therapeutic drug monitoring contributing to better multiple configurations with tailor-made...

Therapeutic drug monitoringContributing to better patient care

With the cobas modular platform (cobas 4000 and 6000 analyzer series and cobas 8000 modular analyzer series) Roche has developed a platform concept based on a common architecture that delivers tailor-made solutions for diverse workload and testing requirements. The cobas modular platform is designed to reduce the complexity of laboratory operation and provide efficient and compatible solutions for network cooperation.

Flexible and intelligent solutions •Multipleconfigurationswithtailor-madesolutionsforhigher

efficiency and productivity•Consolidationofclinicalchemistryandimmunochemistrywith

more than 200 parameters for cost and workflow improve-ments

•Futuresustainabilitythrougheasyadaptationtochangingthroughput and parameter needs

•Consistencyofinteractionwithhardware,softwareand

reagents for less training and more staff flexibility•Consistencyofpatientresultsduetoauniversalreagent

concept

cobas® modular platformFlexible configurations for tailor made solutions

cobas 8000 modular analyzer series Large volume

38 configurations

cobas 6000 analyzer series Midvolume

7 configurations

cobas 4000 analyzer series Low volume

3 configurations

<c 502>

<c 501>

<c 311>

<e 602>

<e 601>

<e 411>

<c 701> <c 702>*

* TDM assays in development

COBAS,COBASC,COBASEandLIFENEEDSANSWERS are trademarks of Roche.

©2011 Roche

RocheDiagnosticsLtd.CH-6343RotkreuzSwitzerlandwww.cobas.com

Therapeutic drug monitoring Precision and method comparison study in routine laboratories on the COBAS INTEGRA® 800 analyzer and cobas c 501 module

IntroductionTherapeutic drug monitoring (TDM) is a common laboratory routine used to measure a serum or plasma drug concentration for patients using drugs that are typically prescribed for long-term intake and which have a narrow therapeutic range. Within this range most patients will experience significant therapeutic effects without an undesirable degree of adverse reactions. Below the range, drugs are most likely ineffective. Above the range, there is a possible toxic side effect without any improvement in the efficacy of the drug. Consequently, precision at the relevant medical decision points – the low and high end of the therapeutic range - is a key performance measure for this range of tests. TDM has experienced a degree of technological change over the past years: historically, HPLC was used for measurement. Today, most tests are run on automated systems to improve laboratory efficiency.

An evaluation of eight TDM tests was carried out on the cobas c 501 module and the COBAS INTEGRA® 800 analyzer. The study was carried out across three sites in Germany.

G. Brandhorst1, M. Shipkova2, E. Rosler3, D. Petrova1, M. Orth2, J. Engelmayer1, E. Wieland2, M. Oellerich1 1 Department of Clinical Chemistry, Universitätsmedizin Goettingen, Germany 2 Klinikum Stuttgart, Department of Clinical Chemistry and Laboratory Medicine, Stuttgart, Germany3 Marienhospital Stuttgart, Stuttgart, Germany

Evaluator Laboratory Country

Hr. Prof. M. OellerichHr. Dr. G. BrandhorstFr. J. EngelmayerFr. S. Götze

Universitätsmedizin Göttingen

Germany, Göttingen

Fr. Dr. M. ShipkovaFr. K. RappFr. S. Stier

Katharinenhospital Stuttgart

Germany, Stuttgart

Hr. Dr. A. E. Rosler Marienhospital Stuttgart

Germany, Stuttgart

Key conclusionThe study clearly demonstrates the consistent performance parity between the COBAS INTEGRA 800 analyzer and cobas c 501 module and the excellence of the intermediate precision of the cobas c 501 module. For six of the eight assays (including Carbamazepine, Phenobarbital, Phenytoin, Theophylline, Vancomycin and Valproic Acid) excellent intermediate precision results were obtained on both analytical systems.

The CVs for both Digoxin and Tobramycin were slightly higher overall - however, the results were still comparable between the two analyzers. The method comparison yielded excellent results for 4 of 8 assays with slopes less or equal to +/- 4%. The remaining assays showed a good comparison (1.05 - 1.07). The results showed an excellent correlation (r) of 0.98 - 1.00.

Detailed results & conclusionsOverall, the comparison between the two Roche systems COBAS INTEGRA 800 analyzer and cobas c 501 module demonstrated very consistent and precise results and excellent % CV at the relevant medical decision points. For intermediate precision, the following detailed results were obtained:Carbamazepine: excellent results with CVs between

2.0 and 4.7% were obtained on both systems.

Digoxin: comparable results on both analyzers. CVs up to 8% measured at low concentration levels.

Phenobarbital: Very good results with CVs below 5.1% with one exception of 6.3%.

Phenytoin: excellent results on both analyzers.Theophylline: excellent results on both analyzers.

Slightly superior results on cobas c 501 module with CVs between 2.4 and 3.0%.

Tobramycin: in mid and high concentration, results superior on cobas c 501 module. However, at the low level a high CV was obtained on this analyzer.

Vancomycin: excellent and well comparable results on both analyzers.

Valproic acid: very good results below 6%. Slightly superior results on COBAS INTEGRA 800 analyzer.

Study designThe study objectives were 1) to analyze the precision of immunoassays based on different technologies and 2) to compare the results using routine samples on the cobas c and COBAS INTEGRA® platforms. For the study, eight routine TDM tests using different test principles have been evaluated. (Table 1).

Samples were collected at each site and shared between the sites. The measurements were done in 2 replicates, 2 runs /day, over 10 days. Intermediate precision was calculated from 40 replicates. The comparison of the methods was performed by calculation of the Passing /Bablok regression analysis. Implausible results were discussed and repeated if necessary.

