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Drug Levels by Mind Map: Drug Levels
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Drug Levels

Quality control: How good should a test be?

Titre du document / Document title An evaluation of analytic goals for assays of drugs: a college of American pathologists therapeutics drug monitoring survey study Auteur(s) / Author(s) ELLIN Ronald J. (1) ; WITTE David B. (2) ; SOLDIN Steven J. (3) ; KLEE George G. (4) ; PALOMAKI Glenn E. (5) ; WANG Edward (6) ; STEELE Bernard W. (7) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s) (1) Department of Pathology and Laboratory medicine, University of Louisville, Louisville, Ky, ETATS-UNIS (2) Collaborative Laboratory Services Laboratory Controls, Ltd, ottumwa, Iowa, ETATS-UNIS (3) Department of Laboratory Medicine, Children's National Medical Center, Departments of Pediatrics and Pathology, The George Whahington University School of Medicine, Whashington, DC, ETATS-UNIS (4) Mayo Clinic and Mayo Foundation, Rochester, Minn., ETATS-UNIS (5) Foundation for Blood Research, Scaraborough, Me, ETATS-UNIS (6) College of American Pathologists, Northfield, Ill., ETATS-UNIS (7) Department of Pathology, University of Miami School of Medicine, Miami, Fla., ETATS-UNIS Résumé / Abstract ○ Objective.-To determine if the levels of imprecision of the commonly used analytic methods for drug measurements are suitable for long-term therapeutic drug monitoring. Design.-In 1996, 4 identical lyophilized samples (2 in the first mailing and 2 in the second mailing 4 months later) were sent to laboratories participating in a nationwide proficiency testing program. Similarly, in 1999, replicates from a liquid pool of spiked sera were mailed 3 times, 4 months apart, to participating laboratories. For each of 11 drugs regulated under the Clinical Laboratory Improvement Amendments of 1988 and 1 metabolite, the total variance for each method was partitioned into withinand between-laboratory components. The total within-laboratory and the total survey coefficients of variation (CVs) for each method were then compared with the acceptable precision criteria of Glick, Burnett, and Fraser for each drug. Setting.-The first 2 mailings of the College of American Pathologists Therapeutic Drug Monitoring surveys for 1996, sets Z and ZM, and the 3 mailings of 1999, sets ZM, Z, and Z2. Main Outcome Measures.-For each drug studied, the CV of each method was compared with the various imprecision criteria, and if greater than any of the criteria, the method was then tabulated as not meeting that specific criterion. Participants.-The approximately 5000 participants of the survey. Results.-The number of methods deemed as not having acceptable total long-term within-laboratory precision by the various criteria ranged from 35% to 88% in 1996 and from 22% to 77% in 1999. Conclusion.-The number of failures possibly indicates that many of the reagent assays being utilized are not precise enough for long-term therapeutic drug monitoring of chronically administered drugs or that the published criteria used to evaluate the data in this study are too stringent. Revue / Journal Title Archives of pathology & laboratory medicine   ISSN 0363-0153   CODEN APLMAS Source / Source 2001, vol. 125, no6, pp. 729-735 (20 ref.) Langue / Language Anglais Editeur / Publisher College of American Pathologists, Northbrook, IL, ETATS-UNIS  (1976) (Revue) Mots-clés anglais / English Keywords Assay ; Drug ; Biochemical analysis ; Clinical biology ; Quality control ; Analytical method ; Survey ; Technique ; Human ; Mots-clés français / French Keywords Dosage ; Médicament ; Analyse biochimique ; Biologie clinique ; Contrôle qualité ; Méthode analytique ; Enquête ; Technique ; Homme ; Mots-clés espagnols / Spanish Keywords Dosificación ; Medicamento ; Análisis bioquímico ; Biología clínica ; Control calidad ; Método analítico ; Encuesta ; Técnica ; Hombre ; Localisation / Location INIST-CNRS, Cote INIST : 2050, 35400009834459.0020 Nº notice refdoc (ud4) : 1059912     @import url(http://www.google.com/cse/api/branding.css);

Precision goals based on upper and lower limits of the dosing interval (Glick, Burnett)

Precision goals based on dosing interval and elimination half-life (Fraser). Does Fraser, who demands biological variation as a basis for analytical precision goals, eliminate biological variation from his formula by using average half-lives? Should biological variation in TDM be interpreted as the change in drug level over time, or as random variation, e.g. in repeated trough levels in a stable patient?

