Therapeutic drug monitoring

OVERVIEW

Therapeutic drug monitoring (TDM) is the individualization of drug dosage by maintaining plasma or blood drug concentrations within a target range (the ‘therapeutic window’)

This helps address the two major sources of variability in drug responses between individuals, the relationships between:

1. dose and plasma concentration (pharmacokinetic variability)
2. drug concentration at the receptor and the response (pharmacodynamic variability)

Clinical efficacy is generally preferred for monitoring drug response (e.g. heart rate with beta-blockade), however, TDM is particularly useful where:

• the drug effect is the absence of something (e.g. seizure control with valproate)
• there is a narrow therapeutic window with a risk of serious toxicity (e.g. aminoglycosides)

CHARACTERISTICS OF DRUGS SUITABLE FOR THERAPEUTIC DRUG MONITORING AND INDICATIONS

Drugs suitable for therapeutic drug monitoring have these characteristics:

• marked pharmacokinetic variability (inter- or intra-individual)
• concentration related therapeutic and adverse effects
• narrow therapeutic index
• defined therapeutic (target) concentration range
• desired therapeutic effect difficult to monitor
• serious consequences (eg. seizures, transplant rejection) if there is therapeutic failure
• a suitable and accessible laboratory assay

Indications for therapeutic drug monitoring include:

• after initiating treatment
• after adjusting dose
• if treatment is failing
• if non-compliance is suspected
• when starting or stopping a potentially interacting drug
• if there is a change in a patient’s physiology (eg. pregnancy, renal or hepatic impairment)
• to assess for drug toxicity or suspected overdose
• to confirm abstinence
• to assist diagnosis – adverse drug effects may mimic disease state

IMPORTANT EXAMPLES

List of drugs that typically undergo therapeutic drug monitoring, with their therapeutic range:

Drug	Therapeutic range (mg/L)
Digoxin	0.5 – 2.1
Amiodarone	1.0 – 2.5
Lignocaine	2.0 – 5.0
Quinidine	2.0 – 5.0
Flecainide	0.2 – 0.9
Mexilitine	0.5 – 2.5
Salicylate	150 – 300
Perhexiline	0.15 – 0.6
Theophylline	10 – 20
Phenytoin	10 – 20
Carbamazepine	5.0 – 12
Sodium valproate	50 – 100
Phenobarbitone	15 – 40
Gentamicin, tobramycin, netilmicin	trough <2; peak >5
Amikacin	trough <5; peak >15
Vancomycin	trough <10; peak 20 – 40
Lithium	0.6 – 1.2

INTERPRETATION OF DRUG LEVELS

Factors to consider to accurately interpret a drug level include:

• time of sampling
• dosage regimen (including dose, dose form, time of drug administration and duration of therapy)
• patient characteristics (eg. age, gender, concomitant disease, ethnicity)
• concomitant medications
• indication for monitoring
• therapeutic range and pharmacokinetics of the drug

Time of sampling

• the least variable point in the dosing interval is the pre-dose or trough concentration
  • for drugs with short half-lives compared to the dosing interval samples should be collected pre-dose
  • for drugs with long half-lives (e.g. phenytoin and amiodarone) it is OK to collect samples at any point in the dosage interval — this is also the case for digoxin at any point after the distribution phase (after 6 hours post-dose)
• for most drugs wait until steady state is achieved until checking levels
  • exceptions are drugs with long half-lives and which can cause severe toxicity, as steady state may not be reached for months
  • allowances must be made if a level is taken before steady state is achieved

PRACTICAL ISSUES AND PROBLEMS

These include:

