| 1. |
- Capiau, Sara, et al.
(författare)
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Official International Association for Therapeutic Drug Monitoring and Toxicology guideline : Development and Validation of Dried Blood Spot-based Methods for Therapeutic Drug Monitoring
- 2019
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 41:4, s. 409-430
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Tidskriftsartikel (refereegranskat)abstract
- Dried blood spot (DBS) analysis has been introduced more and more into clinical practice to facilitate Therapeutic Drug Monitoring (TDM). To assure the quality of bioanalytical methods, the design, development and validation needs to fit the intended use. Current validation requirements, described in guidelines for traditional matrices (blood, plasma, serum), do not cover all necessary aspects of method development, analytical- and clinical validation of DBS assays for TDM. Therefore, this guideline provides parameters required for the validation of quantitative determination of small molecule drugs in DBS using chromatographic methods, and to provide advice on how these can be assessed. In addition, guidance is given on the application of validated methods in a routine context. First, considerations for the method development stage are described covering sample collection procedure, type of filter paper and punch size, sample volume, drying and storage, internal standard incorporation, type of blood used, sample preparation and prevalidation. Second, common parameters regarding analytical validation are described in context of DBS analysis with the addition of DBS-specific parameters, such as volume-, volcano-and hematocrit effects. Third, clinical validation studies are described, including number of clinical samples and patients, comparison of DBS with venous blood, statistical methods and interpretation, spot quality, sampling procedure, duplicates, outliers, automated analysis methods and quality control programs. Lastly, cross-validation is discussed, covering changes made to existing sampling- and analysis methods. This guideline of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology on the development, validation and evaluation of DBS-based methods for the purpose of TDM aims to contribute to high-quality micro sampling methods used in clinical practice.
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| 2. |
- Elens, Laure, et al.
(författare)
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Genetic Predisposition to Poor Opioid Response in Preterm Infants : Impact of KCNJ6 and COMT Polymorphisms on Pain Relief after Endotracheal Intubation
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:4, s. 525-533
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Tidskriftsartikel (refereegranskat)abstract
- Background: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, Val 158 Met) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n 17) or morphine (n 17). Methods: Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes. Results: Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank 7.5, P 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank 14.4, P 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy. Conclusion: We conclude that the KCNJ6 -1250A and COMT 158 Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
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| 3. |
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| 4. |
- Jönsson, Anna K., et al.
(författare)
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A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting
- 2019
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Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:3, s. 348-356
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published. METHODS: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented. RESULTS: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives. CONCLUSIONS: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patient's serum drug level. The compiled serum concentrations and the C/D ratios can support the physician's decision when individualizing dosing and determining treatment strategies for a specific patient.
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| 5. |
- Klaasen, Rolf Anton, et al.
(författare)
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A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients
- 2019
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Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:1, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Belatacept (Nulojix; Bristol-Myers Squibb, New York, NY) is a biological immunosuppressive drug used for the prophylaxis of acute rejection after renal transplantation. Few studies have described belatacept pharmacokinetics, and the effect of therapeutic drug monitoring has not been investigated. We have developed a drug-capture assay (using drug target) to measure belatacept in serum and applied this assay in a pharmacokinetic study in renal transplant recipients. Methods: CD80 was used to trap belatacept onto streptavidin-coated wells. Captured drug was quantified using Eu3+-labeled protein A and time-resolved fluorescence. The assay was applied in a pilot pharmacokinetic study in renal transplanted patients receiving belatacept infusions. Belatacept serum concentrations were determined at several time points between belatacept infusions. A simple population pharmacokinetic model was developed to visualize measured and predicted belatacept serum concentrations. Results: The assay range was 0.9-30 mg/L with accuracy within 91%-99% and coefficients of variation ranging from 1.2% to 3.6%. Predilution extended the measurement range to 130 mg/L with an accuracy of 90% and coefficients of variation of 3.8%. Samples were stable during storage at 48 degrees C for 15 days and during 2 freeze-thaw cycles. Belatacept concentrations were determined in a total of 203 serum samples collected during 26 infusion intervals from 5 renal transplant recipients. The population pharmacokinetic model visualized both measured and predicted concentrations. Conclusions: We have developed an automated, accurate, and precise assay for the determination of belatacept serum concentrations. The assay was successfully applied in a pharmacokinetic study in renal transplant recipients receiving belatacept infusions.
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| 6. |
- Linder, Camilla, et al.