RCV

Accuracy: How true is the truth?

1) Quiz: Is this a significant change in drug level?

A steady state trough level of imipramine in a depressed patient is 500 nmol/L. Another level the next day is 750 nmol/L. Is the second level significantly different from the first?

TCA steady state trough levels

AU: V. E. Ziegler, L. T. Wylie, John T. Biggs TI: Intrapatient variability of serial steady-state plasma tricyclic antidepressant concentrations SO: Journal of Pharmaceutical Sciences VL: 67 NO: 4 PG: 554-555 YR: 1978 CP: Copyright © 1978 Wiley-Liss, Inc., A Wiley Company ON: 1520-6017 PN: 0022-3549 AD: Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO 63110 DOI: 10.1002/jps.2600670431 US: http://dx.doi.org/10.1002/jps.2600670431 AB: Nine or 10 serial steady-state plasma measurements of amitriptyline, desipramine, desmethyldoxepin, doxepin, imipramine, nortriptyline, or protriptyline were made in 23 depressed patients. Each patient was monitored for compliance by pill counts, and sampling time was controlled carefully to determine intrapatient variability of steady-state tricyclic levels on a day-to-day basis. The coefficients of variation during serial sampling of the various ingested drugs were: amitriptyline, 21%; desipramine, 26%; doxepin, 21%; imipramine, 14%; nortriptyline, 13%; and protriptyline, 17%. The therapeutic ranges for the tricyclic antidepressants are relatively wide, so coefficients of variation of these magnitudes indicate that the position of an individual patient in relation to the optimal therapeutic range can be reliably determined on a clinical basis.

Reference change values in therapeutic drug monitoring, an opportunity for research

/.Scand J Clin Lab Invest. 2004;64(3):175-84. The reference change value: a proposal to interpret laboratory reports in serial testing based on biological variation. Ricós C, Cava F, García-Lario JV, Hernández A, Iglesias N, Jiménez CV, Minchinela J, Perich C, Simón M, Domenech MV, Alvarez V. Laboratoris Clínics Hospital Vall d'Hebron, Barcelona, Spain. cricos@hg.vhebron.es BACKGROUND: A proposal to calculate and use the reference change value (RCV) as an objective guide for interpreting the numerical results obtained in clinical laboratory serial testing is introduced in this study. METHODS: A database showing the results of a compilation of 191 publications on biological variation and including information on a number of analytes provided the standardized criterion based on biology for calculating the RCVs. RESULTS: For each of the 261 analytes included in the study, the RCV was determined using Harris's formula, replacing analytical imprecision with the desirable specification of analytical quality based on half the within-subject biological variation at 95% probability levels. The result is a guide for a common criterion to identify clinically significant changes in serial results. CONCLUSIONS: The RCV concept is an approach that can be offered by laboratories to assess changes in serial results. The RCV data in this study are presented as a point of departure for a widely applicable objective guide to interpret changes in serial results. Comment JZ: The RCV equals about 3 times the CVi, the intra-individual biological variation, given a probability of change of 95% bidirectionally, i.e. up or down. CVa, the analytical variation, should be half of CVi or less. CVp: pre-analytical, ignored

Can the lab detect the smallest achievable change in drug level?

Scand J Clin Lab Invest. 2004;64(3):175-84. The reference change value: a proposal to interpret laboratory reports in serial testing based on biological variation. Ricós C, Cava F, García-Lario JV, Hernández A, Iglesias N, Jiménez CV, Minchinela J, Perich C, Simón M, Domenech MV, Alvarez V. Laboratoris Clínics Hospital Vall d'Hebron, Barcelona, Spain. cricos@hg.vhebron.es BACKGROUND: A proposal to calculate and use the reference change value (RCV) as an objective guide for interpreting the numerical results obtained in clinical laboratory serial testing is introduced in this study. METHODS: A database showing the results of a compilation of 191 publications on biological variation and including information on a number of analytes provided the standardized criterion based on biology for calculating the RCVs. RESULTS: For each of the 261 analytes included in the study, the RCV was determined using Harris's formula, replacing analytical imprecision with the desirable specification of analytical quality based on half the within-subject biological variation at 95% probability levels. The result is a guide for a common criterion to identify clinically significant changes in serial results. CONCLUSIONS: The RCV concept is an approach that can be offered by laboratories to assess changes in serial results. The RCV data in this study are presented as a point of departure for a widely applicable objective guide to interpret changes in serial results. RCV = 3 CVi Probability of change 95%, bidirectional CVi: intra-individual CVa: analytical CVp: pre-analytical, ignored

2) TDM history: Anticonvulsant levels predict efficacy

...or do they?

