26410174 therapeutic drug monitoring
TRANSCRIPT
Abdullah M. Kharbosh, B.Sc., Pharm
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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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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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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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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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