Effect of local food on lumefantrine bioavailability and population pharmacokinetics in Ugandan children with malaria

Background. Artemether-lumefantrine (AL) is widely adopted as first-line treatment for uncomplicated malaria. Lumefantrine (LUM), the long acting partner drug is critical for cure by eliminating malaria parasites left after artemether exposure. Absorption of LUM is dependent on dietary fat and the basis for the pediatric dose recommendations is unclear. Aim. To explore effect of local foods on oral bioavailability of LUM and describe its population pharmacokinetics (PPK) among under five year old children in Uganda treated for malaria with the aim of optimizing use and provide basis for AL rational dosage guidelines. Methods. In an intensive pharmacokinetics (PK) study, 13 healthy adult volunteers were randomized to participate in an open-label four period crossover design and received a single oral dose of AL (80mg A/ 480mg of LUM) with water, milk, maize porridge or maize porridge with oil on separate occasions. Peak concentrations (Cmax) and area under concentration-time curve (AUC) truncated at 48 hours after a single dose (AUC0-48h) were compared using average bioequivalence techniques (I). Relevance of the findings was assessed among children < 5 years with uncomplicated falciparum malaria who were randomized in a parallel study design to receive standard weight-based AL treatment (Coartem®), 6 doses over 3 days, with either milk or maize porridge with oil (n= 33) (III). Parametric two-sample t-test was used to compare relative oral LUM bioavailability, 0 to 8 h after the first dose (AUC0-8h) (III). This bioavailability study (III) was nested in a population pharmacokinetic (PPK) study (IV) in the same pediatric patient group. After treatment, sparse plasma samples were collected during 28 days’ follow up in all children (n=55). NONMEM was used to describe the PPK profile of LUM and its metabolite, desbutyl-lumefantrine (DBL) (IV). A liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for determination of low concentrations of LUM and DBL in small amounts of plasma (II). Results. The LC-MS/MS method was simple, fast and sensitive requiring only 100 μl of plasma with limits of quantification of 21 and 1.7 ng/ml for LUM and DBL respectively (II). Lumefantrine exposure was comparable in milk and maize porridge plus oil study groups (I & III). In adult healthy volunteers, the bioequivalence criteria was met [maize porridge plus oil group ranges for means ratios (90% CI) of 0.84 –1.88 and 0.85 – 1.69 for Cmax and AUC0-48h respectively, relative to milk (90%CI, 0.80 – 1.25)]. Among pediatric patients, LUM (AUC0-8h) for those dosed with milk (n=16) was comparable to maize porridge plus oil (n=17) arm (GM {95%CI}: 6.01 {3.26-11.1} vs 6.26 {4.5 -8.43} h*μg/ml, p=0.9). A two-compartment PK model with lag time using first order processes characterized the PPK of LUM (IV). Inter-subject variability in apparent oral clearance (CL/F) was explained by body mass index (BMI) and age, while that in apparent volume of distribution of the central compartment (VC/F) was explained by weight. Lumefantrine population mean CL/F, inter-compartment clearance (Q/F), VC/F and apparent volume of distribution of peripheral compartment (VP/F) were 3.19 L/hr, 0.176 L/hr, 28.1 L, and 58.4 L, respectively. Our results indicate that LUM CL/F decreased with age from two to just less than five years (≈20.6%. p=0.04) and LUM CL/F increased with decreasing BMI. Conclusions. The LC MS/MS method is suitable for pediatric studies with repeated sampling and long time follow up. Oil fortified maize porridge can be an alternative to milk in augmenting absorption of LUM. Our findings provide a structural basis for consideration of age and BMI in evaluation of rational AL dosing guidelines among under five year old children

Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children.

