/mL, P < 0.01; and 41,119 (12,850-125,200) versus 199,678 (71,205-251,015) ng · h/mL, P < 0.01]. CONCLUSIONS Co-administration of artemether/Lumefantrine with lopinavir/ritonavir significantly increases Lumefantrine exposure, but decreases artemether exposure. Population pharmacokinetic and pharmacodynamic trials will be highly valuable in evaluating the clinical significance of this interaction and determining whether dosage modifications are indicated.

Philip J Rosenthal - One of the best experts on this subject based on the ideXlab platform.

  • prolonged selection of pfmdr1 polymorphisms after treatment of falciparum malaria with artemether Lumefantrine in uganda
    The Journal of Infectious Diseases, 2011
    Co-Authors: Frederick N Baliraine, Philip J Rosenthal
    Abstract:

    We compared the prevalence of key pfmdr1 alleles between pretreatment Plasmodium falciparum parasite isolates and parasites that emerged after treatment of uncomplicated malaria in a longitudinal cohort of Ugandan children. The pfmdr1 86N, 184F, and 1246D alleles were selected after treatment with artemether-Lumefantrine, but not after artesunate-amodiaquine or amodiaquine-sulfadoxine-pyrimethamine. Remarkably, selection persisted in infections presenting up to about 60 days after treatment with artemether-Lumefantrine. Thus, parasites selected for decreased drug sensitivity can appear long after predicted exposure to antimalarial drugs. Continued surveillance of the clinical efficacy and in vitro activity of new combination therapies is warranted.

  • artemether Lumefantrine versus dihydroartemisinin piperaquine for falciparum malaria a longitudinal randomized trial in young ugandan children
    Clinical Infectious Diseases, 2009
    Co-Authors: Emmanuel Arinaitwe, Abel Kakuru, Moses R Kamya, Bryan Greenhouse, Taylor Sandison, Humphrey Wanzira, Jaco Homsy, Julius N Kalamya, Neil M Vora, Philip J Rosenthal
    Abstract:

    BACKGROUND: Artemisinin-based combination therapies are now widely recommended as first-line treatment for uncomplicated malaria. However, which therapies are optimal is a matter of debate. We aimed to compare the short- and longer-term efficacy of 2 leading therapies in a cohort of young Ugandan children. METHODS: A total of 351 children aged 6 weeks to 12 months were enrolled and followed up for up to 1 year. Children who were at least 4 months of age, weighted at least 5 kg, and had been diagnosed as having their first episode of uncomplicated malaria were randomized to receive artemether-Lumefantrine or dihydroartemisinin-piperaquine. The same treatment was given for all subsequent episodes of uncomplicated malaria. Recrudescent and new infections were distinguished by polymerase chain reaction genotyping. Outcomes included the risk of recurrent malaria after individual treatments and the incidence of malaria treatments for individual children after randomization. RESULTS: A total of 113 children were randomized to artemether-Lumefantrine and 119 to dihydroartemisinin-piperaquine, resulting in 320 and 351 treatments for uncomplicated falciparum malaria, respectively. Artemether-Lumefantrine was associated with a higher risk of recurrent malaria after 28 days (35% vs 11%; P = .001]). When the duration of follow-up was extended, differences in the risk of recurrent malaria decreased such that the overall incidence of malaria treatments was similar for children randomized to artemether-Lumefantrine, compared with those randomized to dihydroartemisinin-piperaquine (4.82 vs 4.61 treatments per person-year; P = .63). The risk of recurrent malaria due to recrudescent parasites was similarly low in both treatment arms. CONCLUSIONS: Artemether-Lumefantrine and dihydroartemisinin-piperaquine were both efficacious and had similar long-term effects on the risk of recurrent malaria. Clinical trials registration. NCT00527800.

