King AbdulAziz University Hospital

Biochem Lab. TDM area revised version 2009

An update of Reference range & Sampling time of currently monitored drugs
(draft version)
____________________________________________________________________________________________________________________
Authors: Dr. Ahmed Shaker. Ali, PhD Associate Prof of pharmacology, TDM specialist
& Mrs. Randa Moumena, BS, (Pharmacy) MS (Clinical chemistry), Senior TDM-Staff.

Disclaimer
• Although the most recent literatures have been utilized and efforts has been taken to
ensure the accuracy of the information presented, this draft version still requires
careful review. Please verify the accuracy of the information before you use it. We
appreciate comments and contributions.
• The information provided is not comprehensive; it focuses on practically important
issues. Debates may exist about some recent protocols.
• Our recommendations are not intended to replace any authorized guidelines.
____________________________________________________________________
Aminoglycosides: 1-Multiple daily dosing (MD) 2-Extended-interval dosing (EID) in neonates

Drug Post Ref. Pre Ref. range Notes

(Peak) range (Trough) µmol/L
µmol/L

Amikacin At 30 min > 35-50 Just MD < 7 • Trough level depends on

post end of Before dosing regimen
EID < 2
30 min IV next dose • Higher peak may be allowed
infusion but in such cases very low
trough should be maintained
• level: ug/ml X 1.7 = umol/L,

Gentamicin As above >13-22 As above MD < 4 AS above

EID < 1
Level ug/ml X 2.2 = umol/ L

• Sampling is usually started after 3rd or 4th dose. Repeated as necessary.

• If infusion time 60 min, take the sample few min after end of infusion.

References *: (ref are continued in pages 5,6)

1. Buritis CA, Aswood ER “ Therapeutic drug monitoring “ In Titez, Fundamentals of Clin. Chemistry, 5th
ed. 2003, PP 608-635
2. Current issues related to TDM : Aminoglycosides ; World of drug information , vol 13, issue 3, 2002
3. Begg EJ, Barclay ML et al TDM of aminoglycosides , B MJ, 47, 23, 1999..
4. Hammett-Stablera C A, and Johns T Laboratory guidelines for monitoring of antimicrobial drugs Clinical
Chemistry 44: 1129-1140, 1998
5. Drug monographs, last update 2004. www.rxmed.com.
6. Koren G; TDM principles in neonates , Clinical Chem, 43, 222, 1997.
7. Kozer E, Parvez S et al “ How high can we Go with phenytoin, Ther. Drug Monit. , 24, 386, 2002
8. Schumacher GE. Choosing optimal sampling times for therapeutic drug monitoring. Clin Pharm. 1985
Jan-Feb; 4(1): 84-92.

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3- High dose (EID) or once daily (OD) regimen in adults *: e.g. amikacin 15 mg/kg or
gentamicin 5 mg/kg
Amikacin Dosing Renal Timed Sample (hr post Expected level ( umol/l ) in adults
interval function dose )
& A- normal renal function
Gentamicin Routine If necessary
Time post 6 12 18
dose (h)
24 h Normal 12 h 6 or 18 h Amik. 11-28 3 – 8 <3
Genta. 5-12 1–4 <1
B- moderate impairment
36 h Mod. Trough 24 h Time post dose (h) trough
Impair. Amik. <2
Genta. <1
• * This protocol for OD regimen in adults is proposed in view of a study done at TDM unit
• Sampling can be started after the 1st dose & accuracy of sampling time is critical
• Peak levels are expected to be very high and extensively variable.
• Trough levels are usually undetectable in-patient with normal renal function.
• In case of impaired renal function, levels at 24 hr or other times depends on degree of renal
impairment, dose, and dosing interval. Detailed tables are available
• Random sample is discouraged and should be restricted to justified clinical conditions. In such
cases the exact time of sampling relative to the last dose should be specified
• Serum creatinine alone may be an inaccurate parameter for assessment of renal function in
elderly. It is recommended to estimate creatinine clearance (Clcr) by an appropriate method.
• Approximate guide for renal function: Normal renal function Clcr> 80 ml/ min. mild
impairment: 60-80, moderate impairment: 40-60, marked impairment < 40 ml/ min
_____________________________________________________
Vancomycin
Post Ref. range Pre Ref. Notes
(Peak) µmol/L ( Trough ) range
µmol/L

1 hr 1 hr :17-27 Just 3 -7 • Determination of peak is not a routine

or 2 hr Before (discouraged ) in adults or children
post end of 60 2hr: 12-17 next dose with normal renal function
min IV infusion • Optimal trough level of 3- 7 umol/L
should be maintained to insure optimal
efficacy
• Higher trough up to 10 umol/L may be
allowed in cases of severe infections.
• Patient under dialysis a [Random] level : 7-11 umol/l has been considered acceptable
-For those patients we recommend sampling time for trough level: 2-3 hr after end of dialysis
• Results in ug/ml X 0.67 = umol