BACKGROUND: The optimal treatment of malaria in human immunodeficiency virus (HIV)-infected children requires consideration of critical drug-drug interactions in coinfected children, as these may significantly impact drug exposure and clinical outcomes. METHODS: We conducted an intensive and sparse pharmacokinetic/pharmacodynamic study in Uganda of the most widely adopted artemisinin-based combination therapy, artemether-lumefantrine. HIV-infected children on 3 different first-line antiretroviral therapy (ART) regimens were compared to HIV-uninfected children not on ART, all of whom required treatment for Plasmodium falciparum malaria. Pharmacokinetic sampling for artemether, dihydroartemisinin, and lumefantrine exposure was conducted through day 21, and associations between drug exposure and outcomes through day 42 were investigated. RESULTS: One hundred forty-five and 225 children were included in the intensive and sparse pharmacokinetic analyses, respectively. Compared with no ART, efavirenz (EFV) reduced exposure to all antimalarial components by 2.1- to 3.4-fold; lopinavir/ritonavir (LPV/r) increased lumefantrine exposure by 2.1-fold; and nevirapine reduced artemether exposure only. Day 7 concentrations of lumefantrine were 10-fold lower in children on EFV vs LPV/r-based ART, changes that were associated with an approximate 4-fold higher odds of recurrent malaria by day 28 in those on EFV vs LPV/r-based ART. CONCLUSIONS: The choice of ART in children living in a malaria-endemic region has highly significant impacts on the pharmacokinetics and pharmacodynamics of artemether-lumefantrine treatment. EFV-based ART reduces all antimalarial components and is associated with the highest risk of recurrent malaria following treatment. For those on EFV, close clinical follow-up for recurrent malaria following artemether-lumefantrine treatment, along with the study of modified dosing regimens that provide higher exposure, is warranted

Artemether-Lumefantrine Pharmacokinetics and Clinical Response Are Minimally Altered in Pregnant Ugandan Women Treated for Uncomplicated Falciparum Malaria.

Artemether-lumefantrine is a first-line regimen for the treatment of uncomplicated malaria during the second and third trimesters of pregnancy. Previous studies have reported changes in the pharmacokinetics and clinical outcomes following treatment with artemether-lumefantrine in pregnant women compared to nonpregnant adults; however, the results are inconclusive. We conducted a study in rural Uganda to compare the pharmacokinetics of artemether-lumefantrine and the treatment responses between 30 pregnant women and 30 nonpregnant adults with uncomplicated Plasmodium falciparum malaria. All participants were uninfected with HIV, treated with a six-dose regimen of artemether-lumefantrine, and monitored clinically for 42 days. The pharmacokinetics of artemether, its metabolite dihydroartemisinin, and lumefantrine were evaluated for 21 days following treatment. We found no significant differences in the overall pharmacokinetics of artemether, dihydroartemisinin, or lumefantrine in a direct comparison of pregnant women to nonpregnant adults, except for a statistically significant but small difference in the terminal elimination half-lives of both dihydroartemisinin and lumefantrine. There were seven PCR-confirmed reinfections (5 pregnant and 2 nonpregnant participants). The observation of a shorter terminal half-life for lumefantrine may have contributed to a higher frequency of reinfection or a shorter posttreatment prophylactic period in pregnant women than in nonpregnant adults. While the comparable overall pharmacokinetic exposure is reassuring, studies are needed to further optimize antimalarial efficacy in pregnant women, particularly in high-transmission settings and because of emerging drug resistance. (This study is registered at ClinicalTrials.gov under registration no. NCT01717885.)

Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria in pregnancy, including asymptomatic infection, has a detrimental impact on foetal development. Individual patient data (IPD) meta-analysis was conducted to compare the association between antimalarial treatments and adverse pregnancy outcomes, including placental malaria, accompanied with the gestational age at diagnosis of uncomplicated falciparum malaria infection. METHODS: A systematic review and one-stage IPD meta-analysis of studies assessing the efficacy of artemisinin-based and quinine-based treatments for patent microscopic uncomplicated falciparum malaria infection (hereinafter uncomplicated falciparum malaria) in pregnancy was conducted. The risks of stillbirth (pregnancy loss at ≥ 28.0 weeks of gestation), moderate to late preterm birth (PTB, live birth between 32.0 and < 37.0 weeks), small for gestational age (SGA, birthweight of < 10th percentile), and placental malaria (defined as deposition of malaria pigment in the placenta with or without parasites) after different treatments of uncomplicated falciparum malaria were assessed by mixed-effects logistic regression, using artemether-lumefantrine, the most used antimalarial, as the reference standard. Registration PROSPERO: CRD42018104013. RESULTS: Of the 22 eligible studies (n = 5015), IPD from16 studies were shared, representing 95.0% (n = 4765) of the women enrolled in literature. Malaria treatment in this pooled analysis mostly occurred in the second (68.4%, 3064/4501) or third trimester (31.6%, 1421/4501), with gestational age confirmed by ultrasound in 91.5% (4120/4503). Quinine (n = 184) and five commonly used artemisinin-based combination therapies (ACTs) were included: artemether-lumefantrine (n = 1087), artesunate-amodiaquine (n = 775), artesunate-mefloquine (n = 965), and dihydroartemisinin-piperaquine (n = 837). The overall pooled proportion of stillbirth was 1.1% (84/4361), PTB 10.0% (619/4131), SGA 32.3% (1007/3707), and placental malaria 80.1% (2543/3035), and there were no significant differences of considered outcomes by ACT. Higher parasitaemia before treatment was associated with a higher risk of SGA (adjusted odds ratio [aOR] 1.14 per 10-fold increase, 95% confidence interval [CI] 1.03 to 1.26, p = 0.009) and deposition of malaria pigment in the placenta (aOR 1.67 per 10-fold increase, 95% CI 1.42 to 1.96, p < 0.001). CONCLUSIONS: The risks of stillbirth, PTB, SGA, and placental malaria were not different between the commonly used ACTs. The risk of SGA was high among pregnant women infected with falciparum malaria despite treatment with highly effective drugs. Reduction of malaria-associated adverse birth outcomes requires effective prevention in pregnant women