  • artemether Lumefantrine versus dihydroartemisinin piperaquine for falciparum malaria a longitudinal randomized trial in young ugandan children
    Clinical Infectious Diseases, 2009
    Co-Authors: Emmanuel Arinaitwe, Abel Kakuru, Moses R Kamya, Bryan Greenhouse, Taylor Sandison, Humphrey Wanzira, Jaco Homsy, Julius N Kalamya, Neil M Vora, Philip J Rosenthal
    Abstract:

    Background Artemisinin-based combination therapies are now widely recommended as first-line treatment for uncomplicated malaria. However, which therapies are optimal is a matter of debate. We aimed to compare the short- and longer-term efficacy of 2 leading therapies in a cohort of young Ugandan children. Methods A total of 351 children aged 6 weeks to 12 months were enrolled and followed up for up to 1 year. Children who were at least 4 months of age, weighted at least 5 kg, and had been diagnosed as having their first episode of uncomplicated malaria were randomized to receive artemether-Lumefantrine or dihydroartemisinin-piperaquine. The same treatment was given for all subsequent episodes of uncomplicated malaria. Recrudescent and new infections were distinguished by polymerase chain reaction genotyping. Outcomes included the risk of recurrent malaria after individual treatments and the incidence of malaria treatments for individual children after randomization. Results A total of 113 children were randomized to artemether-Lumefantrine and 119 to dihydroartemisinin-piperaquine, resulting in 320 and 351 treatments for uncomplicated falciparum malaria, respectively. Artemether-Lumefantrine was associated with a higher risk of recurrent malaria after 28 days (35% vs 11%; P = .001]). When the duration of follow-up was extended, differences in the risk of recurrent malaria decreased such that the overall incidence of malaria treatments was similar for children randomized to artemether-Lumefantrine, compared with those randomized to dihydroartemisinin-piperaquine (4.82 vs 4.61 treatments per person-year; P = .63). The risk of recurrent malaria due to recrudescent parasites was similarly low in both treatment arms. Conclusions Artemether-Lumefantrine and dihydroartemisinin-piperaquine were both efficacious and had similar long-term effects on the risk of recurrent malaria. Clinical trials registration. NCT00527800.

  • effectiveness of quinine versus artemether Lumefantrine for treating uncomplicated falciparum malaria in ugandan children randomised trial
    BMJ, 2009
    Co-Authors: Jane Achan, Moses R Kamya, Philip J Rosenthal, Grant Dorsey, James K Tibenderana, Daniel J Kyabayinze, Fred Wabwire Mangen, Umberto Dalessandro, Ambrose Talisuna
    Abstract:

    Objective To compare the effectiveness of oral quinine with that of artemether-Lumefantrine in treating uncomplicated malaria in children. Design Randomised, open label effectiveness study. Setting Outpatient clinic of Uganda’s national referral hospital in Kampala. Participants 175 children aged 6 to 59 months with uncomplicated malaria. Interventions Participants were randomised to receive oral quinine or artemether-Lumefantrine administered by care givers at home. Main outcome measures Primary outcomes were parasitological cure rates after 28 days of follow-up unadjusted and adjusted by genotyping to distinguish recrudescence from new infections. Secondary outcomes were adherence to study drug, presence of gametocytes, recovery of haemoglobin concentration from baseline at day 28, and safety profiles. Results Using survival analysis the cure rate unadjusted by genotyping was 96% for the artemether-Lumefantrine group compared with 64% for the quinine group (hazard ratio 10.7, 95% confidence interval 3.3 to 35.5, P=0.001). In the quinine group 69% (18/26) of parasitological failures were due to recrudescence compared with none in the artemether-Lumefantrine group. The mean adherence to artemether-Lumefantrine was 94.5% compared with 85.4% to quinine (P=0.0008). Having adherence levels of 80% or more was associated with a decreased risk of treatment failure (0.44, 0.19 to 1.02, P=0.06). Adverse events did not differ between the two groups. Conclusions The effectiveness of a seven day course of quinine for the treatment of uncomplicated malaria in Ugandan children was significantly lower than that of artemether-Lumefantrine. These findings question the advisability of the recommendation for quinine therapy for uncomplicated malaria in Africa. Trial registration ClinicalTrials.gov NCT00540202.

