Clinical Pharmacokinetics. Therapeutic Drug Monitoring of Phenytoin

Transcription

1 Clinical Pharmacokinetics Therapeutic Drug Monitoring of Phenytoin Dr. Maysa Suyagh School of Pharmacy University of Jordan Phenytoin primarily used as an anticonvulsant and has been used in the treatment of certain types of cardiac arrhythmias. It is usually administered orally in single or divided doses of 200 to 400 mg/day mg/kg/d for children (6 months 16 years old) and 4 6 mg/kg/d for adults When a rapid therapeutic effect is required, a loading dose of mg/kg (1000 mg for most adult patients) can be administered by oral or IV routes. IM route should be avoided because of slow and erratic absorption. Fosphenytoin is a more soluble ester of phenytoin and can be administered by the IV or IM route. Absorption of fosphenytoin by the IM route is more rapid than the oral route but slower than the IV route of administration

2 Why monitor? Phenytoin serum concs should be measured in most patients. Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis. Thus, during dosage titration it is difficult to tell if the patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time. Phenytoin serum concs are also valuable tools to avoid adverse drug effects. Patients are more likely to accept drug therapy if adverse reactions are held to the absolute minimum. Because phenytoin follows nonlinear or saturable pharmacokinetics, it is fairly easy to attain toxic concs with modest changes in drug dose. Do you remember this figure?

3 Therapeutic Concs The usual therapeutic range for total (unbound + bound) phenytoin serum concs when the drug is used in the treatment of seizures is µg/ml. Since phenytoin is highly bound (~90%) to albumin, it is prone to plasma protein binding displacement due to a large variety of factors unbound or "free" phenytoin concs are widely available. The generally accepted therapeutic range for unbound phenytoin concs (C u ) is 1 2 µg/ml, which is simply 10% of the lower and upper bounds for the total conc range, respectively. (C u = f B C) Note: for routine TDM, total phenytoin conc is still the mainstream way to monitor therapy in most patients. unbound drug conc monitoring is more expensive and takes longer time than total conc monitoring. When is it important to monitor the unbound conc? Toxic concs In the upper end of the therapeutic range >15 µg/ml some patients will experience minor central nervous system depression side effects such as drowsiness or fatigue. At total phenytoin concs>20 µg/ml, nystagmus may occur and can be especially prominent upon lateral gaze. At total concs >30 µg/ml, ataxia, slurred speech, and/or incoordination similar to ethanol intoxication can be observed. If total phenytoin concs are >40 µg/ml, mental status changes, including decreased mentation, severe confusion or lethargy, and coma are possible. Drug-induced seizure activity has been observed at concs >50 60 µg/ml. Not all patients with "toxic" phenytoin serum concs in the listed ranges will exhibit signs or symptoms of phenytoin toxicity. Rather, phenytoin concs in the ranges given increase the likelihood that an adverse drug effect will occur.

4 Basic clinical pharmacokinetic parameters Phenytoin is primarily eliminated by hepatic metabolism (>95%). mainly via the CYP2C9 enzyme system with a smaller amount metabolized by CYP2C19. About 5% of a phenytoin dose is recovered in the urine as unchanged drug. Phenytoin follows Michaelis-Menten or saturable PK. This is the type of nonlinear pharmacokinetics that occurs when the number of drug molecules overwhelms or saturates the enzyme's ability to metabolize the drug. When this occurs, steady-state drug serum concs increase in a disproportionate manner after a dosage increase. In this case the rate of drug removal is described by the classic Michaelis- Menten relationship that is used for all enzyme systems: rate of metabolism (V) = (V m C) / (K m + C), V m is the maximum rate of metabolism in mg/d, C is the phenytoin conc in mg/l, K m is the substrate conc in mg/l, and where the rate of metabolism = V m /2. The patients in the figure represent the following Vm and Km values:, 300 mg/day, 7 mg/l, 500 mg/day, 4 mg/l;, 500 mg/day, and 2 mg/l;, 600 mg/day, 4 mg/l. Note: for patients with a low Km value, the range of doses that will result in a Css ave between 10 and 20 mg/l is very narrow. Capacity limited metabolism The clearance of phenytoin is not a constant as it is with linear PK, but is conc- or dose-dependent. phenytoin follows saturable pharmacokinetics with average Michaelis-Menten constants of V max = 500 mg/d and K m = 4 mg/l. The therapeutic range of phenytoin is mg/l. Unfortunately, there is so much interpatient variability in Michaelis-Menten pharmacokinetic parameters for phenytoin (typically V max = mg/d and K m = 1 15 mg/l) that dosing the drug is extremely difficult. Since Km values for phenytoin are generally below the usual therapeutic range, nearly all patients will display capacitylimited metabolism for phenytoin.