Strong correlation of lumefantrine concentrations in capillary and venous plasma from malaria patients.

BackgroundLumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined.MethodsVenous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1.ResultsIn children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases.ConclusionsCapillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies

Strong correlation of lumefantrine concentrations in capillary and venous plasma from malaria patients.

BACKGROUND:Lumefantrine is a long-acting antimalarial drug with an elimination half-life of over 3 days and protein binding of 99 percent. Correlation of lumefantrine concentrations from capillary plasma via fingerprick (Cc) versus venous plasma (Cv) remains to be defined. METHODS:Venous and capillary plasma samples were collected simultaneously from children, pregnant women, and non-pregnant adults at 2, 24, 120hr post last dose of a standard 3-day artemether-lumefantrine regimen they received for uncomplicated malaria. Some of the enrolled children and pregnant women were also HIV-infected. Samples were analyzed via liquid chromatography tandem mass spectrometry. Linear regression analysis was performed using the program Stata® SE12.1. RESULTS:In children, the linear regression equations for Cc vs Cv at 2, 24, and 120hr (day 7) post dose are [Cc] = 1.05*[Cv]+95.0 (n = 142, R2 = 0.977), [Cc] = 0.995*[Cv]+56.7 (n = 147, R2 = 0.990) and [Cc] = 0.958*[Cv]+18.6 (n = 139, R2 = 0.994), respectively. For pregnant women, the equations are [Cc] = 1.04*[Cv]+68.1 (n = 43, R2 = 0.990), [Cc] = 0.997*[Cv]+37.3 (n = 43, R2 = 0.993) and [Cc] = 0.941*[Cv]+11.1 (n = 41, R2 = 0.941), respectively. For non-pregnant adults, the equations are [Cc] = 1.05*[Cv]-117 (n = 32, R2 = 0.958), [Cc] = 0.962*[Cv]+9.21 (n = 32, R2 = 0.964) and [Cc] = 1.04*[Cv]-40.1 (n = 32, R2 = 0.988), respectively. In summary, a linear relationship with a slope of ~1 was found for capillary and venous lumefantrine levels in children, pregnant women and non-pregnant adults at 2hr, 24hr and 120hr post last dose, representing absorption, distribution, and elimination phases. CONCLUSIONS:Capillary and venous plasma concentration of lumefantrine can be used interchangeably at 1:1 ratio. Capillary sampling method via finger prick is a suitable alternative for sample collection in clinical studies

Facilitators and Barriers to Uptake of the Med Safety Mobile App for Adverse Drug Reaction Reporting by Health Workers in Uganda: A Qualitative Study