  • artemether Lumefantrine versus amodiaquine plus sulfadoxine pyrimethamine for uncomplicated falciparum malaria in burkina faso a randomised non inferiority trial
    The Lancet, 2007
    Co-Authors: Issaka Zongo, Philip J Rosenthal, Grant Dorsey, Christian Dokomajilar, Noel Rouamba, Halidou Tinto, Robert T Guiguemde, Jean Bosco Ouedraogo
    Abstract:

    BACKGROUND: Artemisinin-based combination regimens are widely advocated for malarial treatment, but other effective regimens might be cheaper and more readily available. Our aim was to compare the risk of recurrent parasitaemia in patients given artemether-Lumefantrine with that in those given amodiaquine plus sulfadoxine-pyrimethamine for uncomplicated malaria. METHODS: We enrolled 521 patients aged 6 months or older with uncomplicated falciparum malaria in Bobo-Dioulasso, Burkina Faso. Patients were randomly assigned to receive standard doses of either artemether-Lumefantrine (261) or amodiaquine plus sulfadoxine-pyrimethamine (260) for 3 days. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. The study is registered at controlled-trials.gov with the identifier ISRCTN54261005. FINDINGS: Of enrolled patients, 478 (92%) completed the 28-day study. The risk of recurrent symptomatic malaria was lowest in the group given amodiaquine plus sulfadoxine-pyrimethamine (1.7%vs 10.2%; risk difference 8.5%; 95% CI 4.3-12.6; p=0.0001); as was the risk of recurrent parasitaemia (4.7%vs 15.1%; 10.4%; 5.1-15.6; p=0.0002). Nearly all recurrences were due to new infections. Recrudescences were four late treatment failures with artemether-Lumefantrine and one early treatment failure with amodiaquine plus sulfadoxine-pyrimethamine. Both regimens were safe and well tolerated, with pruritus more common with amodiaquine plus sulfadoxine-pyrimethamine than with artemether-Lumefantrine. Each regimen selected for new isolates with mutations that have been associated with decreased drug susceptibility. INTERPRETATION: Amodiaquine plus sulfadoxine-pyrimethamine was more effective than was artemether-Lumefantrine for the treatment of uncomplicated malaria. For regions of Africa where amodiaquine plus sulfadoxine-pyrimethamine continues to be effective, this less expensive and more available regimen should be considered as an alternative to blanket recommendations for artemisinin-based combination treatment for malaria.

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  • population pharmacokinetics and pharmacodynamics of artemether and Lumefantrine during combination treatment in children with uncomplicated falciparum malaria in tanzania
    Antimicrobial Agents and Chemotherapy, 2010
    Co-Authors: Sofia Friberg Hietala, Anna Annerberg, Niklas Lindegardh, Andreas Martensson, Billy Ngasala, Sabina Dahlstrom, Zul Premji, Anna Farnert
    Abstract:

    The combination of artemether (ARM) and Lumefantrine is currently the first-line treatment of uncomplicated falciparum malaria in mainland Tanzania. While the exposure to Lumefantrine has been associated with the probability of adequate clinical and parasitological cure, increasing exposure to artemether and the active metabolite dihydroartemisinin (DHA) has been shown to decrease the parasite clearance time. The aim of this analysis was to describe the pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and Lumefantrine in African children with uncomplicated malaria. In addition to drug concentrations and parasitemias from 50 Tanzanian children with falciparum malaria, peripheral parasite densities from 11 asymptomatic children were included in the model of the parasite dynamics. The population pharmacokinetics and pharmacodynamics of artemether, dihydroartemisinin, and Lumefantrine were modeled in NONMEM. The distribution of artemether was described by a two-compartment model with a rapid absorption and elimination through metabolism to dihydroartemisinin. Dihydroartemisinin concentrations were adequately illustrated by a one-compartment model. The pharmacokinetics of artemether was time dependent, with typical oral clearance increasing from 2.6 liters/h/kg on day 1 to 10 liters/h/kg on day 3. The pharmacokinetics of Lumefantrine was sufficiently described by a one-compartment model with an absorption lag time. The typical value of oral clearance was estimated to 77 ml/h/kg. The proposed semimechanistic model of parasite dynamics, while a rough approximation of the complex interplay between malaria parasite and the human host, adequately described the early effect of ARM and DHA concentrations on the parasite density in malaria patients. However, the poor precision in some parameters illustrates the need for further data to support and refine this model.