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 Digoxin (lanoxin)
Sampling time Therpeutic Notes
range
Random 1.2.2.6 • Sampling at least > 6 hr post dose is indicated due to
sample ( > 8 hr long distribution phase ( about 6 hr ).
post dose ) • Note the overlap between therapeutic and potentially
potential toxic toxic levels.
level > 1.5 • Critical values nmol /L 3.0 adults, 3.8 in pediatrics
nmol/L • Digoxin level should be interpreted in view of Clinical
observations, ECG, renal & thyroid function &
electrolyte levels. Insure patient compliance & sampling
at steady state before increasing the dose.
• When Fab digoxin (Digibin ) is used for management
of toxicity , digoxin level becomes irrelevant
• Samples from Neonates & pregnant women may
contain substances, which interfere with some assays
( False higher results ). Some drugs may cause false
lower results e.g. spironolactone, carnerone, high dose
hydrocortisone

Anti-epileptic drugs [AEDs]

Drug Sampling time Ref range Notes
umol/L
Trough Peak

Carbamazepine Just ------ 20.50 • At levels > 35-50 side effects may be
(tegretol ) before observed e.g. nystagmus, deplopia,
next dose drowsiness and ataxia specially if used
with other AEDs .At levels > 50 these
side effects are more common.
• Critical level > 60 umol/L
• Repeat assay within 3-4 wks after
initiation of therapy . CBZ stimulates its
own metabolism leading to shorter
half-life. ( possibly lower level at steady
state )

Phenobarbital Just 1 hr 65- 170 • High levels up to 200 umol/L may be

before post IV allowed cautiously in severe cases of
next dose dose neonatal seizures Critical value 250
• In all cases of high levels, further
follow up is indicated to avoid
accumulation .
• Neonates subjected to asphyxia have
reduced clearance. Reduce the dose &
consider careful monitoring .

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 Anti-epileptic drugs [AEDs] cont.
Drug Sampling time Notes
Ref range
Trough Peak umol/L

Phenytoin- Just 1 hr 40- 80 • Characterized by Non-linear kinetics

(dilantin) before post IV and strong protein binding.
next dose dose • Epilepsy may be controlled at levels
30-40 umol/L; some patients may
require high level up to 100 umol/L.
• Common adverse effects: At level of
80-120, nystagmus, blurred vision at
level of > 120 -150: ataxia, drowsiness,
possibly coma and cardiac toxicity.
• Protein binding of phenytoin is reduced
and higher free level is expected in
neonates, low-albumin, or high bilrubin
level & concomitant administration of
strongly protein bound drugs.
• In all of the above situations :measure
free phenytoin levels if available,
otherwise consider lower level
specially when signs of toxicity are
present .
Valproic acid Just 1 hr 350 -700 • Characterized by nonlinear dose / level
( Depkain ) before post IV relationship due to enhancement of
next dose dose clearance at high levels ( > 530 umol/L).
• The correlation between blood level &
efficacy is not linear .It has an active
metabolite.
• Ref range is not rigid, higher levels up to
1000 may be allowed if clinically needed.
• It may cause hepatic-toxicity or panceratitis
• Children < 2 yr who are receiving other
AEDs or have metabolic problem are at
increased risk of Fulminate hepatitis.
• When used concomitantly with phenytoin,
free levels of both drugs are higher than if
any of them used alone.
• Elevation of AST up to >3 folds may
indicate hepatic-toxicity by Valproic A.
• Sampling is usually started after initiation of therapy and repeated at steady state.(SS)
• Practically SS is attained after 4-5 half-lives of the drug i.e. 3 wks after initiation of therapy of
Carbamazepine, Phenobarbital or phenytoin, but after 3 days in case of Valproic acid.
• Peak level may be requested in case of suspected toxicity. Random sampling is discouraged
however, it is acceptable in case of overdose or toxicity.
• For Carbamazepine & Valp. acid the sampling time should be standardized in relation to dose.
• Clinical Assessment, lab investigations; CBC, liver enzymes should be also considered Blood
levels should be considered within the context of a patient’s Symptoms and signs

4
• Evidence suggests that target ranges for neonates & infants may be lower than those reported for
adults ( phenytoin) or may be higher ( Valproic acid, up to 850 umol/L in children ).