5 At steady state the rate of drug administration equals the rate of drug elimination. The relationship between phenytoin clearance and phenytoin plasma conc (Css ave) is: If C is very small compared to Km clearance will be a relatively constant value (Vm/Km) first order. If C approaches or exceeds Km clearance will decrease and will no longer follow first order This equation is invalid as a predictor of Css ave when (S)(F)(Dose/τ) is equal to or exceeds Vm. Why? What will happen when the rate of administration approaches Vm, the maximum metabolic capacity? PhenytoinVd = 0.65 L/kg (in patients with normal renal function and with normal serum albumin concs) but can be used in all. unaffected by saturable metabolism In obese patients, the volume of distribution for phenytoin is a complex relationship between plasma protein binding, lipid solubility, and tissue perfusion Phenytoint 1/2 is still related to Cl and Vd using the same equation as for linear PK t 1/2 = (0.693 V)/Cl Since clearance is dose- or conc-dependent, half-life also changes with phenytoin dosage or conc changes limited clinical usefulness As doses or concsincrease for a drug that follows Michaelis-Menten pharmacokinetics, clearance decreases and half-life becomes longer for the drug. The clinical implication of this finding is that the time to steady state (3 5 t 1/2 ) is longer as the dose or conc is increased for phenytoin. On average, the time to steady-state serum concs is approximately 5 days at a dosage rate of 300 mg/d and 15 days at a dosage rate of 400 mg/d.

6 Dosage adjustment in obesity Loading dose: Use adjusted body weight (ABW) correction based on a pharmacokinetic study of phenytoin loading doses in obese patients (Abernethy, 1985). The larger correction factor (ie, 1.33) is due to a doubling of V d estimated in these obese patients. ABW = [(Actual body weight IBW) x 1.33] + IBW Maximum loading dose: 2000 mg (Erstad, 2004) Maintenance doses should be based on ideal body weight, conventional daily doses with adjustments based upon therapeutic drug monitoring and clinical effectiveness. (Abernethy, 1985; Erstad, 2002; Erstad, 2004) Note: at earlier sampling times (<40 hr in this case) the apparent half life of the drug is much longer for the 500-mg dose, compared with the other two lower doses. However, the terminal half life of the drug is the same for all three doses if sampling is conducted long enough for drug concentrations to reach the linear range.

7 Time to reach steady state The following equation can be used: An increase in the dose not only results in a more than proportional increase in Css, it also causes a dramatic increase in the time to reach steady state. As the dosing rate approaches Vmax, the time to reach ss increases dramatically. Elimination half life There is no simple expression to describe the elimination half-life for capacity limited elimination. The following equation describes the time course of elimination for phenytoin:

8 The oral bioavailability of phenytoin is very good for capsule, tablet, and suspension dosage forms and approximates 100%. However, the various dosage forms and different manufacturers' products are not considered to be interchangeable At larger amounts, there is some dose-dependency on absorption characteristics. Single oral doses of 800 mg or more produce longer times for maximal concs to occur (T max ) and decreased bioavailability. larger oral doses also produce a higher incidence of gastrointestinal side effects (primarily nausea and vomiting due to local irritation), break maintenance doses larger than 800 mg/d into multiple doses. If oral phenytoin loading doses are given, a common total dose is 1000 mg given as 400 mg, 300 mg, and 300 mg separated by 2- to 6-hour time intervals. Enteral feedings given by NG tube interfere with phenytoin absorption. The solution: stop the feedings, when possible, for 1 2 hours before and after phenytoin administration, and increase the oral phenytoin dose (double or triple) IV or IM phenytoin or fosphenytoin doses could also be substituted while NG feedings were being administered. Although poorly documented, phenytoin oral malabsorption may also occur in patients with severe diarrhea, malabsorptionsyndromes, or gastric resection. Available dosage forms and strengths: Capsules Prompt phenytoin sodium capsules (microcrystalline dissolve quickly): 100 mg Extended phenytoin sodium capsules (dissolve slowly): 30 mg, 100 mg, 200 mg, and 300 mg Tablet 50 mg, chewable Oral suspension 125 mg/5 ml Injection 50 mg/ml (phenytoin sodium) The capsule and injectable preparations consist of the sodium salt (S = 0.92) of phenytoin, whereas the chewable tablet and suspension contain the acid form (S = 1.0) of phenytoin. Although the fosphenytoin injectable product has a salt factor different than 0.92, the content of the fosphenytoin vial is labeled as mg of P.E. or phenytoin equivalent ; therefore, a salt factor (S) of 0.92 should be used in calculations with this product.

9 concs in the range of 5 to 10 mg/l can be therapeutic for some, but concs < 5 mg/l are not likely to be effective.