  • population pharmacokinetics of Lumefantrine in pregnant women treated with artemether Lumefantrine for uncomplicated plasmodium falciparum malaria
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Niklas Lindegardh, Joel Tarning, Elizabeth A Ashley, Rose Mcgready, Mupawjay Pimanpanarak, Benjamas Kamanikom, Anna Annerberg
    Abstract:

    Artemether-Lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of Lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparum malaria on the northwestern border of Thailand. Burmese and Karen women (n = 103) with P. falciparum malaria and in the second and third trimesters of pregnancy were treated with artemether-Lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of Lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of Lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of Lumefantrine contribute to the high rates of failure of artemether-Lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

  • pharmacokinetic study of artemether Lumefantrine given once daily for the treatment of uncomplicated multidrug resistant falciparum malaria
    Tropical Medicine & International Health, 2007
    Co-Authors: Anna Annerberg, Niklas Lindegardh, Elizabeth A Ashley, Rose Mcgready, Kasia Stepniewska, Robert Hutagalung
    Abstract:

    Summary Background  Adherence to antimalarial drug regimens is improved by simple dosing. If the fixed antimalarial drug combination artemether–Lumefantrine (AL) could be given once daily, this should improve adherence and thus effectiveness and lower the risk of selecting for resistance. Methods  In an open randomized study, 43 patients with uncomplicated falciparum malaria were given equivalent doses of AL with 200 ml flavoured milk either as the conventional twice-daily regimen or as a single daily dose for 3 days. The primary end point was a comparison of the areas under the plasma Lumefantrine concentration–time curves (AUC). Secondary end points were the day 42 polymerase chain reaction (PCR)-adjusted cure rates and the tolerability profiles. Results  Lumefantrine pharmacokinetic profiles were obtained for 36 patients. The AUC(0∞) of the once-daily regimen was 30% lower than that in the conventional regimen (P = 0.011) with a median (range) value of 306 (114–5781) μg/ml h, compared with 432 (308–992) μg/ml h. There was no significant difference in the peak plasma concentrations reached. PCR-adjusted cure rate estimates at day 42 of follow-up were 94% (95% CI: 84–100) in the six-dose arm and 85% (70–100) in the three-dose arm (P = 0.3). Conclusion  Artemether–Lumefantrine efficacy is reduced by once-daily dosing, because absorption of Lumefantrine is dose limited. At currently recommended doses, this antimalarial should be given twice daily in a 3-day regimen, with food containing fat. Donnees de base  La compliance aux traitements a base d'antimalariques est amelioree par des doses simples. Si la combinaison a dose fixe d'antimalariques artemether–Lumefantrine pouvait etre administree une fois par jour, cela devrait ameliorer la compliance et donc l'efficacite, et reduire le risque de selection de resistance. Methodes  dans une etude randomisee ouverte, 43 patients presentant une malaria falciparum non compliquee ont recu des doses equivalentes d'artemether–Lumefantrine avec 200 ml de lait aromatise, selon le regime conventionnel i.e: deux