Phenytoin

PHENYTOIN INTRODUCTION ❖Phenytoin is a hydantoin compound related to the barbiturates that are used for the treatment of seizures. It is an effective anticonvulsant for the chronic treatment of tonic-clonic (grand mal) or partial seizures and the acute treatment of generalized status epilepticus. ❖After generalized status epilepticus has been controlled with intravenous benzodiazepine therapy and supportive measures have been instituted, phenytoin therapy is often immediately instituted with the administration of intravenous phenytoin or fosphenytoin. ❖Orally administered phenytoin is used chronically to provide prophylaxis against tonic clonic or partial seizures. ❖Phenytoin is a type 1B antiarrhythmic and is also used in the treatment of trigeminal neuralgia. INTRODUCTION ❖It is usually administered orally in single or divided doses of 200 to 400 mg/day. ❖5–10 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 15-20 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 INTRODUCTION ❖Individualizing the dose of phenytoin is complicated by two major problems. 1) binding of phenytoin to plasma proteins is decreased in patients with renal failure or hypoalbuminemia, and, in certain cases, phenytoin can be displaced by other drugs. 2) the metabolic capacity of phenytoin is limited; therefore, changes in the maintenance dose result in disproportionate changes in steady-state plasma concentrations. The capacity-limited metabolism of phenytoin also eliminates the clinical usefulness of half-life (t½) as a pharmacokinetic parameter and makes estimates of the time required to achieve steady state difficult. Although phenytoin is still commonly used, the difficulty with the capacity-limited metabolism, multiple drug–drug interactions, as well as the long-term side effect profile has limited its use in epilepsy to a second- or third-line agent. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖The usual therapeutic range for total (unbound + bound) phenytoin serum concentrations when the drug is used in the treatment of seizures is 10-20 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. ❖The suggested therapeutic range for unbound phenytoin concentrations is based on the usual unbound fraction (10%) of phenytoin in individuals with normal plasma protein binding. ❖Thus, the generally accepted therapeutic range for unbound phenytoin concentrations is 1-2 μg/mL, which is simply 10% of the lower and upper bounds for the total concentration range, respectively THERAPEUTIC AND TOXIC CONCENTRATIONS ❖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 concentrations above 20 μg/mL, nystagmus may occur and can be especially prominent upon lateral gaze. ❖When total concentrations exceed 30 μg/mL, ataxia, slurred speech, and/or incoordination similar to ethanol intoxication can be observed. ❖If total phenytoin concentrations are above 40 μg/mL, mental status changes, including decreased mental activity, severe confusion or lethargy, and coma are possible. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Drug-induced seizure activity has been observed at concentrations over 5060 μg/mL. ❖Because phenytoin follows nonlinear or saturable metabolism pharmacokinetics, it is possible to attain excessive drug concentrations much easier than for other compounds that follow linear pharmacokinetics. ❖Clinicians should understand that all patients with “toxic” phenytoin serum concentrations in the listed ranges will not exhibit signs or symptoms of phenytoin toxicity. Rather, phenytoin concentrations in the ranges given increase the likelihood that an adverse drug effect will occur. CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖Unbound phenytoin concentrations are an extremely useful monitoring tool when used correctly. ❖The relationship between total concentration (C), unbound or “free” concentration (Cf), and unbound or “free” fraction (fB) is: Cf = fB*C ❖ For routine therapeutic drug monitoring purposes, total phenytoin serum concentrations are still the mainstream way to gauge therapy with the anticonvulsant. ❖In most patients without known or identifiable plasma protein–binding abnormalities, the unbound fraction of phenytoin will be normal (~10%) and unbound drug concentration measurement is unnecessary. CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖At present, unbound drug concentrations are 50%-100% more expensive than total concentrations, take longer to conduct by