10 Problems with the use of phenytoin Individualizing the dose of phenytoin is difficult because: binding of phenytoin to plasma proteins is decreased in patients with renal failure or hypoalbuminemia. the metabolic capacity of phenytoin is limited; changes in the maintenance dose result in disproportionate changes in steady-state plasma concs. The capacity-limited metabolism of phenytoin also eliminates the clinical usefulness of half-life (t 1/2) as a pharmacokinetic parameter and makes estimates of the time required to achieve steady state difficult. Phenytoin is still commonly used in epilepsy but as a secondor third-line agent mainly due to the: difficulty with the capacity limited metabolism, multiple drug-drug interactions, longterm side-effect profile has limited its use Alterations in plasma protein binding Phenytoin therapeutic range of 10 to 20 mg/l represents the total drug conc (bound + free). The usual free fraction of phenytoinis 0.1 approximately 90% of phenytoin in the plasma is bound to serum albumin; about 10% is unbound and free to equilibrate with the tissues where the pharmacologic effects and metabolism occur. It is important to keep in mind that while most of the phenytoin in plasma is bound to plasma albumin, most of the phenytoinis not in plasma. Any phenytoindisplaced off the plasma albumin, while a large percentage of the drug in plasma, is a small percentage of phenytoin in the tissue. The displaced phenytoin will re-equilibrate with the tissue, resulting in: large decrease in the total plasma conc very little change in the unbound or free plasma phenytoinconc very little change in the pharmacologic effect. i.e the total level will appear to be low relative to its potential for pharmacologic effect (therapeutic and/or toxic).

11 changes that occur with decreased protein binding of phenytoin Remember: low hepatic extraction ratio (< 30%) and highly protein bound Disease states and conditions that alter phenytoin plasma protein binding Insufficient Albumin conc(hypoalbuminemia) Displacement by Endogenous Compounds Displacement by Exogenous Compounds Liver disease Hyperbilirubinemia Drug interactions Nephrotic syndrome Jaundice Warfarin Pregnancy Liver disease Valproic acid Cystic fibrosis Renal dysfunction Aspirin (>2 g/d) Burns Trauma Malnourishment Elderly NSAIDs with high albumin binding Refer to textbook applied clinical pharmacokinetics for detailed explanation of the effect of each of these conditions.

12 There are two approaches one can use to interpret phenytoin levels when protein binding is significantly altered. 1-adjust all the parameters (i.e., therapeutic range, volume of distribution, and Km) to those that would be observed in the presence of altered plasma binding. not common 2-convert the measured or observed plasma concwith low binding into that which would be observed under normal binding conditions (C Normal Binding ), and use PK parameters which are based on normal binding. C = observed plasma conc reported by the lab; fu = normal free fraction of phenytoin (fu = 0.1); P = patient's serum albumin in g/dl; P NL = normal serum albumin (4.4 g/dl); C Normal Binding = plasma drug conc that would have been observed if the patient's serum albumin conc had been normal. In this instance, the parameters (i.e., therapeutic range, volume of distribution, and Km) associated with normal plasma protein binding would also be used in any calculations. least likely to result in calculation errors preferred This equation is most useful when a patient has a low serum albumin concbut does not have significantly diminished renal function and is not taking other drugs known to displace phenytoin.

13 In patients with ESKD, the free fraction of phenytoin increases from 0.1 to Some of this change in plasma binding is due to the decrease in serum albumin conc associated with ESKD, and some of the binding changes are due to a change in the binding affinity of phenytoin to serum albumin. When the ClCris > 25 ml/min, the change in the binding affinity is minimal, no adjustment for renal function need to be made use the previous equation In patients with diminished renal function who are not undergoing intermittent hemodialysis, binding affinity is unpredictably altered when the ClCris between 10 and 25 ml/min. If the ClCris < 10 ml/min ANDthe patient is undergoing hemodialysis treatments, binding changes can be significant use the following modified equation: corrects for both serum albumin and renal dysfunction For patients with hypoalbuminemia and a creatinine clearance > 25 ml/min, the equivalent lower and upper end of the conc range would be as follows: For patients with hypoalbuminemia who are receiving dialysis, the equivalent lower and upper end of the conc range would be as follows: Estimated unbound conc = Total conc x 0.1 Note: these equations only provide estimates of the respective concs and the actual unbound phenytoin concs should be measured whenever possible in patients with suspected abnormal plasma protein binding

