Interpreting serum phenytoin concentrations

Let’s start with a patient case.  Patient is an 80 year old female hospitalized for pneumonia with sepsis who during this admission experienced a seizure likely secondary to imipenem/cilastatin.  She has since been on phenytoin for one week and is currently extremely confused, pulling out IV lines, and striking out at the staff.  Serum total phenytoin concentration = 16.4 mg/L.  Her SCr = 2.3 (acutely elevated) and albumin = 1.8 g/dL.  At first glance this phenytoin concentration appears therapeutic (10-20 mg/L).  What is the issue with interpreting this lab?

The utility of interpreting drug concentrations varies drastically with individual agents.  Phenytoin is one of several antiepileptic agents that need to be maintained within a narrow therapeutic range in order to ensure efficacy and avoid toxicity.  Difficulty arises with dosing phenytoin due to two major problems.  First, phenytoin is a highly protein bound drug leaving it susceptible to decreased protein binding in patients with renal failure, hypoalbuminemia, or when displaced by other highly protein bound substances.  Second, the metabolism of phenytoin is saturable at concentrations that vary person-to-person.  This means that while the liver eliminates phenytoin by first-order (or concentration-dependent) elimination at lower concentrations, at higher concentrations the pathway is saturated and only can eliminate a fixed amount over time (think of it as a set milligram elimination over time rather than percent).  In other terms, a change in maintenance dose does not have a proportionate change in drug concentration. 

Phenytoin causes a spectrum of adverse effects if the generally accepted therapeutic range of 10-20 mg/L is exceeded (approximate findings): 

• >20 mg/L: far-lateral nystagmus – alone is not generally a reason to reduce therapy
• >30 mg/L: ataxia, slurred speech
• >40 mg/L: diminished mental capacity, lethargy, confusion
• >50 mg/L: coma

                                  

To correctly interpret phenytoin concentrations, it is important to point out that we generally are assessing total serum concentration (about 90% of which is considered bound) and that only the displaced (free) portion is the active drug.  The therapeutic range (10-20 mg/L), which the patient above is within, refers to total phenytoin concentrations in patients with normal protein binding.  Therefore, if you see a reported total level in a patient with renal failure or hypoalbuminemia, it is necessary to adjust this level to correct for the amount of free drug.

There are two corrective equations commonly used (adoptions of the Sheiner-Tozer equation):

Without renal failure:

Phenytoin_corrected = Phenytoin_{lab reported}

                                  [(0.2 x S_albumin) + 0.1]

With renal failure:

Phenytoin_corrected = Phenytoin_{lab reported}

                                   [(0.1 x S_albumin) + 0.1]

For our patient above, using the above equation, her corrected serum total phenytoin concentration is 58.6 mg/L, significantly higher than what was reported.  This could be a contributing factor for her current mental status.

These equations have been widely adopted and are used to avoid the cost of ordering free phenytoin concentrations and in institutions where the free phenytoin concentration is not available.    Studies have been done that dispute the validity of these equations whereas newer studies have confirmed their accuracy in a critically ill population.

The patient above should have their phenytoin held and the concentration should return to our new understanding of therapeutic before you may consider restarting phenytoin at a reduced dose.

References:

1.  Winter ME, ed. Phenytoin. In: Basic clinical pharmacokinetics, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010:355–402.

photo by kevin dooley