Parameter Expected range guide

System Test principle Measuring range package insert

Carbamazepine 8 – 12 mg/L cobas c 501 module KIMS 0.35 – 20 mg/L

COBAS INTEGRA® 800 analyzer FPIA 0.12 – 20 mg/L

Digoxin 0.6 – 1.2 μg/L cobas c 501 module KIMS 0.3 – 5.0 μg/L

COBAS INTEGRA 800 analyzer KIMS 0.3 – 5.0 μg/L

Phenobarbital 10 – 30 mg/L cobas c 501 module KIMS 2.4 – 60 mg/L

COBAS INTEGRA 800 analyzer FPIA 1.0 – 60 mg/L

Phenytoin 10 – 20 mg/L cobas c 501 module KIMS 0.8 – 40 mg/L


Theophylline 10 – 20 mg/L cobas c 501 module KIMS 0.8 – 40 mg/L


Tobramycin 6 – 10 mg/L and 0.5 – 2.0 mg/L

cobas c 501 module EMIT 0.33 – 10 mg/L


Vancomycin 25 – 40 mg/L and 5 – 10 mg/L

cobas c 501 module EMIT 1.7 – 80 mg/L


Valproic Acid 50 – 100 mg/L cobas c 501 module EMIT 2.8 – 150 mg/L


Table 1: Overview about parameters and test principles

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

COBAS INTEGRA® 800 Abbott AxSym® Abbott Architect®

*Level 3 not measured

0

*

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3

COBAS INTEGRA 800analyzer

Fig. 2: Digoxin

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 3: Phenobarbital

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 4: Phenytoin

Intermediate precision For six of the eight assays excellent intermediate precision results were obtained on both analytical systems. The CVs for both Digoxin and Tobramycin were slightly higher overall - however, the results were still comparable between the two analyzers.

Fig. 1: Carbamazepine

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

cobas c 501module

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

COBAS INTEGRA® 800analyzer

Abbott AxSym® Abbott Architect®

*

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



0

*

cobas c 501module

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3


Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 5: Theophylline

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 6: Tobramycin

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 7: Vancomycin

CV

[%

]

CV

[%

]

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501module

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

COBAS INTEGRA® 800analyzer

Abbott AxSym® Abbott Architect®

*

0

6.0

2.0

4.0

10.0

8.0

12.0

cobas c 501

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3

TDM level1 2 3



*

0

TDM level1 2 3

Abbott AxSym®

Abbott Architect®

TDM level1 2 3*

cobas c 501module

TDM level1 2 3

TDM level1 2 3


Fig. 8: Valproic Acid

Correlation COBAS INTEGRA 800® analyzer vs. cobas c 501 moduleThe method comparison yielded excellent results for 4 of 8 assays with slopes less or equal to +/- 4%. The remaining assays showed a good comparison (1.05 - 1.07). The results showed an excellent correlation (r) of 0.98 - 1.00.

Car

bam

azep

ine

[mg/

L] c

obas

c 5

01 m

odul

e

Carbamazepine[mg/L] COBAS INTEGRA 800 analyzer

Car

bam

acep

in

[mg/

L] c

obas

c 5

01 m

odul

e

Carbamacepin[mg/L] COBAS INTEGRA® 800 analyzer

0.0

10.0

8.0

6.0

4.0

2.0

12.0

14.0

16.0

18.0

20.0

0.0 4.0 8.0 12.0 16.0 20.0

0.0

10.0

8.0

6.0

4.0

2.0

12.0

14.0

16.0

18.0

20.0

0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0 18.0 20.0

0 0.5 1.0 1.5 2.0 2.5 3.03.5

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

AA

GP

2Im

mun

otur

bidi

met

ry g

/Lco

bas

c 5

01 m

odul

e

AAG Immunonephelometry g/L BN II

Dig

oxin

[µg/

L] c

obas

c 5

01 m

odul

e

Digoxin[µg/L] COBAS INTEGRA 800 analyzer

0.0

2.5

2.0

1.5

1.0

0.5

3.0

3.5

4.0

4.5

5.0

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

Fig. 9: Carbamazepine Fig. 10: Digoxin

Phe

noba

rbit

al[m

g/L]

cob

as c

501

mod

ule

Phenobarbital[mg/L] COBAS INTEGRA 800 analyzer

Phe

noba

rbit

al[m

g/L]

cob

as c

501

mod

ule

Phenobarbital[mg/L] COBAS INTEGRA® 800 analyzer

0.0

20.0

10.0

30.0

40.0

50.0

60.0

70.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

0.0

20.0

10.0

30.0

40.0

50.0

60.0

70.0

0.0 10.0 20.0 30.0 40.0 50.0 60.0 70.0

Phe

nyto

in[m

g/L]

cob

as c

501

mod

ule

Phenytoin[mg/L] COBAS INTEGRA 800 analyzer

Phe

nyto

in[m

g/L]

