Capillary Plasma Samples Research Articles

Pharmacokinetics-Pharmacodynamics of High-Dose Ivermectin with Dihydroartemisinin-Piperaquine on Mosquitocidal Activity and QT-Prolongation (IVERMAL).

High‐dose ivermectin, co‐administered for 3 days with dihydroartemisinin‐piperaquine (DP), killed mosquitoes feeding on individuals for at least 28 days posttreatment in a recent trial (IVERMAL), whereas 7 days was predicted pretrial. The current study assessed the relationship between ivermectin blood concentrations and the observed mosquitocidal effects against Anopheles gambiae s.s. Three days of ivermectin 0, 300, or 600 mcg/kg/day plus DP was randomly assigned to 141 adults with uncomplicated malaria in Kenya. During 28 days of follow‐up, 1,393 venous and 335 paired capillary plasma samples, 850 mosquito‐cluster mortality rates, and 524 QTcF‐intervals were collected. Using pharmacokinetic/pharmacodynamic (PK/PD) modeling, we show a consistent correlation between predicted ivermectin concentrations and observed mosquitocidal‐effects throughout the 28‐day study duration, without invoking an unidentified mosquitocidal metabolite or drug‐drug interaction. Ivermectin had no effect on piperaquine's PKs or QTcF‐prolongation. The PK/PD model can be used to design new treatment regimens with predicted mosquitocidal effect. This methodology could be used to evaluate effectiveness of other endectocides.

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.

Primaquine Pharmacokinetics in Lactating Women and Breastfed Infant Exposures.

Primaquine is the only drug providing radical cure of Plasmodium vivax malaria. It is not recommended for breastfeeding women as it causes hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals, and breast milk excretion and thus infant exposure are not known. Healthy G6PD-normal breastfeeding women with previous P. vivax infection and their healthy G6PD-normal infants between 28 days and 2 years old were enrolled. Mothers took primaquine 0.5 mg/kg/day for 14 days. Primaquine and carboxyprimaquine concentrations were measured in maternal venous plasma, capillary plasma, and breast milk samples and infant capillary plasma samples taken on days 0, 3, 7, and 13. In 20 mother-infant pairs, primaquine concentrations were below measurement thresholds in all but 1 infant capillary plasma sample (that contained primaquine 2.6 ng/mL), and carboxyprimaquine was likewise unmeasurable in the majority of infant samples (maximum value 25.8 ng/mL). The estimated primaquine dose received by infants, based on measured breast milk levels, was 2.98 µg/kg/day (ie, ~0.6% of a hypothetical infant daily dose of 0.5 mg/kg). There was no evidence of drug-related hemolysis in the infants. Maternal levels were comparable to levels in nonlactating patients, and adverse events in mothers were mild. The concentrations of primaquine in breast milk are very low and therefore very unlikely to cause adverse effects in the breastfeeding infant. Primaquine should not be withheld from mothers breastfeeding infants or young children. More information is needed in neonates. NCT01780753.

Vitamin D status positively associates with interleukin‐6 and tumour necrosis factor alpha in healthy young children (40.8)

Vitamin D status associates with immune function and duration of illness. The objective was to examine interleukin‐6 (IL‐6) and tumor necrosis factor alpha (TNF) in relation to vitamin D status in healthy children. Children (n=457; 1.8‐5.8 y) were recruited from randomly selected daycares in Montreal. Body mass index Z‐scores for age (BAZ) were calculated using the WHO growth standard. Capillary plasma samples were measured for IL‐6, TNF and C‐related peptide (CRP) (Multiplex assays; Millipore Corp. USA); CRP values > 10 mg/L were excluded. Vitamin D status (chemiluminescence; Liaison, Diasorin Inc.) was categorized using plasma 25‐hydroxyvitamin D (25(OH)D) values <50.0 nmol/L (low; n=52), 50.0‐74.9 nmol/L (adequate; n=189) and 蠅75.0 nmol/L (robust; n=216). Differences among vitamin D status categories were tested using mixed model ANOVA (random effects: age, sex, BMI Z‐score and season) and Tukey’s post hoc test; data are mean ± SD. Average age was 3.7 ± 1.0 y, BAZ 0.5 ± 1.0 kg/m2 and CRP 0.9 ± 1.6 mg/L. By design all pair‐wise differences in 25(OH)D (nmol/L) were observed (low: 40.8 ± 6.7; adequate: 63.4 ± 7.6; robust 100.3 ± 22.4, P<0.001). Highest IL‐6 (low: 9.9 ± 13.0; adequate 9.9 ± 12.9; robust 14.0 ± 14.9 ng/L, P<0.02) and TNF (low: 6.8 ± 3.5; adequate 7.1 ± 3.1; robust 7.8 ± 3.4 ng/L, P<0.03) were observed in the robust group. The data suggests that robust vitamin D status supports innate immune function.Grant Funding Source: Supported by Dairy Farmers of Canada

Population Pharmacokinetics of Lumefantrine in Pregnant Women Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria

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.

Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography–tandem mass spectrometry

An analytical method for the determination of gabapentin in serum obtained from venous blood samples has been developed using high-performance liquid chromatography (HPLC)–tandem mass spectrometry. In addition, a comparative study between capillary plasma samples and venous serum samples was carried out. This demonstrates the potential for the use of the described analytical system using very small amounts of blood. As internal standard ( S)-(+)-α-amino-cyclohexane-propionic acid hydrate was used. Gabapentin and the internal standard are structural isomers, but have different m/ z values for the fragments after collision induced dissolution. Gabapentin has 172→154 and 172→136 transitions and amino-cyclohexane–propionic acid hydrate has a 172→126 transition which can be detected in tandem MS. Analysis of gabapentin was carried out on a C8 HPLC column using an isocratic mobile phase consisting of ammonium acetate (pH 3.0; 5 mM)–methanol (96:4, v/v). The analytical method was validated for venous serum samples. Limit of detection was 1.6 ng/ml and lower limit of quantification was 7.5 ng/ml. R.S.D. values and bias values were within the range of acceptance for all concentration levels. The method developed for venous serum samples is being used in a gabapentin monitoring study using population pharmacokinetic modeling.

Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria

Aims To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. Methods Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg−1 day−1 in 23 paediatric (aged 2–12 years) and 31 adult (aged 16–45 years) Vietnamese patients with uncomplicated falciparum malaria. The population model was developed using NONMEM, incorporating interoccasion variability and accounting for a systematic change in artemisinin pharmacokinetics with time, modelled as a change in oral bioavailability. Results Clinical efficacy, in terms of parasite clearance and fever subsidence times, was comparable between children and adults. A one-compartment model with separate pharmacokinetic estimates for children and adults was found best to describe the disposition of artemisinin after oral administration. The population estimates for artemisinin clearance and distribution volume, respectively, were 432 l h−1 and 1600 l for adults and 14.4 l h−1 kg−1 and 37.9 l kg−1 for children, with an intersubject variability (collectively for both age groups) of 45% and 104%, respectively. The oral bioavailability was estimated to decrease from Day 1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults. Conclusions Artemisinin pharmacokinetic data was successfully derived in both paediatric and adult patients using 2–3 capillary blood samples taken in conjunction with parasitaemia monitoring. This study’s findings advocated the dosing of artemisinin to children according to bodyweight and to adults according to a standard dose.

Artemisinin population pharmacokinetics in children and adults with uncomplicated falciparum malaria.

To investigate the pharmacokinetics of the antimalarial artemisinin in the field setting using sparsely collected data. Artemisinin concentrations were determined by h.p.l.c. in a total of 107 capillary plasma samples collected on the first day and in 33 samples on the last day of a 5-day oral artemisinin regimen of 10 mg kg(-1) day(-1) in 23 paediatric (aged 2-12 years) and 31 adult (aged 16-45 years) Vietnamese patients with uncomplicated falciparum malaria. The population model was developed using NONMEM, incorporating interoccasion variability and accounting for a systematic change in artemisinin pharmacokinetics with time, modelled as a change in oral bioavailability. Clinical efficacy, in terms of parasite clearance and fever subsidence times, was comparable between children and adults. A one-compartment model with separate pharmacokinetic estimates for children and adults was found best to describe the disposition of artemisinin after oral administration. The population estimates for artemisinin clearance and distribution volume, respectively, were 432 1 h(-1) and 16001 for adults and 14.41 h(-1) kg(-1) and 37.91 kg(-1) for children, with an intersubject variability (collectively for both age groups) of 45% and 104%, respectively. The oral bioavailability was estimated to decrease from Day 1 to Day 5 by a factor of 6.9, a value found to be similar for children and adults. Artemisinin pharmacokinetic data was successfully derived in both paediatric and adult patients using 2-3 capillary blood samples taken in conjunction with parasitaemia monitoring. This study's findings advocated the dosing of artemisinin to children according to bodyweight and to adults according to a standard dose.

Der Einfluß von Hämolyse auf Dichtemessungen an Kapillarblutplasma mittels der Biegeschwingermethode

Sampling of capillary blood often yields slightly hemolytic plasma. We investigated the influence of hemolysis on plasma density using the mechanical oscillator technique. Plasma density rose by approximately 0.1 milligram when the hemoglobin content increased by 0.5 milligram. These values correspond to 0.3% hemolysis and were not exceeded in more than 70% of the investigated capillary plasma samples. In general, hemolysis must be taken into account if plasma density measurements are to be made with an accuracy better than 0.5 milligram, which corresponds to 2-3% of the plasma protein content.

A One-stage Factor VIII (Antihaemophilic Globulin) Assay and its Use on Venous and Capillary Plasma

SummaryA one-stage factor-VIII assay is described, based on the method of Lang-dell, Wagner and Brinkhous (1953), in which contact activation is controlled by the addition of a suspension of kaolin to the system. Experiments to show the effect of this modification on the clotting times and reproducibility of the system are presented.The error of the method is expressed in terms of the confidence limits of a random series of field assays, which lay between 64—156% and 76—131% of the observed result.The normal range of factor-VIII concentrations, as determined by this method on venous plasma samples from 116 normal subjects, was 50—170%, with a roughly normal distribution. There was good correlation between the results of one-stage and two-stage factor-VIII assays carried out in parallel on 110 plasma samples and between the observed and expected factor-VIII concentrations of a series of mixtures of normal and haemophilic plasma.The use of the assay on capillary plasma samples is described, and the results compared with those obtained on venous plasma. The practical value of capillary factor-VIII assays is discussed.