IntroductionAdverse drug reactions (ADRs) are an important public health challenge worldwide; however, pharmacovigilance systems are plagued by under-reporting. Mobile technologies, including mobile applications such as Med Safety, could strengthen ADR reporting. We explored the acceptability, and factors that could influence uptake of, Med Safety for ADR reporting by health workers in Uganda.MethodsThe study took place between July and September 2020 in 12 HIV clinics in Uganda and employed a qualitative exploratory research design. We conducted 22 in-depth interviews and 3 mixed-gender focus group discussions (49 participants) with a diverse range of health workers. We analysed the data using a thematic approach.ResultsThere was goodwill among the health workers to adopt Med Safety for ADR reporting and the majority would recommend the app to other health workers. Training with practice increased acceptability of the app. Uptake of the app was favoured by the younger, technology proficient, health worker demographic; the app's offline and two-way risk communication functionalities; availability of free internet hotspots at some health facilities; goodwill and willingness of health workers to report ADRs; and the cumbersome nature of conventional ADR reporting tools. Potential barriers to the uptake of Med Safety were the perceived lengthy processes of initial app registration and completion of multiple screens during ADR reporting; challenges with health workers' smartphones (incompatibility with application, no space for more applications, low battery charge); high cost of internet data; poor internet connectivity; difficulty in recognising ADRs, language barrier and poor feedback to ADR reporters.ConclusionThere was goodwill among the health workers to adopt Med Safety for ADR reporting and the majority would recommend the app to other health workers. Training with practice increased acceptability of the app and should be integral in all future app roll-out campaigns. The identified facilitators and barriers could be used to appropriately guide future research and implementation to promote the uptake of Med Safety for pharmacovigilance in low- and middle-income countries

Home management of malaria with artemether-lumefantrine compared with standard care in urban Ugandan children: a randomised controlled trial.

BACKGROUND: Home management of malaria-the presumptive treatment of febrile children with antimalarial drugs-is advocated to ensure prompt effective treatment of the disease. We assessed the effect of home delivery of artemether-lumefantrine on the incidence of antimalarial treatment and on clinical outcomes in children from an urban setting with fairly low malaria transmission. METHODS: In Kampala, Uganda, 437 children aged between 1 and 6 years from 325 households were randomly assigned by a computer-generated sequence to receive home delivery of prepackaged artemether-lumefantrine for presumptive treatment of febrile illnesses (n=225) or current standard of care (n=212). Randomisation was done by household after a pilot period of 1 month. After randomisation, study participants were followed up for an additional 12 months and information on their health and treatment of illnesses was obtained by use of monthly questionnaires and household diaries, which were completed by the participants' carers. The primary outcome was treatment incidence density per person-year. Analysis of the primary outcome was done on the modified intention-to-treat population, which included all participants apart from those excluded before data collection. This trial is registered with ClinicalTrials.gov, number NCT00115921. FINDINGS: Eight participants in the home management group and four in the standard care group were excluded before data collection; therefore, the primary analysis was done in 217 and 208 participants, respectively. The home management group received nearly twice the number of antimalarial treatments as the standard care group (4.66 per person-year vs 2.53 per person-year; incidence rate ratio [IRR] 1.72, 95% CI 1.43-2.06, p<0.0001), and nearly five times the number given to children with microscopically confirmed malaria in a comparable cohort of children (4.66 per person-year vs 1.03 per person-year, IRR 5.19, 95% CI 4.24-6.35, p<0.0001). Clinical data were available for 189 children in the home management group and 176 in the control group at study end; the main reasons for exclusion were movement out of the study area or loss to follow-up. The proportion of participants with parasitaemia at final assessment in the intervention group was lower than in the control group (four [2%] vs 17 [10%], p=0.006), but there were no other differences in standard malariometric indices, including anaemia. Serious adverse events were captured retrospectively. One child died in each group (home management-severe pneumonia and possible septicaemia; standard care-presumed respiratory failure). INTERPRETATION: Although home management of malaria led to prompt treatment of fever, there was little effect on clinical outcomes. The substantial over-treatment suggests that artemether-lumefantrine provided in the home might not be appropriate for large urban areas or settings with fairly low malaria transmission. FUNDING: Gates Malaria Partnership

Determination of piperaquine concentration in human plasma and the correlation of capillary versus venous plasma concentrations.

BackgroundA considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established.MethodsLiquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at ≥24hr post dose in children, pregnant women and non-pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R2) and visual check.ResultsAn LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C18 column (50x2.0mm, 5μm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI+ as the ion source. This method had a calibration range of 10-1000 ng/mL and carryover was negligible. Correlation analysis revealed a linear relationship: Ccap = 1.04×Cven+4.20 (R2 = 0.832) without transformation of data, and lnCcap = 1.01×lnCven+0.0125, (R2 = 0.945) with natural logarithm transformation. The mean ratio (±SD) of Ccap/Cven was 1.13±0.42, and median (IQR) was 1.08 (0.917, 1.33).ConclusionsCapillary and venous plasma PQ measures are nearly identical overall, but not readily exchangeable due to large variation. Further correlation study accounting for disposition phases may be necessary