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002216. Therapeutic monitoring of antiepileptic drugs for epilepsy. Tomson T, Dahl ML, Kimland E. Karolinska University Hospital, Department of Neurology, Stockholm, Sweden, S-171 76. torbjorn.tomson@karolinska.se BACKGROUND: The aim of drug treatment for epilepsy is to prevent seizures without causing adverse effects. To achieve this, drug dosages need to be individualised. Measuring antiepileptic drug levels in body fluids (therapeutic drug monitoring) is frequently used to optimise drug dosage for individual patients. OBJECTIVES: To review the evidence regarding the effects of therapeutic drug monitoring upon outcomes in epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialised Register (September 2006), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 4), MEDLINE (January 1966 to April 2005) and EMBASE (1974 to May 2005). No language restrictions were imposed. We checked the reference lists of retrieved articles for additional reports of relevant studies. SELECTION CRITERIA: Randomised controlled trials comparing the outcomes of antiepileptic drug monotherapy guided by therapeutic drug monitoring with drug treatment without the aid of therapeutic drug monitoring. DATA COLLECTION AND ANALYSIS: We based this review on published aggregate data. The main outcomes measured were the proportions of patients achieving a 12-month remission from seizures, reporting adverse effects, and being withdrawn from the treatment they had been randomised to receive. MAIN RESULTS: Only one study met the inclusion criteria for the review. In this open study, 180 patients with newly-diagnosed, untreated epilepsy were randomised to treatment with the antiepileptic drug selected by their physician either with or without therapeutic drug serum level monitoring as an aid to dosage adjustments. The antiepileptic drugs used were carbamazepine, valproate, phenytoin, phenobarbital and primidone. A 12-month remission from seizures was achieved by 60% of the patients randomised to therapeutic drug monitoring (intervention group) and by 61% in the control group. A total of 56% in the intervention group and 58% in the control group were seizure free during the last 12 months of follow up. Adverse effects were reported by 48% in the intervention group and 47% of the control group patients. Of those randomised to therapeutic drug monitoring, 62% completed the two-year follow up compared with 67% of the control group. AUTHORS' CONCLUSIONS: We found no clear evidence to support routine antiepileptic drug serum concentration measurement with the aim of reaching predefined target ranges for the optimisation of treatment of patients with newly-diagnosed epilepsy with antiepileptic drug monotherapy. However, this does not exclude the possible usefulness of therapeutic drug monitoring of specific antiepileptic drugs during polytherapy, in special situations or in selected patients, although evidence is lacking.