cob

as c

501

mod

ule

Phenytoin[mg/L] COBAS INTEGRA® 800 analyzer

0.0

20.0

10.0

5.0

15.0

25.0

30.0

35.0

40.0

45.0

0.0 10.015.05.0 20.025.030.035.040.045.0

0.0

20.0

10.0

5.0

15.0

25.0

30.0

35.0

40.0

45.0

0.0 10.0 15.05.0 20.0 25.0 30.0 35.0 40.0 45.0

Fig. 11: Phenobarbital Fig. 12: Phenytoin

P/B regressionY = 1.074 * X – 0.031md(95) = 1.453N = 77 r = 0.9769t = 0.9026

P/B regression Y = 1.033 * X – 0.005 md(95) = 0.092N = 67 r = 0.9920t = 0.8751

P/B regression Y = 0.982 * X + 0.18md(95) = 1.609N = 58 r = 0.9961t = 0.9525

P/B regression Y = 1.014 * X + 0.074 md(95) = 1.94N = 63 r = 0.9868t = 0.9171

Van

com

ycin

[mg/

L] c

obas

c 5

01 m

odul

e

Vancomycin[mg/L] COBAS INTEGRA 800 analyzer

Van

com

ycin

[mg/

L] c

obas

c 5

01 m

odul

e

Vancomycin[mg/L] COBAS INTEGRA® 800 analyzer

0.0

30.0

10.0

20.0

40.0

50.0

60.0

0.0 50.040.030.020.010.0 60.0

0.0

30.0

10.0

20.0

40.0

50.0

60.0

0.0 50.040.030.020.010.0 60.0

Val

proi

c A

cid

[mg/

L] c

obas

c 5

01 m

odul

e

Valproic Acid[mg/L] COBAS INTEGRA 800 analyzer

Val

proi

c A

cid

[mg/

L] c

obas

c 5

01 m

odul

e

Valproic Acid[mg/L] COBAS INTEGRA® 800 analyzer

Val

proi

c A

cid

[mg/

L] c

obas

c 5

01 m

odul

e

Valproic Acid[mg/L] COBAS INTEGRA® 800 analyzer

0.0

60.0

20.0

40.0

80.0

100.0

120.0

0.0 100.080.060.040.020.0 120.00.0

60.0

20.0

40.0

80.0

100.0

120.0

0.0 100.080.060.040.020.0 120.0

0.0

60.0

20.0

40.0

80.0

100.0

120.0

0.0 100.080.060.040.020.0 120.0

Fig. 15: Vancomycin Fig. 16: Valproic Acid

P/B regression Y = 1.05 * X + 0.226md(95) = 1.34N = 81 r = 0.9952t = 0.9511


Theo

phyl

line

[mg/

L] c

obas

c 5

01 m

odul

e

Theophylline[mg/L] COBAS INTEGRA 800 analyzer

Theo

phyl

line

[mg/

L] c

obas

c 5

01 m

odul

eTheophylline

[mg/L] COBAS INTEGRA® 800 analyzer

Theo

phyl

line

[mg/

L] c

obas

c 5

01 m

odul

e

Theophylline[mg/L] COBAS INTEGRA® 800 analyzer

0.0

20.0

10.0

5.0

15.0

25.0

30.0

35.0

0.0 10.0 15.05.0 20.0 25.0 30.0 35.00.0

20.0

10.0

5.0

15.0

25.0

30.0

35.0

0.0 10.0 15.05.0 20.0 25.0 30.0 35.0

0.0

20.0

10.0

5.0

15.0

25.0

30.0

35.0

0.0 10.0 15.05.0 20.0 25.0 30.0 35.0

Tobr

amyc

in[m

g/L]

cob

as c

501

mod

ule

Tobramycin[mg/L] COBAS INTEGRA 800 analyzer

Tobr

amyc

in[m

g/L]

cob

as c

501

mod

ule

Tobramycin[mg/L] COBAS INTEGRA® 800 analyzer

Tobr

amyc

in[m

g/L]

cob

as c

501

mod

ule

Tobramycin[mg/L] COBAS INTEGRA® 800 analyzer

0.0

7.0

5.0

4.0

3.0

1.0

2.0

6.0

8.0

9.0

10.0

0.0 5.0 6.04.03.02.01.0 7.0 8.0 9.0 10.00.0

7.0

5.0

4.0

3.0

1.0

2.0

6.0

8.0

9.0

10.0

0.0 5.0 6.04.03.02.01.0 7.0 8.0 9.0 10.0

0.0

7.0

5.0

4.0

3.0

1.0

2.0

6.0

8.0

9.0

10.0

0.0 5.0 6.04.03.02.01.0 7.0 8.0 9.0 10.0

Fig. 13: Theophylline Fig. 14: Tobramycin


P/B regression Y = 1.069 *X – 0.041 md(95) = 0.473N = 47 r = 0.9911t = 0.9541

COBAS, COBAS C, COBAS INTEGRA and LIFE NEEDS ANSWERS are trademarks of Roche. All other trademarks are property of their respective owners.

©2011 Roche

Roche Diagnostics Ltd.CH-6343 RotkreuzSwitzerlandwww.cobas.com

AcknowledgementA special thank you to all investigators - especially I. Domke and A. Fahle - at the various locations for performing the study. Thanks also to the Roche colleagues for their dedicated support.

CarbamazepineONLINE TDM Carbamazepine, CARB2 Kinetic interaction of microparticles in solution (KIMS) immunoassay for the quantitative in vitro determination of carbamazepine in serum and plasma on cobas c systems*

IndicationCarbamazepine is an anticonvulsant drug used for the treatment of trigeminal neuralgia,1 all forms of partial epilepsy, generalized tonic-clonic (grand mal) seizures, as well as simple and complex partial seizures.2,3,4 Some dosage forms, e.g. Equetrol, have been approved for treating bipolar mood disorder.5 The specific mechanism of carbamazepine is proposed as a depressant action on the transmission through the nucleus ventralis anterior of the thalamus.2,3 In combination with other clinical information, monitoring carbamazepine levels provides physicians with an effective tool to aid in adjusting dosage and achieving optimal therapeutic effect while avoiding both sub-therapeutic and toxic drug levels.

