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

ABSTRACT: 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.

SUBMITTER: Huang L

PROVIDER: S-EPMC6095545 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Huang Liusheng L Mwebaza Norah N Kajubi Richard R Marzan Florence F Forsman Camilla C Parikh Sunil S Aweeka Francesca T FT

PloS one 20180816 8

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 30114201

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Project description: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.

Project description:BackgroundGuidelines for the emergency management of mild traumatic brain injury have been used for over a decade and are considered safe. However, they recommend computerized tomography for at least half of these patients. The Scandinavian Neurotrauma Committee guideline uses serum S100B protein level to rule out intracranial hemorrhage. Analysis of capillary serum S100B protein level has not yet been employed for this purpose. The primary aim of this study was to investigate the correlation and agreement of capillary and venous serum S100B protein level over a spectrum of concentrations typical for mild traumatic brain injury.MethodsEighteen patients with traumatic intracranial hemorrhage and 39 volunteers without trauma to the head within the past 7 days were recruited. Blood was sampled from patients with intracranial hemorrhage daily up to four consecutive days and healthy volunteers were sampled once during the study. One venous and two capillary samples were drawn at each sampling event. Samples were analyzed using the Cobas e411 S100 electrochemiluminescence assay.ResultsMedian serum S100B protein level of capillary sampling 1 was 0.12 (IQR 0.075-0.21) μg/l and median serum S100B protein level of capillary sampling 2 was 0.13 (IQR 0.08-0.22) μg/l. Median serum S100B protein level of all venous samples was 0.05 (IQR 0.03-0.07) μg/l. Correlation plots of capillary and venous samples showed poor correlation and Bland-Altman plots showed a large dispersion of samples and wide limits of agreement.ConclusionThe results of this study indicate that correlation and agreement between capillary and venous samples are low, and because of this, we cannot recommend studies on capillary serum S100B protein level to rule out intracranial hemorrhage in mild traumatic brain injury. Given the limitations of the current sampling and analysis methods of capillary protein S100B protein level, we conclude that evaluating its predictive ability to rule out intracranial hemorrhage should be withheld until more reliable methods can be incorporated into the study design.

Project description:Pregnancy has considerable effects on the pharmacokinetic properties of drugs used to treat uncomplicated Plasmodium falciparum malaria. The role of pharmacogenetic variation on anti-malarial drug disposition and efficacy during pregnancy is not well investigated. The study aimed to examine the effect of pharmacogenetics on lumefantrine (LF) pharmacokinetics and treatment outcome in pregnant women.Pregnant women with uncomplicated falciparum malaria were enrolled and treated with artemether-lumefantrine (ALu) at Mkuranga and Kisarawe district hospitals in Coast Region of Tanzania. Day-7 LF plasma concentration and genotyping forCYP2B6 (c.516G>T, c.983T>C), CYP3A4*1B, CYP3A5 (*3, *6, *7) and ABCB1 c.4036A4G were determined. Blood smear for parasite quantification by microscopy, and dried blood spot for parasite screening and genotyping using qPCR and nested PCR were collected at enrolment up to day 28 to differentiate between reinfection from recrudescence. Treatment response was recorded following the WHO protocol.In total, 92 pregnant women in their second and third trimester were included in the study and 424 samples were screened for presence of P. falciparum. Parasites were detected during the follow up period in 11 (12%) women between day 7 and 28 after treatment and PCR genotyping confirmed recrudescent infection in 7 (63.3%) women. The remaining four (36.4%) pregnant women had reinfection: one on day 14 and three on day 28. The overall PCR-corrected treatment failure rate was 9.0% (95% CI 4.4-17.4). Day 7 LF concentration was not significantly influenced by CYP2B6, CYP3A4*1B and ABCB1 c.4036A>G genotypes. Significant associations between CYP3A5 genotype and day 7 plasma LF concentrations was found, being higher in carriers of CYP3A5 defective variant alleles than CYP3A5*1/*1 genotype. No significant influence of CYP2B6, CYP3A5 and ABCB1 c.4036A>Genotypes on malaria treatment outcome were observed. However, CYP3A4*1B did affect malaria treatment outcome in pregnant women followed up for 28 days (P = 0.018).Genetic variations in CYP3A4 and CYP3A5may influence LF pharmacokinetics and treatment outcome in pregnant women.

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

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

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