Comparative Pharmacokinetics of Cholecalciferol in Dogs from 2 Different Oral Formulations Using Corrective Measures to Overcome Interference from Endogenous Cholecalciferol

Drug Research ◽  
2017 ◽  
Vol 67 (07) ◽  
pp. 388-395 ◽  
Author(s):  
Harilal Patel ◽  
Prakash Patel ◽  
Chandrakant Bhatt ◽  
Ashok Ghoghari ◽  
Urvesh Patel ◽  
...  
Keyword(s):  
Solid Phase ◽  
Statistical Significance ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Serum Samples ◽  
Time Profiles ◽  
Corrective Measures ◽  
Oral Formulations ◽  
Free Serum

AbstractThe aim of the preclinical investigation was to obtain single dose pharmacokinetics in dogs from 2 different oral cholecalciferol formulations using corrective measures to overcome the interference of endogenous cholecalciferol. 6 dogs were fasted overnight and the following day received 60 000 IU dose cholecalciferol [reference, Eris®, vs. test, Sunbless®] by oral dosing. Blood samples were collected on day 0 (baseline establishment) and after dosing on day 1 up to 28 days. The serum samples were extracted using protein precipitation/solid phase extraction and analysed to determine cholecalciferol by LC-MS/MS assay with calibrators prepared from cholecalciferol free serum. Standard pharmacokinetic analysis was carried out to assess pharmacokinetic parameters. An un-paired t-test was employed for comparing statistical significance between formulations. Serum cholecalciferol concentration vs. time profiles for the 2 formulations was almost superimposable. None of the pharmacokinetic parameters showed statistically significant differences (p>0.05) between the 2 treatments. For example: Cmax (ng/mL) and AUCinf (ng.h/mL) derived after the baseline corrections were 708.65 and 38 877.18 for reference and 743.71 and 40 665.51 for test, respectively. Pharmacokinetics of cholecalciferol was comparable between reference vs. test formulations. The procedures, baseline correction and employment of cholecalciferol devoid serum, can be readily adopted in future pharmacokinetic studies in animals or humans.

scholarly journals Bioequivalence assessment of the two brands of glimepiride tablets

2006 ◽  
Vol 63 (12) ◽  
pp. 1015-1020 ◽  
Author(s):  
Dusan Jovanovic ◽  
Dragan Stojsic ◽  
Milica Zlatkovic ◽  
Jasmina Jovic-Stosic ◽  
Miodrag Jovanovic
Keyword(s):  
Confidence Interval ◽  
Statistical Significance ◽  
Area Under The Curve ◽  
Pharmacokinetic Parameters ◽  
Maximal Concentration ◽  
Serum Samples ◽  
Oral Formulations ◽  
Mild Hypoglycaemia ◽  
Level Of Significance ◽  
Definition Of

Background/Aim. Glimepiride, as an antidiabetic from the group of sulfonylurea, is administered perorally in the treatment of diabetes mellitus. The aim of this study was to compare pharmacokinetic profiles and relative bioavailabilities of the two oral formulations of glimepiride, generic and innovator tablets, after a single dose of the active drug. Methods. An oral dose of 6 mg glimepiride was given under fasting conditions to 24 healthy volunteers. A one-week washout period was applied between the two consecutive periods. The serum samples obtained before dosing, and at various time points up to 48 hours, were analyzed for glimepiride concentration using the validated highperformance liquid chromatographic method with ultraviolet detection. Pharmacokinetic parameters representing early (maximal concentration, time to reach maximal concentration) and total exposure (area under the curve from the time 0 to the infinite time) to glimepiride were obtained and further analyzed using the multifactorial analysis of variance and the non-parametric Wilcoxon signed ranks test. Comparison of the secondary kinetic variables was only descriptive. Results. The point estimates of the ratios of geometric means (test/reference) of maximal concentrations and areas under the curve were 1.046 (90% confidence interval: 0.906?1.208) and 1.022 (90% confidence interval: 0.856?1.220), respectively, while the median values of times to reach maximal concentration, at 5% level of significance, did not differ significantly. Both formulations were well tolerated. Transient mild hypoglycaemia, which had been noted in 6 participants, resolved spontaneously within 30?60 minutes. Conclusion. Since all the parametric 90% confidence intervals for the log-transformed main variables of glimepiride were within the 0.80 and 1.25 interval, accepted as the definition of bioequivalence, and the differences in times to reach maximal concentration also did not reach statistical significance, studied tablets were considered bioequivalent.