the laboratory and have results returned to clinicians, and are not available at all laboratories. ❖Generally, unbound phenytoin serum concentration monitoring should be restricted to those patients with known reasons to have altered drug plasma protein binding. Exceptions to this approach are patients with an augmented or excessive pharmacologic response compared to their total phenytoin concentration. ❖For example, if a patient has a satisfactory anticonvulsant response to a low total phenytoin concentration, one possible reason would be abnormal plasma protein binding (20%) for some unidentified reason, so that even though the total concentration was low (5 mcg/mL), a therapeutic unbound concentration was present in the patient (Cf = fBC = 0.2 * 5 mcg/mL = 1 mcg/mL). CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖Conversely, if a patient has a possible phenytoin related adverse drug reaction and the total phenytoin concentration is within the therapeutic range, a possible reason could be abnormal protein binding (20%) for an unidentified reason, so that even though the total concentration appeared to be appropriate (15 mcg/mL), a toxic unbound concentration was present in the patient (Cf = fBC = 0.2 * 15 mcg/mL = 3 mcg/mL). ❖Unbound phenytoin serum concentrations should be measured in patients with factors known to alter phenytoin plasma protein binding. These factors fall into three broad categories: (1) lack of binding protein where there are insufficient plasma concentrations of albumin, (2) displacement of phenytoin from albumin binding sites by endogenous compounds, and (3) displacement of phenytoin from albumin binding sites by exogenous compounds. When multiple factors that decrease phenytoin plasma protein binding are present in a patient, the free fraction can be as high as 30%-40%. CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖Low albumin concentrations, known as hypoalbuminemia, can be found in patients with liver disease or the nephrotic syndrome, pregnant women, cystic fibrosis patients, burn patients, trauma patients, malnourished individuals, and the elderly. Albumin concentrations below 3 g/dL are associated with high phenytoin unbound fractions in the plasma. ❖Patients with albumin concentrations between 2.5 and 3 g/dL typically have phenytoin unbound fractions of 15%-20%, while patients with albumin concentrations between 2.0 and 2.5 g/dL often have unbound phenytoin fractions greater than 20%. ❖Albumin is manufactured by the liver so patients with hepatic disease may have difficulty synthesizing the protein. Patients with nephrotic syndrome waste albumin by eliminating it in the urine. Malnourished patients can be so nutritionally deprived that albumin production is impeded ❖Displacement of phenytoin from plasma protein–binding sites by endogenous substances can occur in patients with hepatic or renal dysfunction. CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖Once the free fraction (fB) has been determined for a patient with altered phenytoin plasma protein binding where C is the total concentration and Cf is the unbound concentration), it is often(fB = Cf/C, not necessary to obtain additional unbound drug concentrations. If the situations that caused altered plasma protein binding are stable (albumin or bilirubin concentration, hepatic or renal function, other drug doses, etc), total phenytoin concentrations can be converted to concurrent unbound values and used for therapeutic drug monitoring purposes. ❖For example, an endstage renal failure patient is receiving phenytoin therapy as well as valproic acid and warfarin. ❖The concurrently measured total and unbound phenytoin concentrations are 5 μg/mL and 1.5 μg/mL, respectively, yielding an unbound fraction of 30% (fB = Cf/C = 1.5 μg/mL/5 μg/mL = 0.30). CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖The next day, a total phenytoin concentration is measured and equals 6 μg/mL. The estimated unbound concentration using this information would be 1.8 μg/mL: Cf = fBC = 0.30 • 6 μg/mL = 1.8 μg/mL. ❖Of course, if the disease state status or drug therapy changes, a new unbound phenytoin fraction will be present and need to be remeasured using an unbound/total phenytoin concentration pair. ❖When unbound phenytoin concentrations are unavailable, several methods have been suggested to estimate the value or a surrogate measure of the value. CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖The most common surrogate is an estimation of the equivalent total phenytoin concentration that would provide the same unbound phenytoin concentration if the patient had a normal unbound fraction value of 10%. ❖These calculations “normalize” the total phenytoin concentration so that it can be compared to the usual phenytoin therapeutic range of 10-20 μg/mL and used for dosage adjustment purposes. ❖The equation for hypoalbuminemia is: CNormalBinding = C/(X • Alb + 0.1), ❖ where CNormalBinding is the normalized total phenytoin concentration in μg/mL, C is the actual measured phenytoin concentration in μg/mL, X is a constant equal to 0.2 if protein binding measurements were conducted at 37°C or 0.25 if conducted at 25°C, and Alb is the albumin concentration in g/dl CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖If the patient has end-stage renal disease (creatinine clearance <10-15 mL/min), the same equation is used with a different constant value ❖(X = 0.1) ➔ CNormalBinding = C/(0.1* Alb + 0.1), ❖Because these methods assume that the normal unbound fraction of phenytoin is 10%, the estimated unbound phenytoin concentration (CfEST) is computed using the following formula: ❖(CfEST) = 0.1*CNormalBinding CLINICAL USEFULNESS OF UNBOUND PHENYTOIN CONCENTRATIONS ❖A different approach is taken by the equations used for patients with concurrent valproic acid administration. In this case, the unbound phenytoin concentration (CfEST) is estimated using simultaneously measured total phenytoin (PHT in μg/mL) and valproic acid (VPA in μg/mL) concentrations: CfEST = (0.095 + 0.001*VPA)*PHT. ❖This value is compared to the usual therapeutic range for unbound phenytoin concentrations (1-2μg/mL) and used for dosage adjustment purposes. It should be noted that these equations only provide estimates of their respective concentrations, and actual unbound phenytoin concentrations should be measured whenever possible in patients with suspected abnormal phenytoin plasma protein binding. EXAMPLE 1 ❖JM is an epileptic patient being treated with phenytoin. Albumin = 2.2 g/dl and normal renal function. His total phenytoin concentration is 7.5 μg/mL. Assuming that any unbound concentrations performed by the clinical laboratory will be conducted at 25°C, compute an estimated normalized phenytoin concentration for this patient. ❖Answer: ❖CNormalBinding = C/(0.25 * Alb + 0.1)= 7.5/(0.25*2.2+0.1)=11.5 mg/L ❖CfEST = 0.1* CNormalBinding= 0.1*11.5 =1.2 mg/L ❖This patient’s estimated normalized total phenytoin concentration is expected to provide an unbound concentration equivalent to a total phenytoin concentration of 11.5 μg/mL for a patient with normal drug protein binding (CfEST = 1.2 μg/mL). Because the estimated total value is within the therapeutic range of 10-20 μg/mL, it is likely that the patient has an unbound phenytoin concentration within the therapeutic range. If possible, this should be confirmed by obtaining an actual, measured unbound phenytoin concentration. EXAMPLE 2 ❖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 concentration is 7.5 μg/mL. Compute an estimated normalized phenytoin concentration for this patient. ❖Answer: ❖CNormalBinding = C/(0.1 * Alb + 0.1)= 7.5/(0.1*2.2+.1)=23.4 mg/L ❖CfEST = 0.1* CNormalBinding=0.1*23.4 =2.3 mg/L ❖This patient’s estimated normalized total phenytoin concentration is expected to provide an unbound concentration equivalent to a total phenytoin concentration of 23.4 μg/mL for a patient with normal drug protein binding (CfEST = 2.3 μg/mL). Because the estimated total value is above the therapeutic range of 10-20 μg/mL, it is likely that the patient has an unbound phenytoin concentration above the therapeutic range. If possible, this should be confirmed by obtaining an actual, measured unbound phenytoin concentration. EXAMPLE 3 ❖PM is an epileptic patient being treated with phenytoin and valproic acid. He has a normal albumin concentration and normal renal function. His steady-state total phenytoin and valproic acid concentrations are 7.5 μg/mL and 100 μg/mL, respectively. Compute an estimated unbound phenytoin concentration for this patient. ❖Answer: ❖CfEST = (0.095 + 0.001*VPA)*PHT ➔ CfEST = (0.095 + 0.001*100)*7.5= 1.5 mg/L ❖This patient’s estimated unbound phenytoin concentration is expected to be within the therapeutic range for unbound concentrations. If possible, this should be confirmed by obtaining an actual, measured unbound phenytoin concentration. CLINICAL PHARMACOKINETIC PARAMETERS: BIOAVAILABILITY ❖Phenytoin is completely absorbed (F = 1.0) from most currently available products ❖In addition, there are different salt forms of phenytoin. 