Test principle: Kinetic interaction of microparticles in solution (KIMS)

Liquid, ready-to-use,two-reagent formulation eliminates the need for mixing

Aggregation indicatesabsence of target drug in sample

Bi-drug hapten conjugatedmicro-particles+Anti-carbamazepine antibody

Anti-carbamazepine antibody+Streptavidine coated latex beads

Bi-drug hapten conjugatedmicro-particles+Anti-carbamazepine antibody+Drug in sample

Lack of aggregation indicates presence of target drug in sample

Negative

Positive

R1 R2

Aggregation

No aggregation



Antibody conjugatedMicro-particles+Drug-conjugate

Antibody conjugatedMicro-particles+Drug-conjugate+Drug in sample


Negative

Positive

R1 R2

Aggregation

No aggregation






Negative Positive

R1 R2

Aggregation No aggregation

Biotinylated drug

•Biotinylateddrughaptenservesasbindingpartner to

•anti-carbamazepineantibody •Streptavidincoatedlatexbeads•Acompetitivereactiontoalimitedamount

of specific anti-carbamazepine antibody takes place between the hapten and free carbamazepine in the sample

•Adecreaseinapparentsignalis proportionate to the amount of drug present in the sample

* all cobas c systems except cobas c 111 analyzer

Carbamazepine test characteristics

Reaction time 10 min

Test principle Kinetic interaction of microparticles in solution (KIMS)

Calibration 6-point after reagent lot change, and as required following quality control procedures

Traceability Standardized against USP reference standards

Sample material Serum, Plasma (sodium or lithium heparin plasma and K2-EDTAplasma)

Sample volume 2 μL

Measuring range 0.35 – 20 μg/mL (1.5 – 85 μmol/L)

Carbamazepine expected values guideTroupin et al. 6 – when used as sole agentShorvon et al. 7

8 – 12 μg/mL (33.8 – 50.8 μmol/L) 4 – 8 μg/mL (16.9 – 33.8 μmol/L)

Repeatability (Within-run precision) Control 1Control 2Control 3

Mean μg/mL μmol/L CV%2.7 11.4 3.58.2 34.7 2.113.9 58.8 1.3

Intermediate precision (total precision/between-run precision/between-day precision)Control 1Control 2Control 3


COBAS,COBASCandLIFENEEDSANSWERS are trademarks of Roche.

©2011 Roche


Order information

Online TDM Carbamazepine 100 tests 04490819 190

Preciset TDM I Calibrators CALA-F Diluent

6 x 5 mL 1 x 10 mL

03375790 190 Codes 691-696

TDM Control Set Level I Level II Level III

2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536 190 Code 310 Code 311 Code 312

References

1 Blom,S.(1962).Trigeminalneuralgia:itstreatmentwithanewanticonvulsantdrug

(G-32883). Lancet: 839-840.

2 Eadie,M.J.,Tyler,J.H.(1974).AnticonvulsantTherapy:PharmacologicalBasisandPractice.

Edinburgh,GreatBritain.Churchill Livingstone. Chap. 7.

3 Penry,J.K.,Newmark,M.E.(1979).Theuseofantiepilepticdrugs.Ann Int Med. 90: 207-218.

4 Scheuer,M.L.,Pedley,T.A.(1990).Theevaluationandtreatmentofseizures.N Engl J Med;

322(21): 1468- 1474

5 bipolar disorder

6 Troupin,A.,Ojemann,L.M.,Halpem,L.,etal.(1977).Carbamazepine-adoubleblindcompari-

son with phenytoin. Neurology; 27: 511-519.

7 Shorvon,S.D.,Chadwick,D.,Galbraith,A.W.,etal.(1978).Onedrugforepilepsy.Br Med J. 1:

474–476.

InterferencesPatients with renal insufficiency, such as those on hemodialysis, may exhibit carbamazepine levels in serum or plasma that are not consistent with clinical expectations for patients with normal renal function. If results are greater than the expected range, determine if the patient has renal insufficiency.

Key ONLINE TDM points•highspecificitytoparentdrug•negligiblecross-reactivitytoabroadspectrumofcompounds•nosignificantinterferenceto16commondrugs•noHAMAcross-reactivity

DigoxinONLINE TDM Digoxin, DIG Kinetic interaction of microparticles in solution (KIMS) immunoassay for the quantitative in vitro determination of digoxin in serum and plasma on cobas c systems*

IndicationDigoxin is a digitalis glycoside which is widely used in the treatment of various heart conditions. Digoxin exerts a positive inotropic effect which increases the contractile response of the myocardial fibers in patients experiencing congestive heart failure.1 Cardiac glycosides can also produce several electrophysiological effects that produce negative chronotropic effects on the human heart.2 These effects tend to slow down and regulate a rapid, irregular beat found in patients experiencing cardiac arrhythmias.3 Due to its extremely narrow therapeutic range, monitoring digoxin concentration provides physicians with an effective tool to aid in achieving optimal therapeutic effect while avoiding both sub-therapeutic and toxic drug levels.




Bi-drug hapten conjugatedmicro-particles+Anti-carbamazepine antibody

Bi-drug hapten conjugatedmicro-particles+Anti-carbamazepine antibody+Drug in sample


Negative

Positive

R1 R2

Aggregation

No aggregation






Negative

Positive

R1 R2

Aggregation

No aggregation






Negative Positive

R1 R2


•Liquid,ready-to-use,two-reagentformulation •anti-digoxinmonoclonalantibody •Conjugateddigoxinderivative

microparticles•Acompetitivereactiontoalimitedamount

of specific anti-digoxin antibody takes place •Aggregationindicatesabsenceoftarget

drug in sample•Lackofaggregationindicatespresence

of drug in sample•Bymonitoringthechangeinscatteredlight

or absorbance, a concentration dependant curve is obtained


Digoxin test characteristics



Calibration 6-pointafterreagentlotchange,andasrequiredfollowingqualitycontrol procedures


