Tdm Practical Guide Part1

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

Amikacin

Post (Peak)

Ref. range µmol/L

At 30 min > 35-50 post end of 30 min IV infusion

Pre (Trough)

Ref. range µmol/L

Just Before next dose

MD < 7 EID < 2

Notes

• • •

Gentamicin As above

>13-22

As above

MD < 4 EID < 1

• •

Trough level depends on dosing regimen Higher peak may be allowed but in such cases very low trough should be maintained level: ug/ml X 1.7 = umol/L,

AS above 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 & Gentamicin

• • • • • • • •

Dosing interval

Renal function

Timed Sample (hr post dose ) Routine

If necessary

24 h

Normal

12 h

6 or 18 h

36 h

Mod. Impair.

Trough

24 h

Expected level ( umol/l ) in adults

A- normal renal function Time post 6 12 18 dose (h) Amik. 11-28 3 – 8 <3 Genta. 5-12 1–4 <1 B- moderate impairment Time post dose (h) trough 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 (Peak)

Ref. range µmol/L

Pre ( Trough )

Ref. range µmol/L

1 hr 1 hr :17-27 or 2 hr post end of 60 2hr: 12-17 min IV infusion

Just Before next dose

3 -7

Notes

• • •

• •

Determination of peak is not a routine (discouraged ) in adults or children with normal renal function 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 range

Random 1.2.2.6 sample ( > 8 hr post dose ) potential toxic level > 1.5 nmol/L

Notes • • • •

• •

Sampling at least > 6 hr post dose is indicated due to long distribution phase ( about 6 hr ). Note the overlap between therapeutic and potentially toxic levels. Critical values nmol /L 3.0 adults, 3.8 in pediatrics 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] Sampling time Drug Trough

Carbamazepine (tegretol )

Just before next dose

Peak ------

Ref range

Notes

umol/L

20.50

•

• •

At levels > 35-50 side effects may be observed e.g. nystagmus, deplopia, 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 before next dose

1 hr post IV dose

65- 170

• • •

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High levels up to 200 umol/L may be allowed cautiously in severe cases of 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 .

Anti-epileptic drugs [AEDs] cont. Sampling time Drug Phenytoin(dilantin)

Trough

Peak

Just before next dose

1 hr post IV dose

Notes

Ref range umol/L

40- 80

• • •

•

•

Valproic acid ( Depkain )

Just before next dose

1 hr post IV dose

350 -700

• • • • • •

• • • • • •

Characterized by Non-linear kinetics and strong protein binding. 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 . Characterized by nonlinear dose / level relationship due to enhancement of 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 Peak (C2)

Trough *

Two hr post Just before oral Next dose administration

Reference range KIDENY transplant patients (KTP) Target peak level nmol/L ( ±20 % may be allowed ) Time post level Time post Level 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 Trough * 12 hr post dose

Reference range therapeutic range 5-20 ng/ml Notes :

• • • •

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.

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Theophylline Route

Sampling time Routine Optional

Reference range & notes Level depends on indications : Asthma Trough : 55 –110 Apnea: Tough : 30-60 , • • • •

Oral Slow IV (30 min ) Cont. Infusion

Trough (pre) Trough (pre) 6 -12 hr during infusion

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.

-----Peak :1 h post dose Peak 1 hr post IV LD

Methotrexate Sampling time

Potentially toxic level

Timed sample ( hr Post dose )

Level depend on the regimen and the time of sampling

•

Routine : at 24 h and /or at 48 h

•

If necessary at 72 hr

Sampling time Potentially toxic level (hr post dose ) umol/L 24 h >10 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) • •

Optimal: 4-5 hr post dose Timed sample .

Potentially toxic level Simplified guide for Potentially toxic levels umol/L 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.)

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