14 Adjustment of Serum Concentration in Adults With Low Serum Albumin Measured Total Phenytoin Concentration (mcg/ml) Patient's Serum Albumin (g/dl) Adjusted Total Phenytoin Concentration (mcg/ml) Adjusted concentration = measured total concentration divided by [(0.2 x albumin) + 0.1]. Adjustment of Serum Concentration in Adults With Renal Failure (Clcr 10 ml/min) Measured Total Phenytoin Concentration (mcg/ml) Patient's Serum Albumin (g/dl) Adjusted Total Phenytoin Concentration (mcg/ml) Adjusted concentration = measured total concentration divided by [(0.1 x albumin) + 0.1]. Questions JM is an epileptic patient being treated with phenytoin. He has hypoalbuminemia (albumin = 2.2 g/dl) and normal renal function (creatinine clearance = 90 ml/min). His total phenytoin conc is 7.5 mg/l. Compute an estimated normalized phenytoin conc for this patient (both total and unbound) LM is an epileptic patient being treated with phenytoin. He has hypoalbuminemia (albumin = 2.2 g/dl) and poor renal function (creatinine clearance = 10 ml/min). His total phenytoin conc is 7.5 mg/l. Compute an estimated normalized phenytoin conc for this patient (both total and unbound)

15 Question E.W., a 56-year-old, 60-kg woman, has chronic renal failure and a seizure disorder. She undergoes hemodialysis treatments three times a week, has a serum albumin of 3.3 g/dl, and takes 300 mg/day of phenytoin. Her reported steady-state plasma phenytoin concentration is 5 mg/l. What would be her phenytoin concentration if she had a normal serum albumin concentration and normal renal function? Should her daily phenytoin dose be increased? Is it necessary to make dose adjustments or to administer a phenytoin replacement dose following dialysis? Drug displacement: Drugs also can displace phenytoin from plasma protein binding sites. It is usually difficult to estimate the extent of drug displacement from protein binding sites because the conc of the displacing agent is seldom known. One exception to this rule is the situation in which serum concs of both valproic acid and phenytoin are being monitored. When the serum valproic acid conc is < 20 mg/l, the displacement of phenytoin appears to be minimal adjustment of the phenytoin conc is probably not warranted. When the valproic acid conc increases, phenytoin displacement from plasma protein binding sites increases. At valproic acid concs of approximately 70 mg/l, phenytoin serum concs decrease by 40% An equation was developed to help correct or adjust for the displacement of phenytoin by valproic acid: Unbound phenytoin conc in the presence of valproic acid unbound fraction Note: the two drug concs should be measured (obtained) at the same time. In addition, there should not be any other factors present that would alter plasma binding (e.g., hypoalbuminemia, renal failure, other displacing drugs).

16 The drug interaction between valproic acid and phenytoin: a closer look

17 Side effects A number of long-term phenytoin side effects, such as gingival hyperplasia, folate deficiency, and peripheral neuropathy, do not appear to be easily related to plasma phenytoin concs. CNS side effects do correlate to some degree with plasma conc. Far-lateral nystagmus Usually occurs in patients with plasma phenytoin concs > 20 mg/l. The conc range associated with this effect, however, is broad (15 mg/l to > 30 mg/l) often used to monitor phenytoin therapy, seldom considered a true drug side effect or toxicity (not a reason to reduce the phenytoin dose) Other CNS symptoms such as ataxia and diminished mental capacity are frequently observed in patients with concs exceeding 30 mg/l and 40 mg/l, respectively. In addition, precautions should be taken when phenytoinfor injection is administered by the IV route because the propylene glycol diluent has cardiac depressant properties. Fosphenytoin is more soluble than phenytoin for injection and does not contain propylene glycol as a diluent. However, fosphenytoin does have similar effects on the myocardium and cardiovascular system (bradycardia and hypotension) but to a lesser extent. The maximum recommended rate of IV administration is 50 mg/min for phenytoin for injection 150 mg/min for fosphenytoin, slower rates of infusion are often used, especially when larger loading doses are administered.

18 Time to sample Depending on the disease state being treated and the clinical condition of the patient, the time of sampling for phenytoin can vary greatly. In patients requiring rapid achievement and maintenance of therapeutic phenytoinconcs, monitor phenytoin concs within 2 to 3 days of initiating therapy to ensure that the patient's metabolism is not remarkably different from that which would be predicted by average literature-derived PK parameters. A second phenytoin conc would normally be obtained in another 3 to 5 days; subsequent doses of phenytoin can then be adjusted. If the plasma phenytoin concs have not changed over a 3- to 5-day period, the monitoring interval can usually be increased to once weekly in the acute clinical setting. In stable patients requiring long-term therapy, phenytoin plasma concs are generally monitored at 3- to 12-month intervals The time required to achieve steady state with phenytoin can be prolonged plasma levels of phenytoin should be monitored before steady state to avoid sustained periods of low or high phenytoin concs. Nevertheless, these early phenytoin concs must be used cautiously in the design of new dosing regimens. Trough concs are generally recommended for routine monitoring Initial dosage determination PK method Accurate estimates for Vm and Km are not available for many important patient population. There is fold variation in these PK parameters initial doses derived from the parameters will not be successful in achieving desired goals for all patients. Phenytoin monitoring, including unbound conc measurement if altered protein binding is suspected, is important component of therapy.