Cyclosporine A (Neoral )
Sampling time Reference range

Peak (C2) Trough * KIDENY transplant patients (KTP)

Target peak level nmol/L ( ±20 % may be allowed )
Two hr post Just before
oral Next dose Time post level Time post Level
administration transplantatio transplantation
n
1st month 1400 4-6 months 1080
2nd month 1245 7-12 months 750
rd
3 month 1160 > 12 months 660
Trough level nmol/L in (KTP)
Induction therapy ( up to 3 months 125- 300
after KTP )
maintenance therapy 80-200
Notes :
• Insure accurate sampling time & correct order
• Trough level is not a routine practice in KTP , it may
be requested in case of suspected toxicity or Pk studies
• To convert results : nmol/L to ug./ml multiply by
0.0012.
* The drug is nalyzed in whole blood ( EDTA –tube )/ keep in ice.
------------------------------------------------------------------------------
Tacrolimus (FK-506, prographt)- [ now available in trial basis ]
Sampling time Reference range

Trough * therapeutic range 5-20 ng/ml

Notes :
12 hr post dose • Insure accurate sampling time
• The whole blood level should be interpreted in view
of other laboratory & clinical data.
• Absorption and clerance varies with age, transplant
organ, co-administration of other drugs etc
•
The drug is analyzed in whole blood ( EDTA –tube )/ keep in ice.

5
 Theophylline
Route Sampling time Reference range & notes
Routine Optional Level depends on indications :
Asthma Trough : 55 –110 Apnea: Tough : 30-60 ,

• Samples taken before steady state or several hours

after stopping infusion can show false low level.
• Steady sate is attained within 1-2 days in children or
adults
• steady state is attained after at least 5-7 days in
neonates
• Sampling during infusion should be from other arm
& infusion rate should be constant.
Oral Trough ------
(pre)
Slow IV Trough Peak :1 h
(30 min ) (pre) post dose
Cont. 6 -12 hr Peak 1
Infusion during hr post
infusion IV LD

Methotrexate
Sampling time Potentially toxic level
Timed sample ( hr Post dose ) Level depend on the regimen and the time of sampling

• Routine : Sampling time Potentially toxic level

at 24 h and /or at 48 h (hr post dose ) umol/L
24 h >10
• If necessary at 72 hr 48 h >1
72 h >0.1
Notes : Sampling time is critical. The above ref is applicable
for high dose MTX plus leucovorin therapy.

Acetaminophen
Sampling time (hr post dose) Potentially toxic level
• Optimal: 4-5 hr post dose Simplified guide for Potentially toxic levels umol/L
• Timed sample . 4 hr post dose > 900 At 12 hr > 225
8 hr > 450 At 24 hr post dose > 25
• Special graph is applicable for more accurate interpretation
• In case of toxicity, and unknown time of administration: Take
two timed samples

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 Ref. Cont.
9. Nicholson PW, Dobbs SM, Rodgers EM Ideal sampling time for drug. Br J Clin Pharmacology. 1980
May; 9(5): 467-702
10. Robinson JD, Tylor WJ, Interpretation of serum drug concentration In Therapeutic drug monitoring and
pharmacokinetic “ ABBOTT diagnostic division, Iriving Texas, 1986. Pp31
11. . The therapeutic drug monitoring .web site by Nasr Anaizi http://www.thedrugmonitor.com/
12. Sandimmun Neoral® Monitoring.http:// www.transplantationschweiz.ch/d/ sandimmun/ monitoring.aspx
13. Patient management by Neoral C2 monitoring: An international consensus statement
Gary Levy; Eric Thervet; John Lake; Kazuharu Uchida; on behalf of the CONCERT group
TRANSPLANTATION 2002;73:S12-S18

14. Warner A, Privitera M and Bates D’ Standards of laboratory practice: Antiepileptic drug monitoring.
Clin chemistry, 44, 1085, 1998.
15. Patsalos PN ; TDM in epilepsy, The National Society of epilepsy.2002. www.e-epilepsy.org.uk

16. Clinical validation studies of neoral C2 monitoring: a review

Björn Nashan; Edward Cole; Gary Levy; Eric Thervet
TRANSPLANTATION 2002;73:S3-S9
17. Recommendations for the Implementation of Neoral C2 Monitoring in Clinical Practice
Edward Cole; Karsten Midtvedt; Atholl Johnston; James Pattison; Catherine O’Grady
TRANSPLANTATION 2002;73:S19-S22
18. The TDM Guidelines Regional Laboratory for Toxicology London , 2002. .
http://www.toxlab.co.uk/tdm.htm
19. Barclay M and Begg The practice of digoxin therapeutic drug monitoring
Journal of the New Zealand Medical Association, 12-December-2003, Vol 116
No1187
20. Yi Hon Y, and William E. Evans W. Ea Making TDM work to optimize cancer
chemotherapy: a multidisciplinary team approach (Clinical Chemistry.
1998;44:388-400.)