test

Therapeutic drug monitoring (TDM) and other reasons to measure drug levels

toxicity

absorbed

metabolism

drug interactions

protein binding

TDM/toxicology tests in Hamilton

  St. Josephs Hospital - Toxicology (Methods included JHPLC, JGC J911, JGCMS, JHPLC, JIMX) Test Order Count Query - January 2008 to December 2008 Test Name Count AMOBARBITAL 5 BUTABARBITAL 5 BUTALBITAL 5 SECOBARBITAL 5 MAPROTILINE 6 PENTOBARBITAL 6 IMIPRAMINE 14 IMIPRAMINE+DESIPRAMINE 14 FLUVOXAMINE 15 SERTRALINE 15 METHSUXIMIDE 18 PROPAFENONE 20 WARFARIN 20 DESIPRAMINE 23 DISOPYRAMIDE 23 IBUPROFEN 26 DESMETHYLTRIMIPRAMINE 27 TRIMIPRAMINE 27 TRIMIPRAMINE+DESMETHYLTRIM 27 ISONIAZIDE 30 PAROXETINE 31 ETHANOL 39 FLUOXETINE 44 NORFLUOXETINE 44 TRAZODONE 50 ETHOSUXIMIDE 51 AMITRIPTYLINE 66 AMITRIPTYLINE+NORTRIPTYLINE 66 GLYBURIDE 112 AMIODARONE 129 DESMETHYLAMIODARONE 129 24h U HOMOVANILLIC ACID 155 24h URINE HOMOVANILIC AC 155 HVA AREA 155 HVA CALC FACTOR 155 HVA INTERNAL STD 155 URINE HOMOVANILLIC ACID 155 CLOMIPRAMINE 185 CLOMIPRAMINE+DESMETHYLCLOMIP. 185 DESMETHYLCLOMIPRAMINE 185 DRUG FACTOR 206 I.S. TEST AREA 227 NORTRIPTYLINE 236 ETHYLENE GLYCOL 252 CYCLOSPORIN A 2h 303 DRUG AVERAGE FACTOR 311 URINE VANILLYL MAND. ACID 336 VMA AREA 336 VMA CALC FACTOR 336 VMA INTERNAL STD 336 24h URINE 5-HIAA 385 5-HIAA AREA 385 5-HIAA CALC FACTOR 385 5-HIAA DILUTION FACTOR 385 5-HIAA INTERNAL STD 385 URINE 5-HIAA 385 ETHANOL, URINE 389 ETHANOL GC 410 GABAPENTIN 413 METABOLITE AREA 460 METABOLITE AVERAGE FACTOR 460 LAMOTRIGINE 465 ISOPROPANOL 468 ACETONE 476 METHANOL 479 DRUG AREA 516 MYCOPHENOLIC ACID 542 24h URINE DOPAMINE 573 DOPAMINE, URINE 573 URINE EPINEPHRINE 573 URINE NOREPINEPHRINE 573 CONFIRMATION OF DRUG SCREEN 629 24h URINE VMA 672 MET AREA 779 MET CALC FACTOR 779 MET INTERNAL STANDARD 779 URINE METANEPHRINES 779 CLOBAZAM 812 CLOBAZAM+DESCLOBAZAM 812 DESMETHYLCLOBAZAM 812 24h URINE EPINEPHRINE 1146 24h URINE NOREPINEPHRINE 1146 CYCLOSPORIN A (DIL) 1155 24h URINE METANEPHRINE 1558 AMPHETAMINE/METHAMP., URINE 1820 EDDP-METHADONE METABOL., URINE 1820 THC METABOLITE, URINE 1823 BENZODIAZEPINE, URINE 1824 COCAINE, URINE 1824 OXYCODONE, URINE 1825 OPIATES, URINE 1826 URINE CREATININE 1835 CLOZAPINE 2772 CLOZAPINE+DESMETHYLCLOZAPINE 2772 DESMETHYLCLOZAPINE 2772 ANGIOTENSIN CONVERTING EN 2795 CYCLOSPORIN A 3658 TACROLIMUS 6496

3) TDM is difficult

Chromatography and sample preparation

Analogies in Physiology?

HPLC

GC

Ion selective electrodes

Analogies in Physiology?

Immunoassay

Other challenges:

interferences, false positives, negatives

preanalytical errors, often overlooked, but critical in TDM: Sampling time

postanalytical errors

4) Interpretation: Is this a toxic level or a therapeutic level?

What the drug does to the body

Agonist, antagonist, inverse agonist, did you think that's all?, ligand-biased efficacy, TDM may be most useful, when each patient serves as their own historical control to determine an individualized, safe and effective range of drug levels, rather than trusting a historical average from a different population, measured with a differently biased method (therapeutic interval).

Personalized medicine without genomics: Personal therapeutic intervals

What is a therapeutic range?

Therapeutic ranges are determined like reference intervals of other lab measurements such as glucose or sodium levels by clinical studies in certain populations. Unfortunately, as with endogenous chemicals in health and disease (sodium, by the way, is not endogenous, but dietary), therapeutic intervals always overlap with toxic ranges. What are health and therapeutic effects? Who decides what disease and toxicity are? How do these things vary, between different drug effects, from person to person, in the same person over time, depending on the environent?

What the body does to the drug

5) How to calculate the next dose?

6) What is the future of therapeutic drug management?

pharmacodynamic monitoring

phenotyping

metabolomics

genotyping

drive-by-whole-genome-scanning

omics and multivariate biomarkers

this and that

lab tests for poisoned patients

Take home message: Ask yourself: Will I do anything differently after the test result? If the answer is no, rethink whether the test is necessary.