19 Michaelis-Menten Parameter Estimates Normal adults with normal liver and renal function as well as normal plasma protein binding have an average phenytoin V max of 7 mg/kg/d and K m of 4 mg/l. Michaelis-Menten parameters for younger children (6 months 6 years) are V max = 12 mg/kg/d and K m = 6 mg/l older children (7 16 years) V max = 9 mg/kg/d and K m = 6 mg/l. These are the only parameters required to estimate a maintenance dose for phenytoin. Volume of Distribution Estimate The volume of distribution for patients with normal phenytoin plasma protein binding is estimated at 0.7 L/kg for adults. For obese individuals 30% or more above their ideal body weight, the volume of distribution can be estimated using the following equation: V = 0.7 L/kg [IBW (TBW IBW)] This parameter is used to estimate the loading dose (LD in milligrams) for phenytoin, if one is indicated: LD = (Css V)/S Selection of Appropriate PK Model and Equations When given by short-term IV infusion or orally, phenytoin follows a onecompartment pharmacokinetic model. When oral therapy is required, an extended phenytoin capsule dosage form that has good bioavailability (F = 1), supplies a continuous release of phenytoin into the gastrointestinal tract is commonly used, and provides a smooth phenytoin serum conc/time curve that emulates an IV infusion after once or twice daily dosing. The equation used to calculate loading doses (LD in mg) is based on a simple one-compartment model: LD = (Css V)/S The Michaelis-Menten PK equation that computes the average phenytoin steady-state serum conc (Css in mg/l) is widely used and allows maintenance dosage (MD) calculation:

20 Steady-State conc Selection The generally accepted therapeutic ranges for total and unbound phenytoin concs are mcg/ml and 1 2 mcg/ml, respectively, for the treatment seizures. For patients with altered phenytoin plasma protein binding it is more important to have the unbound conc within its therapeutic range than the total conc. To establish that the unbound fraction (f B ) is altered for a patient, phenytoin total and unbound concs should be simultaneously measured from the same blood sample: f B = C f /C. As long as the disease states or conditions that caused altered phenytoin plasma protein binding are stable, a previously measured unbound fraction can be used to convert newly measured total phenytoin concs to their unbound equivalent (C f = f B C). Phenytointherapy must be individualized for each patient in order to achieve optimal responses and minimal side effects. Questions TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial seizures who requires therapy with oral phenytoin. He has normal liver and renal function. Suggest an initial phenytoin dosage regimen designed to achieve a steady-state phenytoin conc equal to 12 mg/l. UO is a 10-year-old, 40-kg male with simple partial seizures who requires therapy with oral phenytoin. He has normal liver and renal function. Suggest an initial phenytoin dosage regimen designed to achieve a steadystate phenytoin conc equal to 12 mg/l.

21 Use of Phenytoin Serum Concs to Alter Doses A variety of methods are used to estimate new maintenance doses or Michaelis-Menten parameters when one steady-state phenytoin serum conc is available. The Graves-Cloydmethod allows adjustment of phenytoin doses using one steady-state conc. Because it uses a power function, it is computationally intensive. The Vozeh-Sheinermethod utilizes a specialized graph and Bayesian pharmacokinetic concepts to individualize phenytoin doses using a single steady-state conc. Because of this, a copy of the graph paper with population orbits must be available, and plotting the data is time consuming. If two or more steady-state phenytoinserum concsare available from two or more daily dosage rates, it may be possible to calculate and use pharmacokinetic parameters to alter the phenytoin dose. Two graphical methods allow the computation of V max and K m for patients receiving phenytoin, but they are cumbersome and time consuming. The Mullen method uses the same specialized graph as the Vozeh-Sheiner method, but computes the patient's own Michaelis-Menten parameters instead of Bayesian pharmacokinetic estimates. The Luddenmethod uses standard graph paper to plot the conc-time data, and V max and K m are computed from the intercept and slope of the resulting line. Vozeh-Sheiner or Orbit Graph The eccentric circles or orbits represent the fraction of the sample patient population whose Km and Vm values are within that orbit.