• toxicity from different drugs may be related to:
  • peak drug concentrations (e.g. theophyline-induced seizures and arrhythmias)
  • mean concentrations (e.g. aminoglycoside-induced ototoxicity)
• hospital laboratories typically measure total plasma concentrations
  • for protein bound drugs it is the unbound fraction that is pharmacologically active (e.g. phenytoin)
  • Sodium valproate and salicylate show non-linear binding in the therapeutic range, so interpretation of total drug concentrations is difficult
• measured concentrations should be correlated with clinical evidence of efficacy/ toxicity
  • e.g. ‘sub-therapeutic’ digoxin level with slow ventricular response rate likely means the digxoin dose is adequate
  • e.g. seizures despite a ‘therapeutic’ phenytoin level, suggests phenytoin is ineffective and an additional or alternate anti-epileptic drug may be required
• drug effects are not usually ‘all or none’, there is typically a dose-response relationship, i.e. drug effects still occur outside the therapeutic window
• due to individual variation a proportion of the population will have clinical efficacy at ‘subtherapeutic’ drug concentrations
• active metabolites may not be measured

ANTIBIOTICS

Overview

• TDM is always indicated for aminoglycosides and vancomycin due to the relatively narrow therapeutic windows
• TDM for other antimicrobial drugs is unproven, but can be useful in some circumstances/ patient groups (such as the critically ill)

Gentamicin

• TDM is useful if
  • directed therapy (after the first dose)
  • therapy is planned for >48 hours
  •  empirical therapy (up to 48 hours of therapy) and renal function is changing rapidly or in patients with altered pharmacokinetics
• patients with altered gentamicin pharmacokinetics:
  • critically ill with severe sepsis or septic shock
  • renal replacement therapy
  • severe burns
  • cystic fibrosis
  • pregnancy
  • ascites
  • morbid obesity
• Once-daily or less frequent dosing
  • goal is to target adequate area under the concentration–time curve (AUC) with an undetectable trough (predose) plasma concentration
  • to calculate the AUC, the aminoglycoside plasma concentration needs to be obtained at two time points after drug dosing (usually 5 minutes after completion of the infusion, and 6 to 8 hours postdose)
  • A computer program is used to calculate the AUC, which is then used to estimate the appropriate subsequent aminoglycoside dose (e.g. Aladdin, and TCIWorks [URL])
  • Computer programs that use population pharmacokinetic models and Bayesian statistics only require one plasma concentration measurement
  • A target AUC of 80 or 100 mg.h/L has been advocated, but consensus is lacking
  • Trough plasma concentrations cannot be used to monitor once-daily (or less frequent) dosing as they are often below the laboratory detection limit and correlate poorly with overall exposure
  • Measure the plasma concentration on the first dose of directed therapy, then usually every 48 hours, but more frequently if renal function is changing rapidly
• Multiple-daily (synergistic) dosing
  • The AUC approach is not required for multiple-daily (8-hourly or 12-hourly) dosing regimens
  • trough (predose) concentration target is 0.5 to 1 mg/L
  • if impaired renal function, it may be necessary to change from 8-hourly to 12-hourly dosing to maintain the trough concentration in this range
  • measure trough concentration at least twice weekly if normal and stable renal function, other wise more frequently
  • consider stopping gentamicin if renal function markedly worsening

Vancomycin

• TDM is important in the critically ill
  • Augmented renal clearance and abnormal volumes of distribution (eg severe burns,sepsis, trauma or generalised oedema)
  • Renal impairment (including those receiving renal replacement therapy)
  • MRSA infections to reduce risk of underdosing and selection of resistance
• Target range
  • Trough levels are taken an hour before the scheduled timing of the dose
  • trough: 10 to 20 mg/L
  • trough: 15 to 20 mg/L for complicated infections or the critically ill
  • a trough concentration up to 25 mg/L may be used to improve penetration of vancomycin into the cerebrospinal fluid for CNS infections
• Loading dose (considered the first dose)
  • 25mg / kg (actual body weight) up to 3g if normal renal function (max 2.5g if GFR <60
• Maintenance dosing according to renal function (seek expert pharmacist advice)
  • GFR >90: 20 mg/kg (actual body weight) q12h and check trough level before the 4th dose
  • GFR 60-90: 15 mg/kg (actual body weight) q12h and check trough level before the 4th dose
  • GFR 20-60: 15 mg/kg (actual body weight) q24h and check trough level before the 3rd dose
  • GFR <20: 15 mg/kg (actual body weight) q48h and check trough level after 48h
• Dose adjustments
  • If trough level is too low, increase dosage by adjusting either the dose or the dose interval
  • If trough level is too high, withhold the dose until the trough level is in target range and restart at a reduced dose
  • Continuous infusion of vancomycin is especially useful for patients requiring higher or more frequent doses
  • Intermittent haemodialysis: take trough level before dialysis and dose vancomycin after dialysis
  • Continuous renal replacement therapy: dose as per weight and renal function, consider daily trough levels
• Monitor creatinine and consider more frequent TDM if renal function is unstable

