Comparison of lumefantrine, mefloquine, and piperaquine concentrations between capillary plasma and venous plasma samples in pregnant women with uncomplicated falciparum and vivax malaria.

Capillary samples offer practical benefits compared with venous samples for the measurement of drug concentrations, but the relationship between the two measures varies between different drugs. We measured the concentrations of lumefantrine, mefloquine, piperaquine in 270 pairs of venous plasma and concurrent capillary plasma samples collected from 270 pregnant women with uncomplicated falciparum or vivax malaria. The median and range of venous plasma concentrations included in this study were 447.5 ng/mL (8.81-3,370) for lumefantrine (day 7, n = 76, median total dose received 96.0 mg/kg), 17.9 ng/mL (1.72-181) for desbutyl-lumefantrine, 1,885 ng/mL (762-4,830) for mefloquine (days 3-21, n = 90, median total dose 24.9 mg/kg), 641 ng/mL (79.9-1,950) for carboxy-mefloquine, and 51.8 ng/mL (3.57-851) for piperaquine (days 3-21, n = 89, median total dose 52.2 mg/kg). Although venous and capillary plasma concentrations showed a high correlation (Pearson's correlation coefficient: 0.90-0.99) for all antimalarials and their primary metabolites, they were not directly interchangeable. Using the concurrent capillary plasma concentrations and other variables, the proportions of venous plasma samples predicted within a ±10% precision range was 34% (26/76) for lumefantrine, 36% (32/89) for desbutyl-lumefantrine, 74% (67/90) for mefloquine, 82% (74/90) for carboxy-mefloquine, and 24% (21/89) for piperaquine. Venous plasma concentrations of mefloquine, but not lumefantrine and piperaquine, could be predicted by capillary plasma samples with an acceptable level of agreement. Capillary plasma samples can be utilized for pharmacokinetic and clinical studies, but caution surrounding cut-off values is required at the individual level.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT01054248.

Effect of CYP3A5*3 genotypes on lumefantrine plasma concentrations among malaria-HIV-infected women.

Aim: We aimed to assess the effect of a functional polymorphism of CYP3A5 on lumefantrine pharmacokinetics. Patients & methods: Sixty-nine women diagnosed with malaria received standard doses of artemether-lumefantrine. Concentration-time data for lumefantrine and genotyping data were obtained for each participant. Pharmacokinetic-genotype associative relationships were assessed using linear regressions, Mann-Whitney U-test or Kruskal-Wallis statistics. Results: Average age and weight (standard deviation) of the patients were 33 (6.8) years and 59.5 (11.6) kg, respectively. CYP3A5*3 genotype associated with the log-transformed maximum concentration with the median (interquartile range) values of 8279 (6516-13,420) and 6331 (4093-8631) ng/ml (p = 0.032) among the carriers and noncarriers of CYP3A5*3, respectively. Besides, the NR1I3 c.152-1089T>C genotypes had an associative trend with the lumefantrine area under the curve (AUC0-96h) and clearance. Conclusion:CYP3A5*3 genetic variant is associated with a high maximum plasma concentration of lumefantrine. This warrants further investigations on the association between CYP3A5*3 gene variants, lumefantrine pharmacokinetics and electrophysiological effect.

Microextraction by packed sorbent and high performance liquid chromatography for simultaneous determination of lumefantrine and desbutyl-lumefantrine in plasma samples.

A bioanalytical method for the determination of lumefantrine and its metabolite desbutyl-lumefantrine in plasma samples using microextraction by packed sorbent (MEPS) and high-performance liquid chromatography was developed and validated. A complete factorial planning and surface response approach were employed to optimize the extraction parameters sample volume, dilution, aspirated sample volume and extraction cycles. The method employed C18 MEPS sorbent and diazepam as internal standard (IS). Separation was performed on a Luna C18 column (250 mm × 4.6 mm, 5 µm) at 35 °C, with mobile phase composed of acetonitrile and 0.05 % trifluoroacetic acid (68:32, v/v), detection at 305 nm and injection volume of 25 µL. The developed method showed to be selective, precise, accurate and linear in the range of 50-5000 ng/mL for lumefantrine and desbutyl-lumefantrine. Using the optimized MEPS procedure, high recovery rates were obtained for both analytes and IS (92.2 %-99.0 %). The method was successfully applied for the determination of lumefantrine and its metabolite in human plasma samples after oral administration of lumefantrine tablets in healthy volunteers.

Enantioselective LC-ESI-MS/MS method for quantitation of (-)-lumefantrine and (+)-lumefantrine in mice plasma and application to a pharmacokinetic study.

We developed and validated a simple, sensitive, selective, and reliable LC-MS/MS-ESI method for the direct quantitation of lumefantrine (LFN) enantiomers [(-)-LFN and (+)-LFN] in mice plasma as per regulatory guideline. LFN enantiomers and carbamazepine (internal standard) were extracted from mice plasma using Strata X SPE (solid-phase extraction) cartridges. Good resolution between enantiomers was achieved on a Chiralpak IA-3 column using an isocratic mobile phase (0.1% of diethyl amine in methanol), which was delivered at a flow rate of 0.8 mL/min. Detection and quantitation were performed using multiple reaction monitoring mode following the transitions m/z 530.27 → 512.30 and 237.00 → 194.00 for LFN enantiomers and the internal standard, respectively, in the positive-ionization mode. The proposed method provided accurate and reproducible results over the linearity range of 2.39-895 ng/mL for each enantiomer. The intra- and inter-day precisions were in the range of 1.03-6.14 and 6.36-8.70 and 2.03-4.88 and 5.82-11.5 for (-)-LFN and (+)-LFN, respectively. Both (-)-LFN and (+)-LFN were found to be stable under different stability conditions. The method was successfully used to delineate stereoselective pharmacokinetics of LFN enantiomers in mice after an oral administration of rac-LFN (20 mg/kg). The pharmacokinetic results indicated that the disposition of LFN enantiomers was stereoselective in mice.

Usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with artemether-lumefantrine in Tanzania.

BACKGROUND: Day 7 plasma lumefantrine concentration is suggested as a predictor for malaria treatment outcomes and a cut-off of ≥ 200 ng/ml is associated with day 28 cure rate in the general population. However, day 7 lumefantrine plasma concentration can be affected by age, the extent of fever, baseline parasitaemia, and bodyweight. Therefore, this study assessed the usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with generic or innovator drug-containing artemether-lumefantrine (ALu) in Tanzania. METHODS: This study was nested in an equivalence prospective study that aimed at determining the effectiveness of a generic ALu (Artefan®) in comparison with the innovator's product (Coartem®). Children with uncomplicated malaria aged 6-59 months were recruited and randomized to receive either generic or innovator's product. Children were treated with ALu as per World Health Organization recommendations. The clinical and parasitological outcomes were assessed after 28 days of follow up. PCR was performed to distinguish recrudescence and re-infections among children with recurrent malaria. Analysis of day 7 lumefantrine plasma concentration was carried out using a high-performance liquid chromatographic method with UV detection. RESULTS: The PCR corrected cure rates were 98.7% for children treated with generic and 98.6% for those treated with the innovator product (p = 1.00). The geometric mean (± SD) of day 7 plasma lumefantrine concentration was 159.3 (± 2.4) ng/ml for the generic and 164 (± 2.5) ng/ml for the innovator groups, p = 0.87. Geometric mean (± SD) day 7 lumefantrine plasma concentration between cured and recurrent malaria was not statistically different in both treatment arms [158.5 (± 2.4) vs 100.0 (± 1.5) ng/ml, (p = 0.28) for generic arm and 158.5 (± 2.3) vs 251.2 (± 4.2) ng/ml, (p = 0.24) for innovator arm]. Nutritional status was found to be a determinant of recurrent malaria (adjusted hazardous ratio (95% confidence interval) = 3(1.1-8.2), p = 0.029. CONCLUSION: Using the recommended cut-off point of ≥ 200 ng/ml, day 7 plasma lumefantrine concentration failed to predict malaria treatment outcome in children treated with ALu in Tanzania. Further studies are recommended to establish the day 7 plasma lumefantrine concentration cut-off point to predict malaria treatment outcome in children.

Safety and tolerability of single low-dose primaquine in a low-intensity transmission area in South Africa: an open-label, randomized controlled trial.

BACKGROUND: To reduce onward falciparum malaria transmission, the World Health Organization recommends adding single low-dose (SLD) primaquine to artemisinin-based combination treatment in low transmission areas. However, uptake of this recommendation has been relatively slow given concerns about whether individual risks justify potential community benefit. This study was undertaken to generate comprehensive local data on the risk-benefit profile of SLD primaquine deployment in a pre-elimination area in South Africa. METHODS: This randomized, controlled open-label trial investigated adding a single low primaquine dose on day 3 to standard artemether-lumefantrine treatment for uncomplicated falciparum malaria. Efficacy, safety and tolerability of artemether-lumefantrine and primaquine treatment were assessed on days 3, 7, 14, 28 and 42. Lumefantrine concentrations were assayed from dried blood spot samples collected on day 7. RESULTS: Of 217 patients screened, 166 were enrolled with 140 randomized on day 3, 70 to each study arm (primaquine and no primaquine). No gametocytes were detected by either microscopy or PCR in any of the follow-up samples collected after randomization on day 3, precluding assessment of primaquine efficacy. Prevalence of the CYP2D6*4, CYP2D6*10 and CYP2D6*17 mutant alleles was low with allelic frequencies of 0.02, 0.11 and 0.16, respectively; none had the CYP2D6*4/*4 variant associated with null activity. Among 172 RDT-positive patients G6PD-genotyped, 24 (14%) carried the G6PD deficient (A-) variant. Median haemoglobin concentrations were similar between treatment arms throughout follow-up. A third of participants had a haemoglobin drop > 2 g/dL; this was not associated with primaquine treatment but may be associated with G6PD genotype [52.9% (9/17) with A- genotype vs. 31% (36/116) with other genotypes (p = 0.075)]. Day 7 lumefantrine concentrations and the number and nature of adverse events were similar between study arms; only one serious adverse event occurred (renal impairment in the no primaquine arm). The artemether-lumefantrine PCR-corrected adequate clinical and parasitological response rate was 100%, with only one re-infection found among the 128 patients who completed 42-day follow-up. CONCLUSIONS: Safety, tolerability, CYP2D6 and G6PD variant data from this study support the deployment of the WHO-recommended SLD primaquine without G6PD testing to advance malaria elimination in South African districts with low-intensity residual transmission. Trial registration Pan African Clinical Trial Registry, PACTR201611001859416. Registered 11 November 2016, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=1859.