Abdullah M. Kharbosh, B.Sc., Pharm

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MTDM Guidelines

ObjectivesObjectives

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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MTDM Guidelines

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 Benefit

Harm Harm

Level Level

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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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MTDM Guidelines

The Concept of Therapeutic Range

Drug Level / Effect

• Pos dose level (Peak)

• Pre dose Level (Trough)

• Random Level

• Sub-Optimal Levels

• Therapeutic Level

• Toxic Level

Drug Level / Dose time

Therapeutic Range

A therapeutic Response can be expected

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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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MTDM Guidelines

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 2.Ascites3.Dialysis/Renal dysf, CrCl <20 ml/min 4.Neutropenia

5.Burns on >20% of body surface6.Enterococcal Endocarditis7.Gram +ve infections (as synergy)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 dosingTraditional Dosing

Amikacin< 5 μg/ml; 4 hrs pre the next dose

Pre (trough): 1-4 μg/ml; 30 min pre 4th dosePost (Peak): 20-30 μg/ml; 30 min post IVI of 4th dose

Time to Steady State10-24 hrs

Gentamicin< 1 μg/ml; 4 hrs pre the next dose

Pre (trough): 0.5-2 μg/ml; 30 min pre 4th dosePost (Peak): 6-10 μg/ml; 30 min post IVI of 4th dose

Time to Steady State24-36 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 !!

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

Serum Concentration:

Mild-moderate infectionSever infection

Vancomycin Pre (Trough):10–15 μg/ml; 30 min pre 4th dose

Pre (Trough):15- 20 μg/ml; 30 min pre 4th dose

Time to Steady State24-48 hrs

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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)

LoadingLoadingMaintenanceMaintenance

Total Digitalization Dose (TDD) μg/kgDaily Maintenance Dose μg/kg

POIV/IMPOIV/IM

0.75-1.5 mg 0.5-1 mg0.125-0.5 mg0.1-0.4 mg

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Digoxin

Different Dosage forms: different systemic bioavailabilities (F)

Serum Concentration

TherapeuticCHF: 0.5-0.8 ng/ml Arrhythmias: 0.8-2 ng/ml

Subtherapeutic<0.5 ng/ml

Toxic > 2.4 ng/ml

IV100%

Tablet50-85%

Elixir70-85%

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

Appropriate Sampling TimeTime To SSTherapeutic

Range

AmikacinTraditional dosing:Pre level (trough)Post level (Peak)Once daily dose:

1-4 μg/ml20-30 μg/ml < 5 μg/ml

GentamicinTraditional dosing:Pre level (trough)Post level (Peak)Once daily dose:

0.5-2 μg/ml6-10 μg/ml<1 μg/ml

Vancomycin (trough)Mild-moderate infectionSever infection

10 – 15 μg/ml15- 20 μg/ml

10-24 hrs 30 min before 4th dose 30 min after completion of IVI of 4th dose4 hours before the next dose

24-36 hrs 30 min before 4th dose30 min after completion of IVI of 4th dose 4 hours before the next dose

30 min before 4th 24-48 hrs

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TDM Guidelines

Appropriate Sampling TimeTime To SSTherapeutic Range

Digoxin (Arrhythmia)

Digoxin (CHF)

• 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

Procainamide

Quinidine

Carbamazepine

Phenobarbitone

Phenytoin

Valproic acid 50 – 100 μg/ml 2-4 d 30 min before next dose, 2-4 d after initiation of therapy

LD: 2 hrs post IV LD; (OR 24 hr post PO LD)MD: 30 min before next dose, after 7-10 d

7-35 d10-20 μg/ml

15 – 40 μg/ml

4 – 12 μg/ml

2 – 5 μg/ml

2 – 5 μg/ml

1.5 – 5 μg/ml

0.5 – 0.8 ng/ml

0.8 – 2 ng/ml5-7 d 6 hrs post dose to just before next dose

(Trough level)

With LD: 0.5-1.5 hrs, No LD: 6-12 hrs

30 minutes before next dose

30 minutes before next dose

30 minutes before next dose at steady state

After IV LD: 2 hrs, MD: 2-4 weeks1-4 wks

2-4 d

1-2 d

15-25 hrs

6-15hrs

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Role of Nurse in TDM

Thank Thank UU

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