Analysis of phase I pharmacokinetic studies with targeted molecules based on gender and age

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2521-2521
Author(s):  
S. Di Segni ◽  
I. Sperduti ◽  
A. Cinquina ◽  
M. Contestabile ◽  
B. Nuvoli ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Parameter ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Targeted Agents ◽  
Female Population ◽  
Male And Female ◽  
Age Related ◽  
The Impact

2521 Background: Pharmacokinetic parameters are usually not sufficiently correlated with patient characteristics, such as age, gender, or excretory organ function, and with outcome measures. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions and acting as a predictive/prognostic factor. Methods: We analyzed Phase I/II oncology trials of solid tumors with targeted agents enrolling Male and Female population (age>18yrs), reporting pharmacokinetic analysis, published between 2000 and 2007. We excluded trials involving Radiation therapy alone, Hematological malignancies, and trials of Gender related pathology (ovarian, prostate and breast cancer). Standard descriptive statistics was used. Results: 160 phase I and II trials involving 48 targeted agents has been selected. 44%, 37% and 19% of the population enrolled for PK analysis is respectively male, female or unknown gender. 65% of the trials have male preponderance. Authors did not specified number of male and female if only a group of patients enrolled in the trial was submitted to pharmacokinetic analysis. 95% of the trials enrolled patients > 65years, while 16% of the trials enrolled patients >80years. But only 3% of studies specified individual patient age and less than 6% of papers showed the number of male and female for each dose level, while about 10% of studies considered ethnicity as a characteristic. Conclusions: What emerged from our analysis is the irregularity and the lack of important informations when reported for publication. Knowing the impact of important prognostic/predictive factor of such clinical parameter (age, gender) we believe that more informations should be reported in the trials in order to evaluate if Toxicity and Efficacy could be gender or age related. Definitive data will be presented at the meeting. No significant financial relationships to disclose.

scholarly journals Low Levels of Pyrazinamide and Ethambutol in Children with Tuberculosis and Impact of Age, Nutritional Status, and Human Immunodeficiency Virus Infection

2006 ◽  
Vol 50 (2) ◽  
pp. 407-413 ◽  
Author(s):  
S. M. Graham ◽  
D. J. Bell ◽  
S. Nyirongo ◽  
R. Hartkoorn ◽  
S. A. Ward ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Nutritional Status ◽  
Hiv Infection ◽  
Statistical Significance ◽  
Severe Malnutrition ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Drug Levels ◽  
Immunodeficiency Virus ◽  
The Impact

ABSTRACT Recent pharmacokinetic studies that included children found that serum drug levels were low compared to those of adults for whom the same dosages were used. This study aimed to characterize the pharmacokinetics of pyrazinamide and ethambutol in Malawian children and to examine the impact of age, nutritional status, and human immunodeficiency virus (HIV) infection. We conducted a pharmacokinetic study of children treated for tuberculosis with thrice-weekly pyrazinamide (n = 27; mean age, 5.7 years) and of a separate group of children treated with thrice-weekly ethambutol (n = 18; mean age, 5.5 years) as portions of tablets according to national guidelines. Malnutrition and HIV infection were common in both groups. Blood samples were taken just prior to oral administration of the first dose, and subsequent samples were taken at intervals of 2, 3, 4, 7, 24, and 48 h after drug administration. Serum drug levels were low in all children for both drugs; in almost all cases, the maximum concentration of the drug in serum (C max) failed to reach the MIC for Mycobacterium tuberculosis. The C max of pyrazinamide was significantly lower in younger children (<5 years) than in older children. The C max of pyrazinamide was also lower for HIV-infected children and children with severe malnutrition, but these differences did not reach statistical significance. No differences were found for ethambutol in relation to age, HIV infection, or malnutrition, but the C max was <2 mg/liter in all cases. Studies of pharmacokinetic parameters and clinical outcomes obtained by using higher dosages of drugs for treatment of childhood tuberculosis are needed, and recommended dosages may need to be increased.

scholarly journals Pharmacokinetic Interaction between Zidovudine and Trimethoprim/sulphamethoxazole in HIV-1 Infected Children

2000 ◽  
Vol 11 (5) ◽  
pp. 254-258 ◽  
Author(s):  
Shannon Dallas ◽  
Stanley E Read ◽  
Susan King ◽  
Gideon Koren ◽  
Reina Bendayan
Keyword(s):  
Half Life ◽  
Statistical Significance ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Number Of Patients ◽  
Glucuronide Metabolite ◽  
Hiv 1