Beta-lactams

• routine monitoring is not usually required, except:
  • patients on long-term IV therapy (>2 weeks)
  • patients with significantly altered pharmacokinetics (e.g. severe critical illness, severe renal impairment)
• 15- 50% of critically ill patients have suboptimal beta lactam plasma concentrations, especially those with augmented renal clearance (doubling of creatine clearance may be seen in patients with febrile neutropenia, burns, pancreatitis and major trauma)
• TDM is useful if there is an evolving acute kidney injury or if the effect of the prescribed CRRT settings on drug clearance is poorly characterised
• Flucloxacillin
  • perform TDM if poor absorption of oral drug is suspected when treating serious infections such as osteomyelitis
  • expected peak plasma concentration of flucloxacillin 1 hour after a 1 g oral dose is usually 20 to 40 mg/L (total drug, approximately 95% protein bound)
  • Continuous-infusion flucloxacillin (adult dose 8 to 12 g daily)  is likely to be active against MSSA.

Techoplanin

• Target range: trough >10 mg/L (total drug) or peak concentration >20 mg/L
•  patients with serious infections require higher concentrations; monitor the trough concentration and increase the teicoplanin dose if the concentration falls <20 mg/L
• toxicity is unusual at trough concentrations <50 mg/L
• longer half-life than vancomycin, so less frequent monitoring is needed
• Laboratories that perform teicoplanin assays are relatively scarce

Voriconazole

• Evidence for the value of monitoring the voriconazole plasma concentration is accumulating. The .
• Monitoring is generally recommended for patients in whom voriconazole prophylaxis or treatment is likely to be used for more than a few days because:
  • metabolism of voriconazole is saturable and varies considerably between individuals
  • significant hepatotoxicity and neurotoxicity can occur with  sustained high trough concentrations > 5 to 6 mg/L
• Target range: trough concentration 1 to 5 mg/L is commonly recommended
• steady state concentration is usually reached at:
  • 5 to 7 days (no loading dose)
  • day 5 (if loading dose given)

IMMUNOSUPPRESSANTS

TDM for immunosuppressants is particularly important for transplant recipients

Drug	Therapeutic range (microgram/L)
Cyclosporin	50-125  (serum or plasma) 150-400 (whole blood) Concentrations differ for various clinical settings
Sirolimus	5-15 (whole blood)
Tacrolimus	5-20 (whole blood)

References and Links

Journal articles and textbooks

• Birkett DJ. Therapeutic drug monitoring. Aust Prescr 1997;20:9-11 [article]
• Ghiculescu RA. Therapeutic drug monitoring: which drugs, why, when and how to do it. Aust Prescr 2008;31:42-4 [article]
• Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the β-lactam antibiotics: what is the evidence and which patients should we be using it for? The Journal of antimicrobial chemotherapy. 70(12):3178-83. 2015. [pubmed]
• Loh GW, Mabasa VH, Ensom MH. Therapeutic drug monitoring in the neurocritical care unit. Current opinion in critical care. 16(2):128-35. 2010. [pubmed]