Therapeutic drug monitoring refers to the individualization of dosage by maintaining plasma or blood drug concentrations within a target range (therapeutic range, therapeutic window). There are two major sources of variability between individual patients in drug response.
dose and plasma concentration (pharmacokinetic variability)
drug concentration at the receptor and the response (pharmacodynamic variability)
By adjusting doses to maintain plasma drug concentrations within a target range, variability in the pharmacokinetic phase of drug action is greatly reduced.
The major sources of pharmacokinetic variability are:
Compliance
Age - neonates, children, elderly
Physiology - gender, pregnancy
Disease - hepatic, renal, cardiovascular, respiratory
Drug interactions
Environmental influences on drug metabolism
Genetic polymorphisms of drug metabolism
The characteristics of drugs which make them suitable for, or make them require, therapeutic drug monitoring are:
marked pharmacokinetic variability
concentration related therapeutic and adverse effects
narrow therapeutic index
defined therapeutic (target) concentration range
desired therapeutic effect difficult to monitor
One such drug which needs to be monitored is PHENYTOIN SODIUM.
CLINICAL PHARMACOLOGY
Phenytoin sodium is an antiepileptic drug which can be used in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonicclonic (grand mal) seizures.
CALCULATING PHENYTOIN DOSES
When calculating a phenytoin dose for a patient, three main factors must be considered:
serum albumin status
renal function
non-linear metabolism of phenytoin.
Serum albumin status :Phenytoin is usually highly bound to serum albumin. Hypoalbuminemia (low serum albumin)increases the proportion of unbound ('free') phenytoin that is able to exert a pharmacological effect. There is a formula which can be applied to calculate the adjusted phenytoin concentration that would be observed if the patient had a normal serum albumin concentration, using the patient's observed phenytoin level, the abnormal serum albumin concentration and the normal albumin concentration (40g/L).
Renal function : Patients with renal failure have an increased proportion of unbound
phenytoin. This is partly attributable to the decrease in serum albumin associated with advanced renal failure and the change in binding affinity of phenytoin to serum albumin.
Phenytoin metabolism: For most drugs, the rate of metabolism is proportional to the plasma concentration. This follows the principles of first-order kinetics (i.e. doubling the dose of the drug results in an approximate doubling of the plasma concentration). However, the rate of phenytoin metabolism approaches its maximum at therapeutic concentrations. This is described as capacity-limited metabolism, follows the principles of zero-order kinetics. Increasing the maintenance dose of
phenytoin results in disproportionate rises in plasma concentration, which can make dose adjustment difficult.
As a general rule, when steady-state phenytoin concentrations exceed 12mg/L, a daily dose increase should not exceed 25mg,but any increase should be tailored to the individual patient's parameters and potential changes in binding.
The half-life of phenytoin is sometimes reported as 22 hours but, since it increases as the plasma concentration increases, it may be between seven and 42 hours. Many other drugs reach steady state concentrations in four to five half-lives, but with phenytoin this can take much longer, so the time at which a phenytoin level is taken is not crucial. In clinical practice, a trough level (pre-dose) is usually considered acceptable for routine monitoring.
PHENYTOIN PHARMACOKINETIC MONITORING
A. KINETIC PARAMETERS
Bioavailability (F):
0.90 - 1.0
Salt Factor (S):
0.92 - Phenytoin Na+ (caps, IV)
1.0 - Phenytoin Acid (tabs, susp)
Protein Binding:
90% (87-93)
Volume of Distribution (Vd):
0.7L/Kg - Adults
1.0L/Kg - Children
Half-Life (t½):
a function of plasma concentration
average - 22 hours (range 8 - 60 hours)
Elimination:
capacity limited metabolism (Zero order)
1-5% recovered unchanged in the urine
Cpss (SI):
40-80 umol/L (>20umol/L)
Time to Steady State:
2-4 weeks (longer with higher doses)
Conversion factor to metric:
Divide by 4 to convert from umol/L to mg/L
B. DOSING Empiric dosing guidelines (use TBW)
ROUTE
LOADING DOSE*
MAINTENANCE DOSE
IV
15-18 mg/kg - total dose direct at maximum rate of 50 mg/min
OR
Dilute to 5-20 mg/mL with NS & give over 15-30 minutes
5-7 mg/kg/day - in 2 to 3 divided doses
IM
Not recommended
ORAL:
CAPSULES
SUSPENSION
NG TUBE
15-18 mg/kg PO/NG- given as 200-400 mg q2-3h
5-7 mg/kg/day in one daily dose
If > 400 mg/day - two doses
5-7 mg/kg/day in 2 to 3 doses
may need 2-4 times IV/PO dose
hold feeds 2 hrs before and after a single daily dose
Flush tube well with 50mL sterile water
* If Phenytoin level available prior to loading dose, use Equation 1:
Equation 1:
Loading Dose =
[Vd (Cp desired - Cp observed)]/FS
(NB: Must convert Cp to metric units ie. mg/L by dividing SI units by 4 )
C. MONITORING
1) Phenytoin Serum Levels
Loading Dose:
2-4 hours post IV or 24 hours post PO load
Maintenance Dose:
steady state trough levels (10-21 days) or
compare two levels drawn at 2-4 day intervals (e.g. post loading dose level and compare to a follow-up level in 2-4 days); the maintenance dose must not change between the levels; provides estimate of the accumulation or deficiency of a fixed maintenance dose
Seizure Activity:
at the time of a seizure, a phenytoin level helps to estimate a threshold for seizure activity
2) Serum Albumin
Phenytoin is approximately 90% protein bound. Reported levels are based on total phenytoin (bound + free) and levels must be adjusted when serum albumin is reduced:
Equation 2:
Cp normal =
Cp observed / [(0.02 x albumin) + 0.1]
3) Renal Failure (<10mL/min, dialysis)
In patients with renal failure, uremia increases the unbound fraction of phenytoin. These patients also tend to have low serum albumin. In general, aim for therapeutic levels between 20-40 umol/L.
D. DOSAGE ADJUSTMENT
Phenytoin does NOT demonstrate a proportional relationship between drug levels and dose. Due to zero order kinetics, dosage should NOT be increased by more than 50-100mg increments.
OVERDOSE:
Hold dosage until levels are back within the therapeutic range then reduce dosage as per above. As a general rule, hold therapy 1 day for every 20umol/L over 80umol/L
E. TOXICITY
Dose Related:
drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behavior, mental changes, coma
(levels > 200umol/L)
Non-Dose Related:
hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia, hypersensitivity reactions (including Steven's Johnson syndrome), SLE
Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin
CRITICAL EVALUATION OF THERAPEUTIC DOSE MONITORING OF PHENYTOIN SODIUM
Pratik.A.Gada
Roll No.37
M.Sc Clinical Research
Cranfield,2009-2011