fois par jour ou selon un regime a une seule dose quotidienne pendant 3 jours. L'objectif final primaire etait la comparaison des aires sous la courbe (AUC) de la concentration plasmatique de Lumefantrine en fonction du temps. Les objectifs secondaires etaient la mesure des taux de guerison ajustes par les resultats de la reaction en chaine de la polymerase (PCR) au jour 42ieme et les profils de tolerance. Resultats  Les profils pharmacocinetiques de Lumefantrine ont ete obtenus pour 36 patients. Les AUC(0∞) dans le regime ‘‘une fois par jour’’etait 30% inferieur a celles dans le regime conventionnel (p = 0,011) avec une valeur mediane de 306 (114–5781) μg/ml h comparea 432 (308–992) μg/ml h. Il n'y avait aucune difference significative dans les concentrations plasmatiques maximales atteintes. Les taux de guerison ajustes par la PCR au 42ieme jour du suivi etaient de 94% (IC95%: 84–100) dans le groupe a 6 doses et 85% (IC95%: 70–100) dans le groupe a 3 doses (p = 0,3). Conclusion  L'efficacite de l'Artemether–Lumefantrine est reduite dans le regime ‘'une fois par jour‘’ parce que l'absorption du Lumefantrine est dose dependante. Aux doses recommandees actuellement, cet antimalarique devrait etre administre deux fois par jour dans un regime de trois jours, avec la nourriture contenant la matiere grasse. Antecedentes  La adherencia al tratamiento con antimalaricos mejora si se simplifica la dosificacion. Si se pudiese dar la combinacion fija de antimalaricos artemeter–lumefantrina (AL) en una dosis unica por dia, deberia mejorar la adherencia y por lo tanto la efectividad del tratamiento, habiendo un menor riesgo de seleccion de cepas resistentes. Metodos  En un ensayo abierto, aleatorizado, en el que 43 pacientes con malaria no complicada por falciparum recibieron durante tres dias dosis equivalentes de AL con 200ml de leche, bien bajo el regimen convencional de dos veces al dia o en una dosis unica cada dia. El criterio principal de valoracion fue una comparacion de las areas bajo las curvas de la concentracion de lumefantrina en plasma a lo largo del tiempo (ABC). Los criterios secundarios de valoracion fueron las PCR del dia 42, las tasas de curacion ajustadas y los perfiles de tolerabilidad. Resultados  Se obtuvieron los perfiles farmacocineticos de la lumefantrina para 36 pacientes. El ABC (0∞) del regimen unico al dia era un 30% mas bajo que el regimen convencional (p = 0.011) con una media (rango) de 306 (114–5781) μg/ml h comparado con 432 (308–992) μg/ml h. No habia una diferencia significativa entre las maximas concentraciones de plasma alcanzadas. Las tasas de curacion ajustadas por PCR a los 42 dias de seguimiento fueron 94% (95%CI 84–100) para el grupo con 6 dosis y 85% (70–100) para los que recibieron 3 dosis (p = 0.3). Conclusion  La eficacia de artemeter–lumefantrina se reduce al dar una dosis unica, puesto que la absorcion de la lumefantrina esta limitada por la dosis. En las dosis recomendadas en la actualidad, este antimalarico deberia darse dos veces al dia en un regimen de tres dias, acompa,nado con alimentos que contengan grasas.

  • how much fat is necessary to optimize Lumefantrine oral bioavailability
    Tropical Medicine & International Health, 2007
    Co-Authors: Anna Annerberg, Niklas Lindegardh, Elizabeth A Ashley, Kasia Stepniewska, Am Kham, Al Brockman, Pratap Singhasivanon
    Abstract:

