Invited critical review
Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management

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Abstract

Drugs are bound to various serum proteins in different degrees and only unbound or free drug is pharmacologically active. Although free drug concentration can be estimated from total concentration, for strongly bound drugs, prediction of free level is not always possible. Conditions like uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug resulting in drug toxicity even if the concentration of total drug is within therapeutic range. Drug–drug interactions may also lead to a disproportionate increase in free drug concentrations. Elderly patients may have increased free drug concentrations due to hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS and pregnancy. Currently free drug concentrations of anticonvulsants such as phenytoin, carbamazepine and valproic acid are widely measured in clinical laboratories. Newer drugs such as mycophenolic acid mofetil and certain protease inhibitors are also considered as candidates for monitoring free drug concentration.

Section snippets

Mechanism of drug-protein binding

Many drugs bind reversibly to plasma proteins mainly albumin and α1-acid glycoprotein. While drug binding to plasma protein was considered to represent an unspecific physiochemical phenomenon such as absorption of small molecules by activated charcoal, accumulation of evidence indicates that drug binding to serum proteins only occur at few binding sites on proteins.

Albumin is the most abundant protein in human serum with a molecular weight of 66,500 Da. X-ray diffraction study has demonstrated

Drugs which are candidate for free drug monitoring

If the protein binding of a drug is less than 80%, it is not considered as a candidate for free drug monitoring because variation in protein binding may not have clinically significant effect in altering free drug concentrations. An exception is free digoxin monitoring (digoxin is only 25% protein bound), which is very useful in patients overdosed with digoxin and being treated with digibind, the FAB fragment of anti-digoxin antibody. Protein binding of some commonly monitored therapeutic drugs

Historical perspective of free drug monitoring

The first comprehensive report demonstrating the clinical utility of free drug monitoring dated back to 1973 [11]. In a population of 30 epileptic patients, the authors found a better correlation with toxicity (in coordination, ataxia, and nystagmus) and free drug concentrations. Blum et al. described a uremic patient who was well controlled on a total phenytoin concentration of 3 μg/mL, which was far below the recommended therapeutic range of 10- to 20 μg/mL. [12]. Most likely cause of this

When should free anticonvulsant be monitored?

For strongly protein bound anticonvulsants, such as phenytoin, valproic acid and carbamazepine, free drug monitoring is strongly recommended in the following cases.

  • 1.

    Uremic patients

  • 2.

    Patients with chronic liver disease

  • 3.

    Patients with hypoalbuminemia (burn patients, elderly, pregnancy, AIDS etc.)

  • 4.

    Suspected drug–drug interactions where one strongly protein bound drug can displace another strongly protein bound anticonvulsant.

Saliva and tears: alternative to serum for therapeutic drug monitoring

Drugs, which are not ionizable or are un-ionized within the salivary pH range (phenytoin, carbamazepine, theophylline) are candidates for salivary therapeutic drug monitoring [117]. Salivary flow rate vary significantly both between individuals and under different conditions. The use of stimulated saliva has advantage over resting saliva. The salivary flow rate, pH and sampling condition and other pathophysiological factors may influence the concentration of a particular drug in saliva.

Assay techniques for free anticonvulsants

Ultrafiltration using Centrifree Micropartition System is the most common technique for monitoring free drug concentrations in clinical laboratories. Usually 0.8–1.0 mL of serum is centrifuged for 15–20 min to prepare the ultrafiltrates. Then free drug concentrations are measured in the protein free ultrafiltrates. The time of centrifuging to prepare ultrafiltrate is crucial for measuring free drug concentrations. Liu et al. demonstrated that there is a significant difference between measured

Pitfalls of using equations for predicting free phenytoin concentrations

Beck et al. compared free phenytoin concentrations predicted by three different equations with measured values. The authors used the Gugler method, Sheiner–Tozer equation and Sheiner–Tozer nomogram for predicting free phenytoin concentrations from measured total phenytoin concentrations and albumin concentrations. Authors concluded that all three methods for predicting free phenytoin concentrations suffered from bias and should not be used for predicting free phenytoin concentrations. The

Therapeutic drug monitoring of new anticonvulsants

Careful monitoring of liver function test and blood cell counts are strongly recommended for felbamate due to its known toxicity [127]. The suggested therapeutic range is 125–250 mmol/L. The drug is only 20–25% bound to serum protein and currently there is no indication for monitoring free felbamate level. There is no systematic study to establish a therapeutic range for gabapentene. A tentative target range of 70–120 μmol/L have been suggested. There are more indications for therapeutic

Conclusions

Therapeutic drug monitoring of strongly protein bound antiepileptic drugs such as phenytoin, valproic acid and carbamazepine is useful for patients with uremia, liver disease and hypoalbuminemia. Drug–drug interactions may also increase free fractions of antiepileptic drugs without significantly altering total drug concentrations. Monitoring free concentration of immunosuppressant drugs like cyclosporine, tacrolimus and mycophenolic acid may have clinical value but are not usually offered in

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