Sample material Serum,Plasma(LiheparinplasmaandK2-EDTAplasma)

Sample volume 5.5μL

Measuring range 0.3–5.0ng/mL(0.38–6.4nmol/L)

Digoxin Expected Values GuideTherapeutic effects 4

ESC Guidelines for diagnosis and treatment of acute and chronic heart failure5

0.8–2ng/mL (1.0–2.6nmol/L) 0.6–1.2ng/mL (0.77–1.5nmol/L)


Meanng/mL nmol/L CV%0.87 1.1 4.01.8 2.3 1.63.0 3.8 1.0

Intermediate precision (total precision/between-run precision/between-day precision) Control 1Control 2Control 3

Meanng/mL nmol/L CV%0.87 1.1 6.01.8 2.3 2.43.0 3.8 1.6


©2011 Roche


References

1 Lee,K.S.,Klaus,W.(1971).Thesubcellularbasisforthemechanismofinotropicactionof

cardiac glycosides. Pharmacol Rev. 23:193-261.

2 Hoffman,B.F.(1969).In:Fisch,C.,Surawicz,B.,eds.Effectsofdigitalisonelectricalactivityof

cardiac fibers. Digitalis. New York, NY: Grune and Stratton: 93-109.

3 Moe,G.K.,Farah,A.E.(1970).In:Goodman,L.S.,Gilman,A.eds.Digitalisandalliedcardiac

glycosides.ThePharmacologistBasisofTherapeutics.New York, NY. MacMillan Company.

4 Huffman,D.H.,Crow,J.W.,Pentikaimen,P.,Azarnoff,D.L.(1976).Clinicalcardiacstatus,labo-

ratory parameters and digoxin usage. Am Heart J. 91: 28.

5 Dickstein,K.,Cohen-Solal,A.,Filippatos,G.,McMurray,J.J.,Ponikowski,P.,Poole-Wilson,

P.A.,etal.(2008).ESCGuidelinesforthediagnosisandtreatmentofacuteandchronicheart

failure2008:theTaskForcefortheDiagnosisandTreatmentofAcuteandChronicHeart

Failure2008oftheEuropeanSocietyofCardiology.DevelopedincollaborationwiththeHeart

FailureAssociationoftheESC(HFA)andendorsedbytheEuropeanSocietyofIntensiveCare

Medicine (ESICM). Eur Heart J. 29: 2388-442.

Order information

Online TDM Digoxin 250 tests 20737836322


6x5mL 1x10mL

03375790190 Codes691-696

TDM Control Set LevelI LevelII LevelIII

2x5mL 2x5mL 2x5mL

04521536190 Code 310 Code 311 Code 312


PhenobarbitalONLINE TDM Phenobarbital, PHNO2 Kinetic interaction of microparticles in solution (KIMS) immunoassay for the quantitative in vitro determination of phenobarbital in serum and plasma on cobas c systems*

IndicationPhenobarbital is one of the most commonly used drugs for the treatment of grand mal, psychomotor epilepsy and other forms of focal epilepsy. Monitoring the serum level of the drug is essential in order to achieve maximum seizure control while maintaining minimal blood levels to avoid negative side effects.1,2 As with other anti-convulsant drugs, it is imperative that each patient’s dosage be individualized.3




Antibody conjugatedmicro-particles+Drug-conjugate

Antibody conjugatedmicro-particles+Drug-conjugate+Drug in sample


Negative

Positive

R1 R2

Aggregation

No aggregation






Negative Positive

R1 R2


•Phenobarbitalantibodyiscovalentlycoupledto microparticles and the drug derivative is linked to a macromolecule

•Thekineticinteractionofthemicroparticlesin solutions is induced by binding of drug conjugate to the antibody on the microparticles and is inhibited by the presence of phenobarbital in the sample

•Acompetitivereactiontoalimitedamountof specific anti-phenobarbital antibody takes place between the drug conjugate and free phenobarbital in the sample



Phenobarbital test characteristics


Testprinciple Kinetic interaction of microparticles in solution (KIMS)



Sample material Serum, Plasma (K2 or K3-EDTA,lithiumorsodiumheparin)

Sample volume 2 μL

Measuring range 2.4 – 60 μg/mL (10.3 – 258.6 μmol/L)

Phenobarbital expected values guide 10 – 30 μg/mL (43.1 – 129 μmol/L)



Intermediate precision (total precision/between-run precision/between-day precision) Control 1Control 2Control 3


COBAS, COBAS C and LIFE NEEDS ANSWERS are trademarks of Roche.

©2011 Roche


Order information

OnlineTDMPhenobarbital 100 tests 200 tests

04490924 190 05027446 190

PrecisetTDMICalibrators CAL A-F Diluent

6 x 5 mL 1 x 10 mL

03375790 190 Codes 691-696

TDMControlSet Level I Level II Level III

2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536 190 Code 310 Code 311 Code 312

References

1 Johannessen, S.I. (1981). Anti-epileptic drugs: pharmacokinetic and clinical aspects. Ther

Drug Monit. 3(1): 17.

2 Koch-Weser, J. (1981). Serum drug concentrations in clinical perspective. Ther Drug Monit.

3(1): 3-16

3 Pippenger, C.E. (1980). Effective seizure control requires drug monitoring. Battaglia, B.J., ed.

Clin Chem. New Special Section. Washington, DC: American Association of Clinical Chemistry.

1s and 10s.


PhenytoinONLINE TDM Phenytoin, PHNY2 Kinetic interaction of microparticles in solution (KIMS) immunoassay for the quantitative in vitro determination of phenytoin in serum and plasma on cobas c systems*

IndicationPhenytoin has been used extensively for seizure control in patients suffering from grand mal epilepsy, cortical focal seizures and temporal lobe epilepsy.1 Monitoring the serum level of the drug is essential in order to achieve maximum seizure control while maintaining minimal blood levels to avoid negative side effects.1,2,3 Due to individual patient variation in absorption and metabolism, optimum levels may vary.