    Summary Background  Artemether–Lumefantrine (AL) is the only fixed, artemisinin-based combination antimalarial drug which is registered internationally and deployed on a large scale. Absorption of the hydrophobic lipophilic Lumefantrine component varies widely between individuals and is greatly increased by fat coadministration; but patients with acute malaria are frequently nauseated and anorexic, making dietary advice difficult to comply with. The aim of this study was to describe the dose–response relationship between coadministration of fat and relative Lumefantrine bioavailability, in order to determine the minimum amount of fat necessary to optimize absorption. Method  We conducted a multiple crossover pharmacokinetic study in 12 healthy volunteers. This compared the area under the plasma concentration–time curve (AUC) for Lumefantrine after administration of a single dose of AL in the fasting state given with 0, 10, 40, 150 and 500 ml of soya milk corresponding to 0, 0.32, 1.28, 4.8 and 16 g of fat. All volumes of milk supplements were tested in all subjects with a 3- to 4-week washout period in-between. Results  A dose–response relationship was demonstrated between the volume of soya milk administered and Lumefantrine bioavailability. AL administration with soya milk increased the Lumefantrine AUC more than five fold. The population mean estimated volume of soya milk required to obtain 90% of maximum effect (in terms of Lumefantrine AUC) was 36 ml (corresponding to 1.2 g of fat). Conclusions  Coadministration of artemether–Lumefantrine with a relatively small amount of fat (as soya milk) was required to ensure maximum absorption of Lumefantrine in healthy adult volunteers. Donnees de base  Artemether–Lumefantrine (AL) est la seule combinaison d'antimalariques a dose fixe contenant de l'artemisinine qui est enregistree internationalement et disponible a grande echelle. L'absorption du compose Lumefantrine qui est lipophile et hydrophobe varie considerablement selon les individus et est considerablement augmentee par l'administration conjointe de matiere grasse. Mais, les patients presentant une malaria aigue sont frequemment ecoeures et anorexiques, ce qui rend difficile le conseil dietetique a suivre. Le but de cette etude est de decrire le rapport dose–reponse entre la co-administration de matiere grasse et la biodisponibilite relative de la Lumefantrine, afin de determiner la quantite minimum de matiere grasse necessaire pour optimiser l'absorption. Methode  Etude pharmacocinetique de croisement multiple menee chez 12 volontaires sains. Comparaison des aires sous la courbe (AUC) de la concentration plasmatique de Lumefantrine apres une dose unique d'AL administrea jeun avec soit 0–10–40–50 ou 500 ml de lait du soja correspondant a 0–0,32–1,28–4,8 ou 16 g de graisse. Les differents volumes de supplement de lait ont ete testes chez tous les sujets apres une periode d'intervalle de lavage de 3 a 4 semaines. Resultats  Un rapport dose–reponse a ete observe entre le volume de lait du soja administre et la biodisponibilite de Lumefantrine. L'administration d'AL avec du lait du soja a augmente de plus 5 fois l'aire sous la courbe (UAC) de Lumefantrine. La moyenne estimee du volume de lait de soja necessaire pour l'obtention de 90% d'effet maximum (en termes de AUC de Lumefantrine) etait de 36 ml (qui correspond a 1.2 g de matiere grasse). Conclusions  La co-administration de l'artemether–Lumefantrine avec une quantite relativement faible de matiere grasse (e.g: le lait du soja) est necessaire pour assurer l'absorption maximum du Lumefantrine chez des volontaires adultes sains. Antecedentes  Artemeter-lumefantrina (AL) es el unico antimalarico basado en una combinacion de artemisinina con dosis fijas, registrado a nivel internacional y utilizado a gran escala. La absorcion de la lumefantrina, componente hidrofobico-lipofilico, varia ampliamente entre individuos y aumenta considerablemente con la coadministracion de grasa. Sin embargo los pacientes con malaria aguda a menudo se encuentran anorexicos y nauseabundos, siendo dificil que cumplan con las recomendaciones dieteticas. El objetivo de este estudio era describir la relacion dosis repuesta entre la coadministracion de grasas y la biodisponibilidad relativa de la lumefantrina, con el fin de determinar la cantidad minima de grasa necesaria para optimizar la absorcion. Metodo  Estudio famacocinetico, con cruzado multiple, conducido en 12 voluntarios sanos. Se comparo el area bajo la curva de la concentracion en plasma de lumefantrina en el tiempo, tras la administracion de una unica dosis de AL en ayunas, suministrada con 0, 10, 40, 150, 500 ml de leche de soja, que corresponden a 0, 0.32, 1.28, 4.8 y 16 g de grasa. Todos los volumenes de leche fueron probados en todos los sujetos con un periodo de lavado en medio de unas 3 a 4 semanas. Resultados  Se demostro una relacion dosis respuesta entre el volumen de leche de soja administrado y la biodisponibilidad de la lumefantrina. Al administrar AL con leche de soja se aumento el area bajo la curva de la lumefantrina mas de cinco veces. La media poblacional del volumen de leche de soja que se requeria para obtener un 90% del efecto maximo (en terminos del area bajo la curva de lumefantrina) era de 36 ml (correspondiente a 1.2 g de grasa). Conclusiones  Se requirio la coadministracion de artemeter-lumefantrina con una cantidad relativamente peque,na de grasa (como leche de soja) para asegurar la maxima absorcion de la lumefantrina en voluntarios adultos sanos.

