Abdullah M. Kharbosh, B.Sc.

, Pharm
Objectives

Define TDM
Outline the rationale of TDM
Define the clinical indications for TDM
Define therapeutic range, peak & trough concentration
Discuss factors affecting serum drug concentration
Discuss medications require TDM
Discuss the role of nurse in the process of TDM

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What is TDM ?

TDM is the process of using drug serum conc. measurement in

determining drug dosage adjustment to maximize efficacy & safety of
drug use

Benefit

Level

Harm

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Rationale for TDM ?

TDM is helpful in those situations in which:

1) Dosage cannot reliably predict serum concentration
2) The serum conc. has been well correlated with efficacy and
3) The therapeutic "window" of the drug is very small (narrow)
There are few medications that meet these criteria
Most drugs are either fairly safe, not extensively studied or have
other indices (such as the PTT with heparin, INR with warfarin)
that provide a direct indication of therapeutic response

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The Concept of Therapeutic Range

Drug Level / Effect

• Sub-Optimal Levels
• Therapeutic Level
• Toxic Level
Therapeutic A therapeutic
Range Response can
Drug Level / Dose time be expected

• Pos dose level (Peak)

• Pre dose Level (Trough)
• Random Level

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The Process of TDM

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Clinical Indications for TDM

To individualize therapy (starting therapy/dose changes)

To individualize in situations when serum conc. may be changing, such
as conditions of fluctuating hepatic or renal function, & if a new, possibly
interactive, drug is added e.g., prescribing of:
a) Quinidine for someone on a digoxin regimen or
b) Cimetidine for someone taking theophylline
To assess patient compliance
To investigate unexpected lack of efficacy
To confirm ‘effective’ concentrations
To investigate possible toxicity

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Sampling

A major source of error arises from the improper timing of collection

These errors of timing usually fall into one of three categories:
A. Failure to Attain Steady State (4 half lives)
B. Failing to Allow for Distribution Phase (digoxin, vancomycin)
C. Misinterpreting Peak and Trough Levels

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Factors Affecting TDM

Drug administration or blood drawing related

Pharmacokinetic principles related
Laboratory related

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Drug Administration or Blood Drawing

Wrong dose administered

Dose skipped e.g. pt undergo a procedure; nursing error
Dose given at wrong time, blood drawn as ordered
Dose given at right time, blood not drawn at right time
Infusion time too fast or too slow
Infusion hold prior to draw (e.g. another drug given)
Blood drawn form same vein into which drug infused

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Pharmacokinetics

Levels obtained not at steady state

Levels obtained without respect to dosing time
Active metabolites not taken into account
Poor absorption due to any reasons
Drawing levels before distribution to site of action is complete e.g.
digoxin, vancomycin
Fluid status changes (fluid overload, dehydration, third spacing)

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Pharmacokinetics

Inappropriate weight use e.g. obese higher apparent distribution mass,

weight loss
Significant changes in liver or renal function
Significant changes in % of bound &free drug e.g. in hypoalbuminemia
Changes in metabolizing enzyme saturation threshold
Drug interactions
Drug inactivation (penicillins or cephalosporins with aminoglycosides)

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Laboratory

Improper performance of assay

Laboratory transcription or data-entry order
Active metabolites not measured
Assay interference
Improper specimen collection or storage

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Common Drugs in TDM

Aminoglycosides
Vancomycin
Antiepileptics (Phenytoin, Carbamazepine, Valproic acid, Phenobarbitone)
Cyclosporine
Theophylline
Digoxin
Lidocaine
Procainamide
Quinidine

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Aminoglycosides

Adults Once Daily Aminoglycosides (ODA) Dosing

Several studies suggesting that larger doses of aminoglycosides given
once-daily are just as effective as conventional dosing given three times
a day
Eligible Patients (All who require aminoglycoside therapy) Except:

1.Pregnancy 5.Burns on >20% of body surface

2.Ascites 6.Enterococcal Endocarditis
3.Dialysis/Renal dysf, CrCl <20 ml/min 7.Gram +ve infections (as synergy)
4.Neutropenia 8.Hx of hearing loss or vestibular dysf

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Aminoglycosides (once daily dosing)

Gentamicin: 5-7 mg/kg

Amikacin: 15mg/kg
Administer by slow IV infusion over 1 hr
Administer other ABX, such as penicillins
& cephalosporins, at least 1 hr before or
after aminoglycoside infusion

Adjustment of the Dosing Interval:

Order serum level 6-14 hrs post first dose,
then evaluate the level using the Hartford
Nomogram to adjust the dosing interval.
(Consider ordering level in middle of 6-14
hr range, i.e. 10 hrs, due to possibility of
late draws)

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Aminoglycosides

Traditional Dosing Calculation:

Gentamicin: 1-2 mg/kg/dose
– Pulmonary infection in cystic fibrosis: 2.5-3.3 mg/kg/dose Q6-8hr
Amikacin: 5-7.5mg/kg/dose
Administer by slow IV infusion over 30 minutes
Administer other antibiotics, such as penicillins & cephalosporins, at least 1 hr
before or after aminoglycoside infusion

