Browsing by Author "Patel, Parul"

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    Applying dried blood spot analysis: the pathway to better paediatric care.
    (Pharmaceutical Press, 2009) Patel, Parul; Lawson, Graham; Mulla, Hussain; Tanna, Sangeeta
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    Dexamethasone quantification in dried blood spot samples using LC-MS: The potential for application to neonatal pharmacokinetic studies.
    (Elsevier, 2010) Patel, Parul; Tanna, Sangeeta; Mulla, Hussain; Kairamkonda, V.; Pandya, Hitesh; Lawson, Graham
    A high-performance liquid chromatography (LC-MS) method has been developed and validated for the determination of dexamethasone in dried blood spot (DBS) samples. For the preparation of DBS samples whole blood spiked with analyte was used to produce 30µl blood spots on specimen collection cards. An 8mm disc was cut from the dried blood spot and extracted using a combination of methanol: water (70:30, v/v) containing the internal standard, triamcinolone acetonide. Extracts were centrifuged and chromatographic separation was achieved using a Zorbax Eclipse Plus C18 column using gradient elution with a mobile phase of acetonitrile and water with formic acid at a flow rate of 0.2ml/min. LC-MS detection was conducted with single ion monitoring using target ions at m/z 393.1 for dexamethasone and 435.1 for the internal standard. The developed method was linear within the tested calibration range of 15-800ng/ml. The overall extraction recovery of dexamethasone from dried blood spot samples was 99.3% (94.3-105.7%). The accuracy (relative error) and precision (coefficient of variation) values were within the pre-defined limits of ≤15% at all concentrations. Factors with potential to affect drug quantification measurements such as blood haematocrit, the volume of blood applied onto the collection card and spotting device were investigated. Although a haematocrit related effect was apparent, the assay accuracy and precision values remained within the 15% variability limit with fluctuations in haematocrit of ± 5%. Variations in the volume of blood spotted did not appear to affect the performance of the developed assay. Similar observations were made regarding the spotting device used. The methodology has been applied to determine levels of dexamethasone in DBS samples collected from a premature neonate. The measured concentrations were successfully evaluated using a simple 1 compartment pharmacokinetic model. Requiring only a microvolume (30µl) blood sample for analysis, the developed assay is particularly suited to pharmacokinetic studies involving paediatric populations.
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    Dried blood spot sampling with LC-MS analysis for routine therapeutic caffeine monitoring in neonates
    (International Scholarly Research Network, 2012-11) Lawson, Graham; Patel, Parul; Mulla, Hussain; Tanna, Sangeeta
    A liquid chromatography–mass spectrometry (LC-MS) method was developed and validated for the determination of therapeutic levels of caffeine in dried blood spot (DBS) samples. Caffeine is used in the treatment of Apnoea of Prematurity (AoP) in newborn children. Calibration DBS samples were prepared by spotting 15l of whole blood spiked with the analyte onto specimen collection cards. 5mm disks cut from the centre of the DBS were extracted in methanol containing the internal standard. The extract was separated using a Zorbax Eclipse Plus C18 column and the MS, operated in electrospray positive ion mode, used single ion monitoring at m/z 195 for caffeine and 198 for the IS. The overall extraction recovery of caffeine from spiked blood spots was demonstrated to be 44-47%. Validation of the micro-analytical method showed good precision (coefficient of variation) and accuracy (relative error) and specificity and was linear within the tested calibration range 500-25000ng/ml for caffeine. Investigation of different specimen collection papers revealed different matrix effects with significant ion suppression from the FTA Elute paper itself. Requiring only a micro volume (15µl) blood sample for analysis, the developed DBS based micro-analytical method has the potential to facilitate the routine monitoring of caffeine in neonates.
