TDM A biochemists approach (Vancomycin)

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1 TDM A biochemists approach (Vancomycin) Graham Jones Chemical Pathologist SydPath, St Vincent s Hospital, Sydney ANZ TDM Workshop Sydney May 2015

2 Declaration I am a chemical Pathologist (not a clinical pharmacologist)

4 Clinical Chemistry and TDM Many drugs run in chemistry laboratories Many drugs run on chemistry analysers (is there such a thing as a drug analyser?) Many (most?) labs running TDM do not have access to a pharmacologist No speciality for pharmacology in RCPA ( covered by Chemical Pathology) We need to understand each other

5 Clinical Chemistry and TDM Many things in common: Measurement principles Instruments Accreditation requirements But some things different More principles in common than different Clin Chem Pharm.

6 Chemical Pathology - General Pre-analytic: Right test, right patient, right time, right sample, right handling Analytic: precise, accurate (unbiased), within assay range, no interferences Technique specific: immunoassay, HPLC, MS, chemical reaction Post-analytic (reporting): units, significant figures, therapeutic-intervals, patient-specific factors, calculations, interpretation

7 Chemical Pathology - General Pre-analytic: Right test, right patient, right time, right sample, right handling Analytic: precise, accurate (unbiased), within assay range, no interferences Technique specific: immunoassay, HPLC, MS, chemical reaction Post-analytic (reporting): units, significant figures, therapeutic-intervals, patient-specific factors, calculations, interpretation

8 1. Method validation All tests for any purpose must be validated / verified Verified: assays purchased from manufacturer Validated: in-house assays ISO NATA technical Document 17

10 Precision QC run in duplicate over 13 days.

11 Accuracy (v Roche)

12 Method Comparison (v AxSYM)

13 Sample Type

14 Gel Effect

15 7 days in the fridge (on the gel)

16 Interferences (Haemolysis, Lipaemia)

17 Post-analytical (TDM) Units mg/l (of course) Significant figures whole numbers Therapeutic intervals (see later) Critical values (phone limits) > 50 mg/l Routine reporting protocols: Ward-based system (Mediweb)

18 Long Term performance

19 Measurement Uncertainty Long-term QC data (>300 data points) Average CV MU (k=2) Accepted: Criteria: Level % +/- 12.5% Yes SoA Level % +/- 9.4% Yes SoA

20 Special Drugs Weighed-in target Roche IFU - Calibrator: Traceable to USP reference standards An instrument factor of 0.90 is required

Right time, right tube, right handling Analytical Post-analytical:

22 The test in action Pre-pre analytical: will I test? Will a test help the patient Pre-analytical: how will I test? Right time, right tube, right handling Analytical Post-analytical: reporting and delivering (getting) the result Post-post analytical: how do I interpret and act on the result?

23 Post analytical: Reference Intervals Clearly NOT population reference intervals Clinical decision points / therapeutic intervals Lower limit: exceed this to minimise risk of treatment failure Upper limit: stay below this to minimise risk of toxicity 1-Apr-15 Vancomycin 22 H Units mg/l Reference (15 20)

24 Therapeutic Interval SPECIAL FEATURES (unlike reference intervals) Must be derived from clinical studies Cannot be obtained locally Cannot be validated locally Clinical studies define accuracy target Assays should be unbiased relative to method(s) used to perform studies on which decision limits are based Benefit to have common reference limits (SHOULD have common reference limits)

Therapeutic range For twice daily dosing, trough level should be 10 20 mg/l (take first sample just before the fourth dose).

26 Therapeutic range For twice daily dosing, trough level should be mg/l (take first sample just before the fourth dose). A trough >10 mg/l minimises resistance developing but may increase the risk of nephrotoxicity. Some authorities recommend a trough level of mg/l (based on susceptibility, pharmacokinetic and pharmacodynamic data, and clinical experience) to treat serious infections. However, the higher doses required may result in increased adverse effects, eg nephrotoxicity. Limited data suggest that the area under the plasma concentration time curve (AUC) to minimum inhibitory concentration (MIC) ratio (AUC/MIC) may be a useful method to predict vancomycin efficacy when treating serious infections.