22 How to use the Orbit graph (1)Plot the daily dose of acid phenytoin (mg/kg/day) on the vertical line [Rate of Administration (RA)]. (2)Plot the steady state conc (Css ave) on the horizontal line. (3)Draw a straight line connecting Css ave and daily dose through the orbits (line A). (4)The coordinates of the midpoint of the line crossing the innermost orbit through which line A passes are the most probable values for the patient's Vm and Km. (5)To calculate a new maintenance dose, draw a line from the point determined in Step 4 to the new desired Css ave (line B) (6)The point at which line B crosses the vertical line [Rate of Administration (RA)] is the new maintenance dose (mg/kg/day) of acid phenytoin. Question TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial seizures who requires therapy with oral phenytoin. He has normal liver and renal function. The patient was prescribed 400 mg/d of extended phenytoin sodium capsules for 1 month, and the steady-state phenytoin total conc equals 6.2 mg/l. The patient is assessed to be compliant with his dosage regimen. Suggest an initial phenytoin dosage regimen designed to achieve a steady-state phenytoin conc within the therapeutic range.

23 Question GF is a 35-year-old, 55-kg female with tonicclonic seizures who requires therapy with oral phenytoin. She has normal liver and renal function. The patient was prescribed 300 mg/d of extended phenytoin sodium capsules for 1 month, and the steady-state phenytoin total conc equals 10.7 mg/l. The patient is assessed to be compliant with her dosage regimen. Suggest an initial phenytoin dosage regimen designed to achieve a steady-state phenytoin conc of 18 mg/l. Ludden Method This method involves the arrangement of the Michaelis-Menten equation so that two or more maintenance doses (MD, in mg/d of phenytoin) and steady-state concs (Css in mg/l) can be used to obtain graphical solutions for V max and K m : MD = K m (MD / Css) + V max When maintenance dose is plotted on the y-axis and MD/Css is plotted on the x-axis of Cartesian graph paper, a straight line with a y-intercept of V max and a slope equal to K m is found. If three or more dose/conc pairs are available, it is best to actually plot the data so the best straight line can be drawn through the points. However, if only two dose/conc pairs are available, a direct mathematical solution can be used (next slide).

24 The slope: K m = (MD 1 MD 2 )/[(MD 1 /Css 1 ) (MD 2 / Css 2 )] where the subscript 1 indicates the higher dose and 2 indicates the lower dose. Once this has been accomplished, V max can be solved for in the rearranged Michaelis-Menten equation: V max = MD + K m (MD / Css). The Michaels-Menten equation can be used to compute steady-state concs for a given dose or vica versa. Question TD is a 50-year-old, 75-kg (5 ft 10 in) male with simple partial seizures who requires therapy with oral phenytoin. He has normal liver and renal function. The patient was prescribed 400 mg/d of extended phenytoin sodium capsules for 1 month, and the steady-state phenytoin total conc equals 6.2 mg/l. The dosage was increased to 500 mg/d of extended phenytoin sodium capsules for another month, the steady state phenytoin total conc equals 22.0 mg/l, and the patient has some lateral-gaze nystagmus. The patient is assessed to be compliant with his dosage regimen. Suggest a new phenytoin dosage regimen designed to achieve a steady-state phenytoin conc within the therapeutic range.

25 Question GF is a 35-year-old, 55-kg female with tonic-clonic seizures who requires therapy with oral phenytoin. She has normal liver and renal function. The patient was prescribed 300 mg/d of extended phenytoin sodium capsules for 1 month, and the steady-state phenytoin total conc equals 10.7 mg/l. At that time, the dose was increased to 350 mg/d of extended phenytoin sodium capsules for an additional month, and the resulting steady state conc was 15.8 mg/l. The patient is assessed to be compliant with her dosage regimen. Suggest a new phenytoin dosage regimen increase designed to achieve a steady-state phenytoin conc within the upper end of the therapeutic range. Use of Phenytoin Booster Doses to Immediately Increase Serum Concs If a patient has a subtherapeutic phenytoin serum conc in an acute situation, it may be desirable to increase the phenytoin conc as quickly as possible. In this setting, it would not be acceptable to simply increase the maintenance dose and wait for therapeutic steady-state serum concs to be established in the patient. A rational way to increase the serum concs rapidly is to administer a booster dose of phenytoin, a process also known as "reloading" the patient with phenytoin, computed using pharmacokinetic techniques. A modified loading dose equation is used to accomplish computation of the booster dose (BD) which takes into account the current phenytoin conc present in the patient: BD = [(C desired C actual )V] / S, Concurrent with the administration of the booster dose, the maintenance dose of phenytoin is usually increased.

26 Question S.B. is a 37-year-old, 70-kg man with a seizure disorder that has only partially been controlled with 300 mg/day of phenytoin capsules. His plasma phenytoin concentration has been measured twice over the past year and was 8 mg/l both times. Calculate a maintenance dose to achieve a new steady-state concentration of 15 mg/l. Calculate a loading dose that would rapidly increase S.B.'s plasma phenytoin concentration from 8 to 15 mg/l.