OBJECTIVE: To evaluate the effect of the antimicrobial agent trimethoprim/sulphamethoxazole (TMP/SMX) on the pharmacokinetic properties of the antiretroviral drug zidovudine (ZDV).DESIGN: This single dose, open label, crossover study involved the oral administration of ZDV (150 mg/m2) alone and in combination with oral TMP/SMX (2.5 mg/kg) on two separate occasions. Serial blood samples (0 to 8 h) were collected, and concentrations of ZDV and its glucuronide metabolite were quantified using a radioimmunoassay. ZDV pharmacokinetics were determined by noncompartmental analysis.PATIENTS AND SETTING: Six HIV-1 infected children aged four months to five years were recruited from the HIV clinic at The Hospital for Sick Children, Toronto, Ontario. Only three patients completed both study phases and were included in the pharmacokinetic analysis.MAIN RESULTS: With TMP/SMX therapy, no statistically significant changes were observed in ZDV pharmacokinetic parameters. However, there was a trend towards increased ZDV half-life and area under the concentration versus time curve, as well as decreased apparent oral clearance. Similarly, a trend towards an increased half-life of the ZDV-glucuronide metabolite was also observed.CONCLUSION: The changes in ZDV pharmacokinetics in the presence of TMP/SMX did not reach statistical significance, most likely due to the limited number of patients involved. Despite the limited data, a possible interaction between ZDV and TMP/SMX in young HIV-1 infected children should be considered, and patients may require close clinical monitoring.

Intravenous Human Plasma-Derived Augmentation Therapy in α1-Antitrypsin Deficiency: From Pharmacokinetic Analysis to Individualizing Therapy

2008 ◽  
Vol 42 (5) ◽  
pp. 640-646 ◽  
Author(s):  
Nuria Padullés Zamora ◽  
Rafael Vidal Pla ◽  
Pilar Gispert Del Rio ◽  
Rosendo Jardi Margaleff ◽  
Francisco Rodriguez Frias ◽  
...  
Keyword(s):  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Mean Value ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Studies ◽  
Augmentation Therapy ◽  
Serum Samples ◽  
Dosing Regimens ◽  
The Mean ◽  
The Impact

Background: Severs forms of α1-antitrypsin (AAT) deficiency require augmentation therapy by intravenous administration of purified preparations of AAT concentrate. Although standard AAT treatment schedules are widely available, pharmacokinetic studies characterizing AAT serum decay are scarce, and data on the variability of individual patients are almost nonexistent. Objective: To establish individual AAT pharmacokinetics and develop a predictive model based on simple pharmacokinetic characterization that can be used to optimize Individual AAT dosing regimens. Methods: Seven patients with severe hereditary AAT deficiency (PI*ZZ phonotype) with serum AAT levels less than 0.50 g/L Initially received AAT 180 mg/kg every 3 weeks. At 7, 14, and 21 days after AAT administration, serum samples were taken for quantitative AAT analysis and further one-compartment pharmacokinetic analysis. Subsequently, patients were rescheduled (dose and dosing interval) according to their individual responses. The influence of baseline AAT level, age, sex, body weight, and commercial AAT preparation was evaluated. Results: The mean ± SD AAT pharmacokinetic profile was: volume of distribution 127.6 ± 31.9 mL/kg, clearance 10.13 ± 1.84 mL/kg/day, and half-life 8.7 ± 1.0 days. Hence, the mean optimized final AAT dose was 123.1 mg/kg every 2 weeks (range 118.5-125.6). AAT concentrations differed by a mean (geometrical) value of 3.9% (range -4.2% to 6.7%) from the minimum desired AAT serum trough of 0.50 g/L. The impact of baseline AAT levels and commercial AAT preparation used was statistically significant (p = 0.033 and p = 0.035, respectively). Differences between estimated and actual values were slightly lower when baseline AAT levels were taken into consideration, with a mean value ot 3.3% (range -4.2% to 6.1%). Conclusions: AAT augmentation therapy can be effectively individualized on a pharmacokinetic basis with a simple, easily executed method.

scholarly journals Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

2001 ◽  
Vol 45 (6) ◽  
pp. 1803-1809 ◽  
Author(s):  
Sanjeev Krishna ◽  
Nelamangala V. Nagaraja ◽  
Tim Planche ◽  
Tsiri Agbenyega ◽  
George Bedo-Addo ◽  
...  
Keyword(s):  
Body Weight ◽  
Severe Malaria ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Intravenous Route ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Loading Dose

ABSTRACT We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at β phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V 1. Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

scholarly journals Effect of aminophylline on the pharmacokinetics of amikacin in Sprague-Dawley rats

