Clinical Utility of Free Drug Monitoring

Abstract

Most drugs are bound to serum proteins to a various degree. Only unbound or free drug is pharmacologically active. Usually total drug is measured for therapeutic monitoring because there is equilibrium between bound and free drugs, and concentration of free drug can be predicted from total drug concentration. However, under certain conditions this equilibrium is disturbed and the measured free drug concentration can be significantly higher than expected from total drug concentrations, especially for strongly protein-bound drugs. In such case a patient may experience drug toxicity even if the total drug concentration is within the therapeutic range. Conditions like uremia, liver disease and hypoalbuminemia can lead to significant increases in free drug concentration. Therefore, monitoring free phenytoin and free valproic acid is recommended in these patients. Drug-drug interactions can also lead to a disproportionate increase in free drug concentration. One strongly protein-bound drug can significantly displace another strongly protein-bound drug if both drugs share the same binding site. Several over-the-counter pain medications such as salicylate, naproxen, and ibuprofen can cause significant displacement of both phenytoin and valproic acid from albumin binding site. Interestingly, such interactions are absent in uremic patients. Elderly patients may have increased free phenytoin or valproic acid due to hypoalbuminemia. Elevated free phenytoin concentrations have also been reported in patients with AIDS. Although digoxin is 25% bound to protein, monitoring free digoxin is useful in patients with elevated endogenous digoxin-like immunoreactive substances or in patients overdosed with digoxin and being treated with digibind. Monitoring free digoxin can also eliminate interference of Chinese medicines Chan Su and Danshen in serum digoxin measurement by certain immunoassays. However, free drug monitoring is not a routine procedure in clinical laboratories due to technical difficulties and lack of established reference ranges for free drugs.

A Theoretical Method for Normalizing Total Serum Valproic Acid Concentration in Hypoalbuminemic Patients

“…In the case of drugs with high protein binding (a <20%), it may be preferable to determine their free concentration; however, in clinical laboratories, the standard procedure is to monitor the total drug concentration (1 -4), due to technical difficulties and a lack of established reference ranges for free drug concentrations (2,4). The two antiepileptic drugs in which it may be clinically useful to determine the free drug concentration are phenytoin and valproic acid (5,6).…”

“…Valproic acid is extensively bound to albumin (a <10%), and the drug-protein binding depends on both the serum albumin concentration and the drug concentration (2 -7). As a result, the free fraction of this drug is subject to more variation than other highly protein-bound antiepileptic drugs (2). Studies published by Gidal et al (8) and Haraldson et al (9) reported several cases demonstrating the clinical importance of monitoring free valproic acid, as well as the minimal utility of total drug concentration in patients with hypoalbuminemia.…”

“…Studies published by Gidal et al (8) and Haraldson et al (9) reported several cases demonstrating the clinical importance of monitoring free valproic acid, as well as the minimal utility of total drug concentration in patients with hypoalbuminemia. As early as 1980, Levy stressed that serious consideration should be given to the monitoring of free rather than total valproic acid concentration, which can be misleading (7); however, a recent survey by the College of American Pathologists revealed that only 2% of the laboratories which routinely performed total valproic acid determination offered free valproic acid assays (2). For some anticonvulsant drugs, under well-controlled and standardized conditions, the concentration in saliva bears a constant relationship to free serum concentration, but this is not the case for valproic acid (10).…”

Incidence and risk factors for lower alimentary tract mucositis after 1529 courses of chemotherapy in a homogenous population of oncology patients

“…24 Hence, patients with hypoalbuminemia may have increased drug exposure (hence higher toxicity) when treated with agents that undergo extensive hepatic metabolism and/or exhibit high protein binding. 25 Most drugs applied during the induction phase of Total Therapy 3 (Table 1) undergo extensive hepatic metabolism (doxorubicin [Adriamycin], etoposide, cyclophosphamide, and bortezomib) and/or exhibit high protein binding (same agents plus cisplatin). [26][27][28][29][30] Because intravenous melphalan is highly protein-bound (60%-90%, mainly albumin), 20 hypoalbuminemia may also result in higher free melphalan exposure, which in turn may increase the risk for lower alimentary tract mucositis.…”

Protein Binding of Antimicrobials: Methods for Quantification and for Investigation of its Impact on Bacterial Killing

“…Furthermore, drug-drug interactions can lead to changes of unbound fractions of protein-bound drugs (25). The mechanism may be either competitive, meaning that drugs bind to the same site, or noncompetitive, with one drug causing a conformational change in the protein molecule, which, in turn, inhibits the binding of the other drug (19).…”