27 Michaelis-Menten - Vozeh Plot , 0.25, 0.1, 0.05, Vm, Dose Rate mg/kg/day Cp mg/l Km mg/l 2005 David Bourne

28 case study Adjusting phenytoin doses in a patient with co-morbidities This article describes the application of therapeutic drug monitoring to achieve optimal dosing of phenytoin in an elderly patient with co-morbid conditions. By David Jones. The case Mrs JW is a 73-year-old woman admitted to hospital following a fall resulting in right hip pain. This was followed by a range of medical problems including congestive cardiac failure, urinary sepsis, atrial fibrillation, seizures, abnormal liver function tests, poor urine output, a gastrointestinal bleed and Clostridium difficile-associated diarrhoea. Medical and drug history Mrs JW s previous medical history included epilepsy, osteoarthritis, monoclonal gammopathy and thrombocytopenia. She normally receives her medication in a dosette box and was taking the following medicines before admission (confirmed by the ward pharmacist); Amiloride 5mg OD Bumetanide 3mg OD Phenytoin sodium 100mg OM and 325mg ON Simvastatin 40mg ON On admission, her electrolyte levels were as follows: Sodium 138mmol/L Potassium 3.9mmol/L Urea 11.5mmol/L Creatinine 113µmol/L Alkaline phosphatase 350 IU/L (chronic) C-reactive protein 67mg/L White cell count 7.9 x 10 9 /L Platelets 74 x 10 9 /L (chronic) The initial diagnosis was a mechanical fall (i.e. not leading to loss of consciousness), following a number of previous falls, which may have been caused by confusion resulting from a urinary tract infection or urinary sepsis. Plan The immediate plan was to: obtain lying and standing blood pressures, seek physiotherapy input, perform urinalysis, start calcium supplements (Adcal D3;Prostraken, 1 tablet BD) for bone protection, stop the diuretics (the patient was showing clinical signs of dehydration) and take a phenytoin level. Following a discussion between the medical staff and the pharmacist, it was decided not to prescribe a low molecular weight heparin for prophylaxis of venous Calculating phenytoin doses When calculating a phenytoin dose for a patient, three main factors must be considered: serum albumin status, renal function and the 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 thromboembolism because of Mrs JW s low platelet count. The junior doctor asked the ward pharmacist for advice about taking a phenytoin level and was advised to take a trough level in line wth standard practice. The trough phenytoin level was 3mg/L. The usual therapeutic range is 10 20mg/L, so a dose adjustment was required. The pharmacist provided support in calculating the maintenance dose that would achieve a mid-range, steady-state concentration close to 15mg/L. 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, which 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. 172 The British Journal of Clinical Pharmacy Vol.1 June 2009 Copyright of the The British Journal of Clinical Pharmacy. No reproduction in any format is allowed unless permission is granted by the publisher

29 case study Dose calculation A graphical method was applied, as shown in Figure 1. This is referred to as an orbit graph or Vozeh plot. The graph is divided into two sections; on the left hand side, a steady-state phenytoin concentration can be plotted along the x-axis (Cp) against the corresponding dosing rate of phenytoin base in mg/kg/day on the y-axis (V m ). The right hand side of the graph can be used to estimate the most likely values of V m and K m (the plasma concentration at which the rate of metabolism is exactly half the maximum rate), based on population pharmacokinetic studies. The orbits represent the fraction of the sample patient population whose V m and K m values are within that orbit (innermost orbit = 50%, next orbits = 75%, 90% and 95%, respectively, outermost orbit = 97.5%). On admission Mrs JW was taking 425mg of phenytoin sodium daily (100mg OM and 325mg ON), resulting in a steadystate phenytoin concentration of 3mg/L. She weighs 75kg. A new maintenance dose was derived using the following standard method: 1. Calculate V m, the dosing rate of phenytoin, and plot on the y-axis. This should be calculated using the salt fraction of phenytoin sodium capsules, which is 92% of the actual dose (the percentage of the administered salt that is the active constituent). 425mg phenytoin sodium 391mg phenytoin base Therefore the dosing rate (V m ) of phenytoin is: 391mg = 5.2mg/kg/day 75kg 2. Obtain the steady-state phenytoin concentration (Cp) corresponding to the above dosing rate and plot on the x-axis. In this case, the steady-state phenytoin level obtained for this dosing rate was 3mg/L. 3. Decide on a target phenytoin concentration. In most cases, the target concentration is taken to be the average of the therapeutic range, in this case 15mg/L. 4. Connect the two points from parts (1) and (2) above. This is done by drawing a Figure 1: Vozeh plot showing calculation of a new phenytoin maintenance dose to correct a phenytoin level of 3mg/L straight line, passing through the orbits to the right of the graph (the black line in Figure 1). 5. Calculate the new maintenance dose. The new maintenance dose is calculated by drawing another straight line from the middle of the line crossing the innermost orbit, to the new, desired steady-state phenytoin concentration. The point, at which the new line crosses the y-axis, is the new dosing rate of phenytoin base required to achieve the desired phenytoin concentration (the red line in Figure 1). In this case, the new dose rate was 7.8mg/kg/day. The new maintenance dose for Mrs JW was therefore: 7.8mg x 75kg = 585mg/day phenytoin base (equivalent to 635mg/day phenytoin sodium). For ease of administration, the pharmacist suggested rounding down the dose to 600mg/day. Antibiotic complications Over the next week or so, Mrs JW was treated for urinary sepsis. She received intravenous piperacillin with tazobactam (Tazocin;Lederle) 4.5g TDS, and her renal function was monitored regularly. This was later changed to oral ciprofloxacin 500mg BD, following advice from the microbiologist. Quinolone antibiotics such as ciprofloxacin are known to lower a person s seizure threshold and should be avoided in patients with epilepsy. Unfortunately, the switch from IV to oral antibiotics took place over the weekend, when the hospital does not operate a clinical pharmacy service, and during this time Mrs JW suffered a number of seizures. The on-call doctor presumed that the seizures were due to the effect of the quinolone, as opposed to a sub-therapeutic phenytoin concentration. Ongoing monitoring of the patient identified Clostridium difficile-associated diarrhoea, which was thought to be June 2009 Vol. 1 The British Journal of Clinical Pharmacy 173 Copyright of the The British Journal of Clinical Pharmacy. No reproduction in any format is allowed unless permission is granted by the publisher