2019 ◽  
Vol 13 (03) ◽  
pp. 251-254
Author(s):  
Seth Kwabena Amponsah ◽  
Kwabena Frimpong-Manso Opuni ◽  
Kwabena Aboagye Antwi ◽  
Victor Pouzuing Kunkpeh
Keyword(s):  
Elimination Rate ◽  
Test Group ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Sprague Dawley ◽  
Serum Samples ◽  
Sprague Dawley Rats ◽  
Elimination Half ◽  
Apnea Of Prematurity

Introduction: In most resource-poor settings, amikacin is normally co-administered with aminophylline among preterm newborns with infection and apnea of prematurity. There is the likelihood of an interaction between concurrently administered amikacin that is excreted almost solely via kidneys, and aminophylline, which is known to increase filtration fraction. The aim of this study was to evaluate the effect of aminophylline on the pharmacokinetics of amikacin using an animal model. Methodology: Twelve male Sprague-Dawley rats (7 – 8 weeks old) were put into 2 equal groups. The test group received amikacin (10 mg/kg/day) with aminophylline (5 mg/kg/day) via the intraperitoneal route, and the control group received only amikacin (10 mg/kg/day) via the same route. On Day 4, after daily administration of drugs, tail vein blood samples were collected at different time points. Serum samples at each time point for each group were pooled and analyzed by fluorescence polarization immunoassay. Non-compartment pharmacokinetic analysis was used to estimate pharmacokinetic parameters. Area under the concentration-time curves (AUCs) were extrapolated from time 0 to infinity (AUC0→∞). Elimination rate constant (Ke) and elimination half-life (t1/2e) were also estimated. Results: Pharmacokinetic parameters of the control group (amikacin only) vis-a-vis the test group were as follows: Cmax; 42.4 μmol/L vs 19.0 μmol/L, AUC0→∞; 84.9 μmol/L/h vs 41.4 μmol/L/h, Ke; 0.12 hours-1 vs 0.24 hours-1, and t1/2; 5.87 hours vs 2.88 hours, respectively. Conclusion: This study suggests possible interaction between aminophylline and amikacin. However, further studies need to be conducted in humans to ascertain this finding.

scholarly journals A pharmacokinetic comparison of three pharmaceutical formulations of nimesulide in healthy volunteers

2005 ◽  
Vol 62 (12) ◽  
pp. 887-893 ◽  
Author(s):  
Dusan Jovanovic ◽  
Vesna Kilibarda ◽  
Veljko Todorovic ◽  
Olivera Potrebic
Keyword(s):  
Confidence Interval ◽  
Confidence Intervals ◽  
Pharmaceutical Formulations ◽  
Point Estimate ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Serum Samples ◽  
Geometric Means ◽  
Registration Period ◽  
Significant Difference

Background/Aim. Switching the patient from one pharmaceutical formulation of the same drug to another, may lead to therapeutic inadequancy in some cases. To minimize the risk, careful pharmacokinetic studies are desired in the pre-registration period and afterwards. Methods. A randomized, crossover design with one-week wash-out period between each dose was applied. Serum samples, obtained before dosing and at various appropriate time points up to 15 hours, were analyzed for nimesulide content by a high-performance liquid chromatographic method with ultraviolet (UV) detection. The pharmacokinetics and relative bioavailability of three different pharmaceutical formulations containing nimesulide, manufactured by the same pharmaceutical factory, were studied prospectively in 12 healthy subjects of both sexes. A single 100-mg oral dose of nimesulide was given to the volunteers in the form of conventional tablets, mouth dissolving tablets or as a suspension. Analysis of variance, power analysis, 90% confidence intervals, and two one-sided tests were used for the statistical analysis of pharmacokinetic parameters. Results. The tolerability of all preparations was excellent. The respective confidence intervals of the ratios of geometric means of Cmax and AUC0- ? of nimesulide were out of acceptable limits either for conventional tablets in comparison with suspension or for mouth dissolving tablets when compared with conventional tablets. A comparison of mouth dissolving tablets with suspension showed a statistically significant difference between Cmax values (suprabioavailability of mouth dissolving tablets), while the point estimate of the ratio of geometric means of AUC0- ? was 0.945 with the corresponding 90% confidence interval of 0.902 ?0.991. At the 5% level of significance, there were no differences between the formulations under the study in times elapsed to peak serum concentrations, as revealed by the non-parametric Wilcoxon signed ranks test. Conclusion. Only a 90% confidence interval for the relative differences of log-transformed AUC0- ? values of nimesulide absorbed from mouth dissolving tablets vs. suspension was included in the 80% to 125% interval proposed by the Food and Drug Administration (FDA). On that basis, mouth dissolving tablets (Nimulid-MD ?) were considered bioequivalent to Nimulid ? suspension according to the extent of drug absorption. Concerning the comparable amounts of nimesulide available in the systemic circulation after application of these formulations the one might not expect therapeutic failure after switching the patient from one to another.