29 Pre-analytical factors Pre-pre-analytical factors Does this patient need TDM for vancomycin Pre-analytical factors Timing of sample collection Time since last dose Time since change of dose

30 Time since dose X X

31 Time since change of dose X X

33 Time since dose Time since change of dose

36 No trouble surely? Audit - one month Medicines administration database (Medchart) Pathology database (Ultra) 79 TDM samples with matching time and frequency of dosing

37 Figure 1. Estimated time since dose for vancomycin TDM sample collection A samples taken near time of administration (likely to be trough samples) B samples likely to be trough for 12 hourly dosing C samples likely to be trough for 24 hour dosing 79 samples

39 Individual Patient Analysis +3:00 hrs +2:20 hrs Vancomycin 500mg bd (12 hours between dose indicators o )

40 Another patient +2:00

41 Problem: Vancomycin collections Scheduling for morning bloods Failure to adjust for duration of infusion (not sure about this one) Lack of knowledge Lack of awareness of when infusion actually given Difficulty of access in MedChart people don't log into MedChart because it's time consuming Inpatients unavailable (eg. Having a CT scan or surgery) If you are drawing bloods for another test, it is easier to include the Vancomycin levels with that set of bloods, instead of taking more blood later It is easier to order the Vancomycin levels with other tests, rather than enter it as a separate order to be done at a different time. Trying to adjust the wrong dose wanting to stop Vancomycin infusion while waiting for result. St Vincent's Hospital Rational Investigations Ordering Project (April 2014) - Brainstorm

42 Solutions brainstorming Enforce ordering of Vancomycin levels as a separate order. Education regarding the protocol. Education regarding Vancomycin Quicklist in MedChart which calculates and autopopulates dosing (but not times) Creation of a button in Mediweb that shows Vancomycin levels. A one-line education in Medchart on when Vancomycin levels should be taken. Creation of a Web delacy alert. Nursing education on sign off of administration Pre-populated times in Medchart eg. 10am and 10pm Creation of a button in Mediweb listing Vancomycin dosing times. Creation of a button in Mediweb that pops graph up. Blood collectors could collect Vancomycin bloods at different time to other bloods St Vincent's Hospital Rational Investigations Ordering Project (April 2014)

43 Solutions brainstorming Try to time Vancomycin administration with collections (but what if stat dose was too close to bd dose?) Phone call from lab back to orderer when required information not included in order. Information required might be: time dose started,?time dose finished (duration of infusion), time blood taken Vet specimens that are clearly wrong, eg. 4 hourly Report information back to ordering doctor in a useful way, eg. Even suggest a dose change Education regarding button in Mediweb that brings up extra info. Education regarding dose adjustment, ie. There is no need to stop Vanc. Infusion while waiting for result. St Vincent's Hospital Rational Investigations Ordering Project (April 2014)

44 Post-post analytical Decision support Simple rules Sample taken to soon after dose, suggest recollect Sample taken to soon after dose you dolt, recollect as you won t get any results on this useless sample Modelling More complex software Requires all inputs (doses, results, timing, other) The need for the data may improve compliance

45 TDM National Activities Issues are common to all labs / clinical sites A common national approach would be best Collection, reporting units and limits, decision support, phone limits, assay quality etc Suggest TG or AMH consider recommendations on these issues to support uniformity

46 Conclusions TDM and Chem Path have a lot in common TDM has some specific issues Pre-analytical Post analytical As much of this occurs outside the lab a team approach, with IT support seems vital We can learn best practice from each other. Clin Chem Pharm

Coping with Analytical Interferences

Coping with Analytical Interferences (Handling Icteric, Hemolytic and Lipaemic Samples) Graham Jones Department of Chemical Pathology St Vincent s Hospital, Sydney Surabaya Indonesia 2016 Acknowledgements