  • efficacy of artemether Lumefantrine for the treatment of uncomplicated falciparum malaria in northwest cambodia
    Tropical Medicine & International Health, 2006
    Co-Authors: Mey Bouth Denis, Anna Annerberg, Niklas Lindegardh, Reiko Tsuyuoka, Pharath Lim, Sophoan Narann Top, Duong Socheat, Thierry Fandeur, Eva Maria Christophel
    Abstract:

    Summary Objective  To determine the efficacy of artemether–Lumefantrine malaria treatment, as an alternative to artesunate + mefloquine, which is becoming ineffective in some areas of the Thai–Cambodian border. Methods  Two studies were conducted to monitor the efficacy of artemether–Lumefantrine in Sampov Lun referral hospital, Battambang Province, in 2002 and 2003, and one study was conducted to assess the efficacy of mefloquine + artesunate in 2003 for comparison. The studies were performed according to the WHO standardized protocol with a follow-up of 28 days. The therapeutic efficacy tests were complemented with in vitro tests and in 2003, with the measurement of Lumefantrine plasma concentration at day 7 for the patients treated with artemether–Lumefantrine. Results  A total of 190 patients were included: 55 were treated with artemether–Lumefantrine in 2002 (AL2002), 80 with artemether–Lumefantrine and food supplementation in 2003 (AL2003) and 55 with artesunate + mefloquine in 2003 (AM2003). With the per-protocol analysis, the cure rate was 71.1% in study AL2002, 86.5% in study AL2003 and 92.4% in study AM2003. All the data were PCR corrected. The artemether–Lumefantrine cure rate was unexpectedly low in 2002, but it increased with food supplementation in 2003. There was a significant difference (P = 0.02) in Lumefantrine plasma concentrations between adequate clinical and parasitological responses and treatment failure cases. In vitro susceptibility to Lumefantrine was reduced for isolates sampled from patients presenting with treatment failure, but the difference was not statistically different from isolates sampled from patients who were successfully treated. Conclusion  Treatment failure cases of artemether–Lumefantrine are most probably because of low levels of Lumefantrine blood concentration. Further investigations are necessary to determine whether resistance of Plasmodium falciparum isolates to Lumefantrine is present in the region. Objectif  Determiner l'efficacite de l'artemether–Lumefantrine pour le traitement paludisme en tant qu'alternative a l'artesunate + mefloquine qui devient de plus en plus inefficace dans certaines zones dans la frontiere Thailando–Cambodgienne. Methodes  Deux etudes ont ete menees pour mesurer l'efficacite de l'artemether–Lumefantrine dans l'hopital de reference de Sampov Lun dans la province de Battambang en 2002 et 2003 et, dans un but de comparaison, une etude a aussi ete menee pour evaluer l'efficacite de l'artesunate + mefloquine en 2003. Les etudes ont ete menees selon les protocoles standardises de l'OMS avec un suivi de 28 jours. Les tests d'efficacite therapeutique ont ete complementes par des tests in vitro et, en 2003 par la mesure de la concentration plasmatique de Lumefantrine au jour 7 pour les patients traites a l'artemether–Lumefantrine. Resultats  Au total 190 patients ont ete inclus dans l’etude parmi lesquels 55 ont ete traites a l'artemether–Lumefantrine en 2002 (AL2002), 80 a l'artemether–Lumefantrine en plus d'un complement de nourriture en 2003 (AL2003) et 55 a