A Multicenter Study of Recombinant Factor VIII (RecombinateTM) in Previously Treated Patients with Hemophilia A

1997 ◽  
Vol 77 (04) ◽  
pp. 660-667 ◽  
Author(s):  
G C White ◽  
S Courter ◽  
G L Bray ◽  
M Lee ◽  
E D Gomperts ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Recombinant Dna ◽  
Home Treatment ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Open Label ◽  
Treat Ment ◽  
Previously Treated Patients ◽  
Bleeding Episodes

SummaryA prospective, open-label multicenter investigation has been conducted to compare pharmacokinetic parameters of recombinant DNA-derived FVIII (rFVIII) and plasma-derived FVIII concentrate (pdFVIII) and to assess safety and efficacy of long-term home-treat- ment with rFVIII for subjects with hemophilia A. Following comparative in vivo pharmacokinetic studies, 69 patients with severe (n = 67) or moderate (n = 2) hemophilia A commenced a program of home treatment using rFVIII exclusively for prophylaxis and treatment of all bleeding episodes for a period of 1.0 to 5.7 years (median 3.7 years). The mean in vivo half-lives of rFVIII and pdFVIII were both 14.7 h. In vivo incremental recoveries at baseline were 2.40%/IU/kg and 2.47%/IU/kg, respectively (p = 0.59). The response to home treatment with rFVIII was categorized as good or excellent in 3,195 (91.2%) of 3,481 evaluated bleeding episodes. Thirteen patients received rFVIII for prophylaxis for twenty-four surgical procedures. In all cases, hemostasis was excellent. Adverse reactions were observed in only 13 of 13,591 (0.096%) infusions of rFVIII; none was serious. No patient developed an inhibitor to r FVIII.

Liquid Chromatography-Tandem Mass Spectrometry Method for Ticagrelor and its Active Metabolite Determination in Human Plasma: Application to a Pharmacokinetic Study

2020 ◽  
Vol 16 (5) ◽  
pp. 602-608
Author(s):  
Niloufar Marsousi ◽  
Serge Rudaz ◽  
Jules A. Desmeules ◽  
Youssef Daali
Keyword(s):  
Clinical Trial ◽  
Formic Acid ◽  
Human Plasma ◽  
Active Metabolite ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Healthy Male ◽  
Coronary Syndrome ◽  
Healthy Male Volunteers ◽  
Male Volunteers

Background: Ticagrelor is a highly recommended new antiplatelet agent for the treatment of patients with acute coronary syndrome at moderate or high ischemic risk. There is a real need for rapid and accurate analytical methods for ticagrelor determination in biological fluids for pharmacokinetic studies. In this study, a sensitive and specific LC-MS method was developed and validated for quantification of ticagrelor and its Active Metabolite (AM) in human plasma over expected clinical concentrations. Methods: Samples were handled by Liquid-Liquid Extraction (LLE). A linear gradient was applied with a mobile phase composed of formic acid 0.1% and acetonitrile with 0.1% of formic acid using a C18 reversed-phase column. MS spectra were obtained by electrospray ionization in negative mode and optimized at 521.4→360.9 m/z, 477.2→361.2 m/z and 528.1→367.9 m/z transitions for ticagrelor, AM and ticagrelor-d7, respectively. Results: This method allowed rapid elution, in less than 4 minutes, and quantification of concentrations as low as 2 ng/mL for ticagrelor and 1 ng/mL for AM using only 100 μL of human plasma. LLE using hexane/ethyl acetate (50/50) was an optimal compromise in terms of extraction recovery and endogenous compounds interference. Trueness values of 87.8% and 89.5% and precisions of 84.1% and 93.8% were obtained for ticagrelor and AM, respectively. Finally, the usefulness of the method was assessed in a clinical trial where a single 180 mg ticagrelor was orally administered to healthy male volunteers. Pharmacokinetic parameters of ticagrelor and its active metabolite were successfully determined. Conclusion: A sensitive and specific quantification LC-MS-MS method was developed and validated for ticagrelor and its active metabolite determination in human plasma. The method was successfully applied to a clinical trial where a single ticagrelor 180 mg dose was orally administered to healthy male volunteers. The described method allows quantification of concentrations as low as 2 ng/mL of ticagrelor and 1 ng/mL of the metabolite using only 100 μL of plasma.

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