(författare)
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Dried Blood Spot Self-Sampling by Guardians of Children With Epilepsy Is Feasible : Comparison With Plasma for Multiple Antiepileptic Drugs
- 2019
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Ingår i: Therapeutic Drug Monitoring. - : Lippincott Williams & Wilkins. - 0163-4356 .- 1536-3694. ; 41:4, s. 509-518
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dried blood spot (DBS) is an attractive matrix alternative to plasma for the measurement of antiepileptic drug concentrations with the possibility of self-sampling at home. The aim of this study was to evaluate whether DBS concentrations from a children population could be used as an alternative to plasma concentrations in a clinical routine laboratory.METHODS: Children with epilepsy using carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA) had capillary blood collected for routine plasma analysis. DBS samples were collected by guardians or nurses, and the quality of sampling was compared between the groups. DBS samples were analyzed with liquid chromatography-tandem mass spectrometry methods and plasma samples with immunochemical methods. In the comparison between DBS and plasma concentrations, previously analyzed sample data were pooled with data in this study and resulted in 190 comparison pairs. A bioanalytical cross-validation according to European Medicines Agency was performed. Clinicians evaluated the results to understand if a DBS concentration was linked to a different clinical dose recommendation for the patient in comparison with plasma concentrations.RESULTS: Comparison of DBS sample quality showed that 2.3% of the capillary DBS collected by guardians were rejected and 8.0% of the capillary DBS collected by nurses. For DBS, a conversion factor of 0.85 for CBZ and 1.65 for VPA was applied for the comparison with plasma. LTG and LEV results were directly comparable. In the cross-validation, 88% of CBZ, 75% of LTG, 74% of LEV, and 94% of VPA comparisons were within 20% of the difference of the mean, although LEV had a few major differences (+31% to -40%). In 4 of the 190 comparisons, the clinical evaluation indicated a risk of conflicting decisions regarding the need for dose adjustment when using DBS concentrations. However, the risk of negative patient outcomes was considered negligible.CONCLUSIONS: Our study demonstrates that a combination of bioanalytical cross-validation and clinical evaluation is an effective way to describe the applicability of DBS as an alternative to plasma, taking into account how therapeutic drug monitoring is used in specific patient groups. For LTG, converted CBZ and VPA, DBS is a feasible alternative for self-sampling at home. DBS for LEV can only be recommended for nonadherence queries due to the high variability of the plasma/DBS concentration ratios.
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| 7. |
- Skoglund, Karin, et al.
(författare)
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In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:2, s. 230-238
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: CYP3A metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia (CML) patients. The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in CML patients.METHODS: Forty-three CML patients were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.RESULTS: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to non-optimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P=0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
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| 8. |
- Skoglund, Karin, et al.
(författare)
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In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
- 2016
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Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 38:2, s. 230-238
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
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| 9. |
- Skov-Skov Bergh, Marianne, et al.
(författare)
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Distinguishing Between Cyclopropylfentanyl and Crotonylfentanyl by Methods Commonly Available in the Forensic Laboratory
- 2019
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Ingår i: Therapeutic Drug Monitoring. - : LIPPINCOTT WILLIAMS & WILKINS. - 0163-4356 .- 1536-3694. ; 41:4, s. 519-527
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Tidskriftsartikel (refereegranskat)abstract
- Background: The opioid analgesic fentanyl and its analogues pose a major health concern due to its high potency and the increasing number of overdose deaths worldwide. The analogues of fentanyl may differ in potency, toxicity, and legal status, and it is therefore important to develop analytical methods for their correct identification. This can be challenging since many fentanyl analogues are structural isomers. Two fentanyl isomers that have been in the spotlight lately due to difficulties regarding separation and identification are cyclopropylfentanyl and crotonylfentanyl, which have been reported to display nearly identical fragmentation patterns and chromatographic behavior. Methods: Chromatographic separation of cyclopropylfentanyl and crotonylfentanyl by ultra-high-performance liquid chromatography was investigated using 3 different stationary phases (high strength silica T3, ethylsiloxane/silica hybrid C-18, and Kinetex biphenyl) using gradient elution with a mobile phase consisting of 10 mM ammonium formate pH 3.1 and MeOH. Detection was performed by tandem mass spectrometry. In addition, the major metabolites of the 2 compounds formed on incubation with human liver microsomes were identified by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. Results: Baseline separation of cyclopropylfentanyl and crotonylfentanyl was achieved on the ethylsiloxane/silica hybrid C-18 column with retention times of 6.79 and 7.35 minutes, respectively. The major metabolites of the 2 analogues formed by human liver microsomes differed, with the main biotransformation being N-dealkylation and carboxylation for cyclopropylfentanyl and crotonylfentanyl, respectively. We demonstrated the usefulness of the 2 approaches by unambiguously identifying cyclopropylfentanyl, as well as its metabolites, in 2 authentic postmortem blood samples. Conclusions: In this study, we successfully demonstrated that cyclopropylfentanyl and crotonylfentanyl can be distinguished by methods commonly available in forensic laboratories.
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| 10. |
- Toepper, Christoph, et al.
(författare)
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Variable Linezolid Exposure in Intensive Care Unit PatientsPossible Role of Drug-Drug Interactions
- 2016
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Ingår i: Therapeutic Drug Monitoring. - 0163-4356 .- 1536-3694. ; 38:5, s. 573-578
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Tidskriftsartikel (refereegranskat)abstract
- Background:Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population.Methods:Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37 degrees C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (C-min) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, C-min 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted.Results:Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated C-min 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and C-min were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or C-min was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC approximate to 60 mg*h/L, C-min <0.4 mg/L). The median unbound fraction in all 20 patients was 90.9%.Conclusions:Drug exposure after standard doses of linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.
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