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    Dried blood spots and sparse sampling: A practical approach to estimating pharmacokinetic parameters of caffeine in preterm infants
    (Wiley, 2013) Patel, Parul; Mulla, Hussain; Kairamkonda, V.; Spooner, N.; Gade, S.; Della Pasqua, O.; Field, D. J.; Pandya, Hitesh
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    Examples of dried blood spot sampling and analysis to improve paediatric medicine
    (2011-06) Lawson, Graham; Mulla, Hussain; Patel, Parul; Tanna, Sangeeta
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    Facilitating paediatric PK studies: Utility of the dried blood spot technique
    (2009) Patel, Parul; Mulla, Hussain; Pandya, Hitesh; Lawson, Graham; Tanna, Sangeeta
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    Facilitating pharmacokinetic studies in children: a new use of dried blood spots.
    (BMJ, 2010) Mulla, Hussain; Tanna, Sangeeta; Pandya, Hitesh; Patel, Parul
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    An Investigation into the Use of Dried Blood Spot Analysis in Pharmacokinetic Studies
    (De Montfort University, 2011) Patel, Parul
    The ethical and practical issues of obtaining a blood sample pose a significant challenge to performing pharmacokinetic studies in children, infants and neonates. Dried blood spot analysis, based on the collection of a micro blood sample has potential to overcome these difficulties. There are at present a limited number of reports on the utility of dried blood spot analysis in clinical pharmacokinetic studies. The studies described in this thesis were undertaken to investigate the accuracy and precision of dried blood spot sampling coupled with mass spectrometry detection for drug quantification, and clinically validate the robustness and feasibility of this technique for pharmacokinetic studies in preterm neonates. Dried blood spot methods were developed for application to pharmacokinetic studies of test drugs dexamethasone and caffeine. Investigations were focused on the blood collection system, analyte recovery and optimisation of the detection system. In-vitro validation results indicated developed methods were precise, accurate and selective in accordance with the Food and Drug Administration regulatory guidelines on the assessment of bioanalytical methods. Results were not significantly affected by small variations in the blood volume spotted or the presence of petroleum jelly, which is often used on the sampling site during capillary blood collection in neonates. Variability in haematocrit was determined to be the single most important factor affecting assay accuracy. Stability assessments by comparison with freshly prepared samples verified the suitability of sample drying, storage and post sample extraction conditions. An investigation of method transferability between different analytical instruments was undertaken with caffeine to provide an assessment of the robustness of dried blood spot analysis. Results generated from a single and triple quadrupole mass spectrometer were comparable with an expected lower limit of quantification with the latter technique most likely due to a greater ionisation and detection efficiency. Intravenous dexamethasone pharmacokinetics was determined in 5 preterm neonates receiving treatment for chronic lung disease. Individual pharmacokinetic analyses were performed using a one compartment model to estimate primary pharmacokinetic parameters, clearance (mean, 0.18 l/h/kg) and volume of distribution (mean, 1.33 l/kg). The whole blood derived mean estimates were similar to previous plasma clearance and volume estimates of 0.14 l/h/kg and 1.91 l/kg, respectively reported in neonates (n=7). This highlights the potential for dried blood spot analysis as an alternative to conventional plasma based methods for dexamethasone dose optimisation studies in neonates. The population pharmacokinetics of oral / intravenous caffeine was determined in 67 preterm neonates. A one compartment model was used to describe the blood concentration-time data. Model evaluation using a bootstrapping technique confirmed the robustness and stability of the developed model. Pharmacokinetic parameters derived from dried blood spot drug measurements were estimated with precision (relative standard error < 10%) and were comparable to estimates of plasma clearance (mean, 7.3 vs. 7.0 ml/h/kg) and volume of distribution (mean, 593 vs. 851 ml/kg) from a previous population study in neonates (n=110). Weight and postnatal age were the most influential covariates in the clearance model which is in agreement with previous population studies. These results demonstrate that dried blood spot analysis is a practical technique, with significant potential as a robust method for use in clinical pharmacokinetic studies in vulnerable populations such as preterms. Haematocrit related effects on paper will need to be accounted for if this potential is to be realised. Further investigations to determine the reproducibility of capillary blood sampling in neonates and the impact of using blood drug measurements on pharmacokinetic parameter estimation will be necessary before widespread use of the technique is possible.
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