l'artesunate + mefloquine en 2003 (AM2003). L'analyse suivant un protocole standard a revele un taux de guerison de 71,1% pour AL2002, 86,5% pour AL2003 et 92,4% pour AM2003. Toutes les donnees ont ete ajustees avec les resultats de la PCR. Le taux de guerison pour l'artemether–Lumefantrine s'est avere bas de facon inattendue en 2002 mais il a augmente avec le complement de nourriture en 2003. Il y avait une difference significative (p = 0,02) pour les concentrations plasmatiques de Lumefantrine entre d'une part les reponses cliniques et parasitologiques adequates et d'autre part les cas d’echec therapeutique. La susceptibilite in vitro pour la Lumefantrine etait reduite pour les souches isolees de patients presentant un echec therapeutique mais les valeurs n’etaient pas statistiquement differentes de celles de souches isolees de patients traites avec succes. Conclusion  Les cas d’echec therapeutique a l'artemether–Lumefantrine sont plus probablement dus a des concentrations sanguines basses de Lumefantrine. Des investigations supplementaires sont necessaires pour determiner s'il existe une resistance de P. falciparuma la Lumefantrine dans la region. Objetivo  Determinar la eficacia del tratamiento de malaria con artemeter-lumefantrina como alternativa al artesunato + mefloquina, el cual esta dejando de ser efectivo en algunas areas de la frontera entre Tailanda y Cambodia. Metodos  Se llevaron a cabo dos estudios para monitorizar la eficacia de artemeter-lumefantrina en el hospital de referencia de Sampov Lun, provincia de Battambang, entre el 2002 y 2003, asi como un estudio durante el 2003, y a modo de comparacion, para evaluar la eficacia de la mefloquina + artesunato. Estos estudios se realizaron siguiendo el protocolo estandar de la OMS con un seguimiento de 28 dias. Las pruebas de eficacia terapeutica se complementaron con pruebas in vitro y, durante el 2003, con la medicion de la concentracion de lumefantrina en plasma en el dia 7 para los pacientes tratados con artemeter-lumefantrina. Resultados  Se incluyeron 190 pacientes: 55 fueron tratados con artemeter-lumefantrina en el 2002 (AL2002), 80 con artemeter-lumefantrina y suplementacion alimenticia en el 2003 (AL2003), y 55 con artesunato + mefloquina en el 2003. Con el analisis por protocolo, la tasa de curacion fue de 71.1% en el estudio AL2002, 86.5% en el estudio AL2003, y 92.4% en el estudio AM2003. Todos los datos fueron corregidos mediante PCR. La tasa de curacion para el tratamiento con artemeter-lumefantrina fue sorprendentemente baja en el 2002, pero aumento con la suplementacion alimenticia en el 2003. Se encontro una diferencia significativa (p = 0.02) en las concentraciones de lumefantrina en plasma entre casos con una respuesta clinica y parasitologica adecuadas y aquellos con fallo terapeutico. La susceptibilidad in vitro frente a la lumefantrina se redujo para cepas aisladas de pacientes que presentaban fallo en el tratamiento, pero la diferencia no era estadisticamente significativa de aquella para cepas aisladas de pacientes que hubiesen respondido adecuadamente al tratamiento. Conclusions  Los casos de fallo terapeutico con artemeter-lumefantrina probablemente son debidos a bajos niveles de concentracion de lumefantrina en la sangre. Se necesitan mas estudios para determinar si existe resistencia a la lumefantrina entre las cepas de P. falciparum de la region.

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