Negative

Positive

R1 R2

Aggregation

No aggregation






Negative Positive

R1 R2


•Phenytoiniscovalentlycoupledtomicroparticles and the drug derivative is linked to the macromolecule

•Thekineticinteractionofmicroparticlesin solutions is induced by binding of drug conjugate to the anti-body on the microparticles and is inhibited by the presence of phenytoin in the sample

•Acompetitivereactiontoalimitedamount of specific anti-phenytoin antibody takes place betweenthe drug conjugate and free phenytoin in the sample



Phenytoin test characteristics


Testprinciple Kinetic interaction of microparticles in solution (KIMS)



Sample material Serum, Plasma (K2 or K3-EDTA,lithiumorsodiumheparin)

Sample volume 1.7 μL

Measuring range 0.8 – 40 μg/mL (3.2 – 158.4 μmol/L)

Phenobarbital expected values guide4 10 – 20 μg/mL (39.6 – 79.2 μmol/L)






©2011 Roche


Order information

OnlineTDMPhenytoin 100 tests 200 tests

04490932 190 05108411 190

PrecisetTDMICalibrators CALA-F Diluent

6 x 5 mL 1 x 10 mL

03375790 190 Codes 691-696


2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536 190 Code 310 Code 311 Code 312

References

1 Buchthal,F.,Klennox-Buchthal,M.A.(1972).In:AntiepilepticDrugs.WoodburyDM,PenryJK,

SchmidtRP,eds.NewYork,NY:Raven Press. 93. 209.

2 Buchthal,F,Svensmark,O.(1971).Serumconcentrationofdiphenylhydantoin(phenytoin)and

phenobarbital and their relation to therapeutic and toxic effects. Psychiatr Neurol Neurochir.

74: 117-136.

3 Booker,H.E.,Hosokowa,K.,Burdette,R.D.,Darcey,B.(1970).Aclinicalstudyofserumprimi-

done levels. Epilepsia. 11: 395-402.

4 Booker,H.(1978).In:PippengerCE;PerryJKC,JuttH,eds.Anti-epilepticDrugs:Quantitative

AnalysisandInterpretation.NewYork,NY:Raven Press. 253-260.


TheophyllineONLINE TDM Theophylline, THEO2, THE-2 Kinetic interaction of microparticles in solution (KIMS) immunoassay for the quantitative in vitro determination of theophylline in serum and plasma on cobas c systems*

IndicationTheophylline, a bronchodilator, is widely used to treat patients with asthma, apnea (temporary asphyxia) and other obstructive lung diseases. Monitoring the serum level of the drug is essential as individual patients can vary in their rate of theophylline clearance1,2 and severe toxicity has been observed without prior occurrence of minor side effects.3 Several factors can alter theophylline elimination: it is slowed in obese patients, patients with hepatic disease and those on a high carbohydrate, low protein diet. Premature infants have very low rates of theophylline elimination.4 Conversely, theophylline elimination in more rapid among patients who smoke.5 In combination with other clinical data, monitoring serum theophylline levels can provide the physician with useful information to aid in adjusting a patient’s dosage to achieve optimal therapeutic effect while avoiding drug toxicity.







Negative

Positive

R1 R2

Aggregation

No aggregation






Negative Positive

R1 R2


•Theophyllineantibodyiscovalentlycoupledto microparticles and the drug derivative is linked to a macromolecule

•Thekineticinteractionofmicroparticlesinsolution is induced by binding of drug conjugate to the antibody on the microparticles and is inhibited by the presence of theophylline in the sample

•Acompetitivereactiontoalimitedamountof specific anti-theophylline antibody takes place between the drug conjugate and free theophylline in the sample



Theophylline test characteristics



Calibration 6-point after cobas c pack change, after reagent lot change, and as required following quality control procedures


Sample material Serum, Plasma (sodium, ammonium or lithium heparin, K2 or K3-EDTA,sodium citrate)


Measuring range6 0.8 – 40 μg/mL (4.4 – 222 μmol/L)

Phenobarbital expected values guide4 10 – 20 μg/mL (55.5 – 111 μmol/L)






©2011 Roche


Order information

Online TDM Theophylline 100 tests 04491025 190


6 x 5 mL 1 x 10 mL

03375790 190 Codes 691-696

TDM Control Set Level I Level II Level III

2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536 190 Code 310 Code 311 Code 312

References

1 Piafsky, K.M., Ogilvie, R.I. (1975). Drug therapy. Dosage of theophylline in bronchial asthma. N Engl

J Med. 292: 1218-1222.

2 Leung,P.,Kalisker,A.,Bell,T.D.(1977).Variationintheophyllineclearanceratewithtimeinchronic

childhood asthma. J Allergy Clin Immun. 59: 440-444.

3 Zwillich,C.W.,Sutton,F.D.,Neff,T.A.,etal.(1975).Theophylline-inducedseizuresinadults.

Correlation with serum concentrations. Ann Intern Med. 82: 784-787.

4 Ogilvie, R.I. (1978). Clinical pharmacokinetics of theophylline. Clinical Pharmacokinetics. 3: 267-293.

5 Hendeles, L., Weinberger, M.M. (1981). Theophylline therapeutic use and serum concentration

monitoring.In:TaylorWJ,FinnAL,eds.IndividualizingDrugTherapy:PracticalApplicationsof

Drug Monitoring, I. New York, NY:GrossTownsendFrank,Inc.31-66.