30 case study secondary to successive antibiotic treatments. This caused changes in Mrs JW s biochemistry her potassium level fell to 2.9mmol/L (and was treated with oral potassium supplements) and her creatinine rose to 219µmol/L due to dehydration. The pharmacist advised that Mrs JW s phenytoin level should be checked again and monitored closely. The next day her phenytoin level was reported to be 19mg/L. Since this level is at the top end of the therapeutic range and in light of Mrs JW s worsening renal function and reports that she was becoming increasingly drowsy (presumed to be secondary to the phenytoin dose increase), the pharmacist suggested a phenytoin dose review. Dose adjustment The Vozeh plot was used again to calculate a new dose based on Mrs JW s phenytoin concentration of 19mg/L and her recent dose of phenytoin sodium 600mg/day (Figure 2). 600mg phenytoin sodium 552mg phenytoin base. The corresponding dosing rate was therefore: 552mg = 7.4mg/kg/day 75kg As shown in Figure 2, the point at which the red line crosses the y-axis (the new dosing rate of phenytoin base) was 7mg/ kg/day. The new maintenance dose was thus calculated as: 7mg x 75kg = 525mg/day phenytoin base (equivalent to 570mg/day phenytoin sodium). This was rounded down to 550mg/day for convenience. Further monitoring Following this dose reduction, the plan was to monitor Mrs JW closely and check her phenytoin level in five to seven days time. Mrs JW remained seizure free and was not showing any signs of phenytoin toxicity. However, after six days Mrs JW s steady-state phenytoin level was reported to be 23mg/L. This was due to ongoing (but improving) renal impairment and an acute reduction in serum albumin (to 27g/L). Once again, a new maintenance dose was determined, using the same Figure 2: Vozeh plot showing calculation of a new phenytoin maintenance dose to correct a phenytoin level of 19mg/L method and a phenytoin concentration of 23mg/L at a dosing rate of 6.75mg/kg/ day phenytoin base. The new dosing rate was found to be 6.25mg/kg/day. The new maintenance dose was therefore: 6.25mg x 75kg = 469mg/day phenytoin base (equivalent to 509mg/day phenytoin sodium), rounded down to 500mg/day. The remainder of Mrs JW s hospital stay involved rehabilitation and mobilisation, and titration of carvedilol and furosemide doses, which were newly prescribed for her ongoing congestive cardiac failure. Mrs JW continued to take 500mg phenytoin sodium and remained seizure free. Ongoing monitoring was carried out by the pharmacist and, before the patient was discharged, two steady-state phenytoin levels were taken seven days apart, recording 17mg/L and 15mg/L, respectively. The pharmacist arranged a new dosette box for Mrs JW which contained the following medicines: Furosemide 80mg OM and 40mg at lunch Paracetamol 1g QDS Senna 2 tablets ON Sodium docusate 200mg BD Carvedilol 6.25mg BD Phenytoin sodium 250mg BD Mrs JW was discharged, and a routine follow-up appointment at the intermediate care outpatient clinic was scheduled for six weeks time. David Jones is specialist clinical pharmacist at Northumbria Healthcare NHS Foundation Trust. 174 The British Journal of Clinical Pharmacy Vol.1 June 2009 Copyright of the The British Journal of Clinical Pharmacy. No reproduction in any format is allowed unless permission is granted by the publisher