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Aminoglycosides

Serum Concentration:
Once daily dosing Traditional Dosing
Amikacin < 5 μg/ml; 4 hrs pre the Pre (trough): 1-4 μg/ml; 30 min pre 4th dose
next dose Post (Peak): 20-30 μg/ml; 30 min post IVI of
4th dose
Time to Steady State 10-24 hrs
Gentamicin < 1 μg/ml; 4 hrs pre the Pre (trough): 0.5-2 μg/ml; 30 min pre 4th dose
next dose Post (Peak): 6-10 μg/ml; 30 min post IVI of
4th dose
Time to Steady State 24-36 hrs

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Vancomycin

Loading dose is not necessary

Initial recommended dose:15 mg/kg (based on actual body weight)
Not for IM or IV push
Give by slow IV infusion (max: 1 gm over 60 min)
Nephrotoxicity !!
Serum Concentration:
Mild-moderate infection Sever infection
Vancomycin Pre (Trough):10–15 μg/ml; Pre (Trough):15- 20 μg/ml; 30 min pre 4th
30 min pre 4th dose dose
Time to Steady State 24-48 hrs

When CrCl < 25 mg/min: give 1 dose, check random level 24-36 hr post dose & redose
when level < 10 μg/ml OR < 15 μg/ml

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Phenytoin

LD I.V. : 10 – 15 mg/kg , e.g. 1000mg in 100ml of NS administered at rate

of 40mg / minute
MD: 300 mg / day in three divided doses (100 mg TID )
In Status Epilepticus the MD100 mg Q6–8H
Therapeutic level : 10 – 20 μg/ml (Remember low is not always low)
When to draw the level ? This is depend on the disease state being
treated and the clinical condition of the patient
LD: (IV load) After 2 hrs or (PO load) After 24 hrs
MD: Take the trough levels (7-10 days)
MD with LD: at any dose, 30 min before next dose
MD without LD: 30 min before next dose after 7–10 days from initial dose

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Phenytoin

Serum Albumin (corrected phenytoin level):

Phenytoin is ≈ 90% protein bound
Reported levels are based on total phenytoin (bound + free) & levels
must be adjusted when serum albumin is reduced (< 25 g/dl):
Corrected Phenytoin level = Actual phenytoin level / [(0.2 x alb/10) + 0.1]

Renal Failure (<40mL/min,): use this equation

Adjusted phenytoin level = Actual phenytoin level / (0.1 x alb/10) + 0.1

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Digoxin

Indications (Uses)
1) Congestive Heart Failure (CHF) 2) Supraventricular Arrhythmias (AF)

Dose (Adult)
Loading Maintenance
Total Digitalization Dose (TDD) μg/kg Daily Maintenance Dose μg/kg
PO IV/IM PO IV/IM
0.75-1.5 mg 0.5-1 mg 0.125-0.5 mg 0.1-0.4 mg

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Digoxin

Serum Concentration
Therapeutic CHF: 0.5-0.8 ng/ml Arrhythmias: 0.8-2 ng/ml
Subtherapeutic
<0.5 ng/ml
Toxic > 2.4 ng/ml

Different Dosage forms: different systemic bioavailabilities (F)

IV 100%
Tablet 50-85%
Elixir 70-85%

When changing from oral (tablets or liquid) or I.M. to I.V. therapy:

Dosage should be reduced by 20-25%

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TDM Guidelines

Drug Name Therapeutic

Time To SS Appropriate Sampling Time
Range
Amikacin
Traditional dosing:
Pre level (trough) 1-4 μg/ml 10-24 hrs 30 min before 4th dose
Post level (Peak) 20-30 μg/ml 30 min after completion of IVI of 4th dose
Once daily dose: < 5 μg/ml 4 hours before the next dose

Gentamicin
Traditional dosing:
Pre level (trough) 0.5-2 μg/ml 24-36 hrs 30 min before 4th dose
6-10 μg/ml 30 min after completion of IVI of 4th dose
Post level (Peak)
<1 μg/ml 4 hours before the next dose
Once daily dose:

Vancomycin (trough)
24-48 hrs 30 min before 4th
Mild-moderate infection 10 – 15 μg/ml
Sever infection 15- 20 μg/ml

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TDM Guidelines

Drug Name Therapeutic Range Time To SS Appropriate Sampling Time

Digoxin (Arrhythmia) 0.8 – 2 ng/ml

5-7 d 6 hrs post dose to just before next dose
Digoxin (CHF) 0.5 – 0.8 ng/ml (Trough level)

• Initiation of therapy: if LD is given: Draw level within 12-24 hrs after the initial LD administration
• If LD is not given: the level should be obtained after 3-5 d of the therapy
Lidocaine 1.5 – 5 μg/ml 6-15hrs With LD: 0.5-1.5 hrs, No LD: 6-12 hrs

Procainamide 2 – 5 μg/ml 15-25 hrs 30 minutes before next dose

Quinidine 2 – 5 μg/ml 1-2 d 30 minutes before next dose

Carbamazepine 4 – 12 μg/ml 2-4 d 30 minutes before next dose at steady state

Phenobarbitone 15 – 40 μg/ml 1-4 wks After IV LD: 2 hrs, MD: 2-4 weeks

Phenytoin
LD: 2 hrs post IV LD; (OR 24 hr post PO LD)
10-20 μg/ml 7-35 d
MD: 30 min before next dose, after 7-10 d
Valproic acid 50 – 100 μg/ml 2-4 d 30 min before next dose, 2-4 d after initiation
of therapy

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Role of Nurse in TDM

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 Thank U

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