6 Jackson,F.R.,Garrido,R.,Silverman,H.I.,Salem,H.(1973).Bloodlevelsfollowingoraladministration

of theophylline preparations. Ann Allergy. 31: 413-419.


TobramycinONLINE TDM Tobramycin, TOBR2 Kinetic interaction of microparticles in solution (EMIT) immunoassay for the quantitative in vitro determination of tobramycin in serum and plasma on cobas c systems*

IndicationTobramycin is an aminoglycoside antibiotic used in the treatment of infections caused by Pseudomonas aeruginosa, Proteus species, E.coli, Klebsiella, Serratia, Citrobacter, Staphylococcus aureus, Enterobacter and other microorganisms. The half-life of tobramycin in serum or plasma correlates closely with renal function and thus is quite variable between individuals over time.1,2 Serum or plasma tobramycin concentration is also impacted by mode of administration, the volume of extracellular fluid, the duration of the treatment and physiological changes during the illness and therapy. A peak therapeutic range is suggested for antimicrobial effectiveness. However, patients with pre-existing renal damage, or those to whom tobramycin has been administered for prolonged periods, may develop hearing impairment and/or nephrotoxicity.3 Elevated or increasing trough levels are an indication of drug accumulation due to renal impairment. Therefore, the monitoring of tobramycin at peak and trough concentrations is critical in the prevention of these serious complications.4

Test principle: Homogeneous enzyme immunoassay technique (EMIT)

Anti-drug antibody

Drug labeled enzyme is bound to anti-drug-antibody Enzyme inactive

In a competition, the free drug competes with drug-enzyme-conjugate for the antibodyMore drug in the sample more antibody–binding-sites are blocked by drug • less drug-enzyme-conjugates are bound to antibody• more NADH is built

NADH absorbs at 340 nmReaction direction: increase

Substrate = Glucose-6-phosphate

Nicotinamideadenin dinucleotide

Drug labeled enzyme:Enzyme = Glucose-6-phosphate dehydrogenase

The enzyme is only active if not bound to antibody.

Drug sample

No drug in the sample Drug in the sample

NAD+ + + NAD+ + NAD+ + + NAD++

•Theassayisbasedoncompetitionbetweendruginthesampleanddruglabeledwiththeenzymeglucose-6-phosphatedehydrogenase(G6PDH)forantibodybindingsites

•Enyzmeactivitydecreasesuponbindingtotheantibody,sothedrugconcentrationinthesamplecanbemeasuredintermsofenzymeactivity

•ActiveenzymeconvertsoxidizedNADtoNADH,resultinginanabsorbancechangethatismeasuredspectrophotometrically* all cobas c systems except cobas c 111 analyzer

Tobramycin test characteristics


Test principle Homogeneousenzymeimmunoassaytechnique(EMIT)

Calibration

6-pointaftercobas c pack change, after reagent lot change, and as required following quality control procedures. Calibration on cobas c includes a recalibration every 3 days.

Traceability StandardizedagainstUSPreferencestandards

Sample material Serum, Plasma (K2 or K3-EDTA,sodiumcitrate,fluorideoxalate,sodiumorlithiumheparin)


Measuringrange 0.33–10μg/mL(0.71–21.4μmol/L)

Tobramycin expected values guide4 PeakTrough

6–10μg/mL (12.8-21.4μmol/L)0.5–2.0μg/mL(1.1-4.3μmol/L)

Repeatability(Within-runprecision) Control 1Control 2Control 3

Meanμg/mL μmol/L CV%1.6 3.4 4.23.6 7.7 2.87.7 16.5 2.9

Intermediateprecision (totalprecision/between-runprecision/between-dayprecision)Control 1Control 2Control 3



©2011 Roche


Order information

OnlineTDMTobramycin 100 tests 04491033190


6x5mL 1 x 10 mL

03375790190 Codes691-696

TDMControlSet LevelI LevelII LevelIII

2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536190 Code 310 Code 311 Code 312

Multiclean 59mL 04708725190

References

1 Cipoll,R.J.,Seifert,R.D.,Zaske,D.E.,etal.(1980).Systematicallyindividualizingtobramycin

dosage regimens. J Clin Pharm. 20:570-580.

2 Naber,K.G.,Westinfelder,S.R.,Madsen,P.O.(1973).Pharmacokineticsoftheaminoglycoside

antibiotic tobramycin in humans. Antimicrob Agents Chemother. 3:469-473.

3 Sande,M.A.,Mandell,G.L.(1980).AntimicrobialAgents,theaminoglycosides.In:Gilman,A.G.,

Goodman, L.S., Gilman, A., eds. The Pharmacological Basis of Therapeutics. New York, NY:

MacMillan.1162-1180.

4 Baselt,R.C.,Cravey,R.H.(1990).DispositionofToxicdrugsandChemicalsinMan.3rd ed.805-807.


Valproic AcidONLINE TDM Valproic Acid, VALP2 Kinetic interaction of microparticles in solution (EMIT) immunoassay for the quantitative in vitro determination of valproic acid in serum and plasma on cobas c systems*

IndicationValproic acid (VPA) is an anticonvulsant medication which is used mainly for the treatment of primary and secondary generalized seizures, but is also effective against absence seizures.1,2 It is particularly effective in myoclonus and is the drug of choice in photosensitive epilepsy.2 Although VPA is used in conjunction with other anti-epileptic medications, more recent studies have shown benefits of converting treatment to VPA monotherapy.3 Also, a growing body of evidence suggests that VPA is useful in the treatment of affective disorders, in particular lithium-insensitive bipolar disorders.4 Valproic acid has the fewest adverse side effects of all the widely-used anti-epileptic agents. Some incidences of tremor, coma or stupor have been noted – often in conjunction with other co-administration of other anti-epileptic drugs. Pharmacokinetics of VPA are highly variable depending on the form of drug and route of administration, as well as individual variations in metabolism and clearance.5 Therefore, monitoring VPA concentrations during therapy is essential in order to provide the physician with an indicator for adjusting dosage.


Anti-drug antibody








Drug sample




•Enyzmeactivitydecreasesuponbindingtotheantibody,sothedrugconcentrationinthesamplecanbemeasuredintermsof enzyme activity


Valproic Acid test characteristics


Test principle Homogeneousenzymeimmunoassaytechnique(EMIT)

Calibration

6-pointaftercobas c pack change, after reagent lot change, and as requiredfollowingqualitycontrolprocedures. Calibration on cobas c includes a recalibration every 3 days.


Sample material Serum, Plasma (K2 or K3-EDTA,sodiumorlithiumheparin)


Measuringrange 2.8 – 150 μg/mL (19.4 – 1040 μmol/L)

ValproicAcidexpectedvaluesguide 2 50-100μg/mL (346.5-693.0μmol/L)






©2011 Roche


Order information

OnlineTDMValproicAcid

100 tests 200 tests

04491041 190 05108438 190

PrecisetTDMICalibrators CAL A-F Diluent

6x5mL 1x10mL

03375790 190 Codes691-696


2x5mL 2x5mL 2x5mL

04521536190 Code 310 Code 311 Code 312

References

1 Chadwick,D.(1988).Comparisonofmonotherapywithvalproateandotherantiepilepticdrugs

in the treatment of seizure disorders. AM J Med. 84 (suppl 1A): 3-6

2 Wallace,S.J.(1986).Useofethosuximideandvalproateinthetreatmentofepilepsy.Neurol

Clin. 4: 601-616.

3 Wilder, B.J., Rangel, R.J. (1988). Review of valproate monotherapy in the treatment of gener-

alized tonic-clonic seizures. Am J Med. 84 (suppl 1A): 7 -13.

4 Post,R.M.(1989).Emergingperspectivesonvalproateinaffectivedisorders.J Clin Psychiatry.

50: 23-29.

5 Zaccara,G.,Messori,A.,Moroni,F.(1989).Clinicalpharmacokineticsofvalproicacid.Clin

Pharmacokinet. 17: 327-344.


VancomycinONLINE TDM Vancomycin, VANC2 Kinetic interaction of microparticles in solution (EMIT) immunoassay for the quantitative in vitro determination of vancomycin in serum and plasma on cobas c systems*

IndicationVancomycin is a complex glycopeptide antibiotic, which has been used to treat penicillinase-producing staphylococci.1 It is the treatment of choice for antibiotic resistant Staphylococcus aureus,2,3 as well as for the treatment of gram-positive infections where allergies to penicillin or cephalosporin play a role. Vancomycin is also used in the treatment of antibiotic-induced enterocolitis associated with Clostridium difficile and streptococcal or enterococcal endocarditis, the latter in conjunction with an aminoglycoside, when penicillin or ampicillin is not an option.4 Monitoring the peak and trough serum or plasma levels is essential to optimize therapy and avoid potentially serious side effects including ototoxicity, nephrotoxicity, phlebitis and reversible neutropenia.5


Anti-drug antibody








Drug sample




•Enyzmeactivitydecreasesuponbindingtotheantibody,sothedrugconcentrationinthesamplecanbemeasuredintermsof enzyme activity


Vancomycin test characteristics


Testprinciple Homogeneousenzymeimmunoassaytechnique(EMIT)

Calibration 6-pointaftercobas c pack change, after reagent lot change, and as requiredfollowingqualitycontrolprocedures. Calibration on cobas c includes a recalibration every 3 days.

Traceability StandardizedagainstUSPreferencestandards

Sample material Serum,Plasma(K2orK3-EDTA,sodiumcitrate,fluorideoxalate)


Measuring range 1.7–80μg/mL (1.2–55.2μmol/L)

Vancomycin expected values guide4 PeakTrough

25-40μg/L (17.3-27.6μmol/L)5-10μg/L (3.5-6.9μmol/L)

Repeatability(Within-runprecision) Control 1Control 2Control 3


Intermediate precision (totalprecision/between-runprecision/between-dayprecision)Control 1Control 2Control 3



©2011 Roche


Order information

OnlineTDMVancomycin

100 tests 200 tests

04491050190 05108420190


6x5mL 1 x 10 mL

03375790190 Codes691-696


2 x 5 mL 2 x 5 mL 2 x 5 mL

04521536190 Code 310 Code 311 Code 312

References

1 McCormick,M.H.,Stark,W.M.,Pittinger,R.C.,McGuire,J.M.(1956).In:antibioticsAnnual.

New York, NY:MedicalEncyclopedia.606-611.

2 Crossley,K.B.,Landesman,B.,Zaske,D.(1979).Anoutbreakofinfectionscausedbystrainsof

Staphylococcus aureus resistant to methicillin and aminoglycosides. J Infect Dis. 139:273-279.

3 Sorrell,T.C.,Packham,S.,Shanker,M.,Foldes,M.,Munro,R.(1982).Vancomycintherapyfor

methicillin-resistant Staphylococcus aureus. Ann Intern Med. 97: 344-350.

4 Cook,F.V.(1978).Vancomycinrevisited.Ann Intern Med. 88: 813-818.

5 Zaccara,G.,Messori,A.,Moroni,F.(1989).Clinicalpharmacokineticsofvalproicacid.Clin

Pharmacokinet. 17: 327-344.


therapeutic drug monitoring contributing to better multiple configurations with tailor-made...

Documents