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. ❖The rate of phenytoin absorption following oral administration is slow because of the limited aqueous solubility of phenytoin. This is true regardless of whether the prompt or extended absorption oral products are used. Serum concentrations of phenytoin extended absorption products usually peak 3 to 12 hours after oral administration when given as the usual daily maintenance doses. CLINICAL PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION ❖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 + 1.33(TBW − IBW)], ❖This parameter is used to estimate the loading dose (LD in mg) for phenytoin, if one is indicated: LD = Css • V, where Css is the desired total phenytoin concentration in mg/L and V is volume of distribution in L. For example, the volume of distribution for a 70kg,nonobese patient would equal 49 L (V = 0.7 L/kg • 70 kg = 49 L). CLINICAL PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION ❖The loading dose to achieve a total phenytoin concentration of 15 μg/mL is 750 mg [LD = Css • V = 15 mg/L • 49 L = 735 mg, rounded to 750 mg. For an obese individual with a total body weight of 150 kg and an ideal body weight of 70 kg, the volume of distribution would equal 123 L: V = 0.7 L/kg [IBW + 1.33(TBW − IBW)] = 0.7 L/kg [70 kg + 1.33(150 kg − 70 kg)] =123 L. • Remember that maintenance doses should be based on ideal body weight, conventional daily doses with adjustments based upon therapeutic drug monitoring and clinical effectiveness. CLINICAL PHARMACOKINETIC PARAMETERS: CAPACITY LIMITED ELIMINATION ❖Phenytoin is primarily eliminated by hepatic metabolism (>95%). Hepatic metabolism is 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 pharmacokinetics. 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 concentrations 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 = (Vmax * C)/(Km + C), where Vmax is the maximum rate of metabolism in mg/d, C is the phenytoin concentration in mg/L or μg/mL, and Km is the substrate concentration in mg/L or μg/mL where the rate of metabolism = Vmax/2. CLINICAL PHARMACOKINETIC PARAMETERS: CAPACITY LIMITED ELIMINATION CLINICAL PHARMACOKINETIC PARAMETERS: CAPACITY LIMITED ELIMINATION ❖Phenytoin clearance can be computed as follows: Vmax Cl = K m + Ct ❖The clinical implication of Michaelis-Menten pharmacokinetics is that the clearance of phenytoin is not a constant as it is with linear pharmacokinetics, but is concentration or dose dependent. ❖As the dose or concentration of phenytoin increases, the clearance rate (Cl) decreases as the enzyme approaches saturable conditions as shown in the equation above. This is the reason concentrations increase disproportionately after a phenytoin dosage increase. CLINICAL PHARMACOKINETIC PARAMETERS: CAPACITY LIMITED ELIMINATION ❖For example, phenytoin follows saturable pharmacokinetics with average Michaelis-Menten constants of Vmax = 500 mg/d and Km = 4 mg/L. The therapeutic range of phenytoin is 10-20 mcg/mL. ❖ As the steady-state concentration of phenytoin increases from 10 mcg/mL to 20 mcg/mL, clearance decreases from 36 L/d to 21 L/d ➔ ❖Cl = Vmax/(Km + C); Cl = (500 mg/d)/(4 mg/L + 10 mg/L) = 36 L/d; ❖Cl = (500 mg/d)/(4 mg/L + 20 mg/L) = 21 L/d (Unfortunately, there is so much interpatient variability in Michaelis-Menten pharmacokinetic parameters for phenytoin (typically Vmax = 100-1000 mg/d and Km = 1-15 mcg/mL) that dosing the drug is extremely difficult. CLINICAL PHARMACOKINETIC PARAMETERS: CAPACITY LIMITED ELIMINATION ❖As doses or concentrations increase for a drug that follows Michaelis-Menten pharmacokinetics, clearance decreases and half-life becomes longer for the drug ❖Using the above example for clearance and the volume of distribution for a 70kg person (V = 0.7 L/kg • 70 kg ≈ 50 L), half-life changes from 1 day to 1.7 days as phenytoin serum concentrations increase from 10 μg/mL to 20 μg/mL. ❖The clinical implication of this finding is that the time to steady-state (3-5 t1/2) is longer as the dose or concentration is increased for phenytoin. ❖On average, the time to steady-state serum concentrations is approximately 5 days at a dosage rate of 300 mg/d and 15 days at a dosage rate of 400 mg/d. CLINICAL PHARMACOKINETIC PARAMETERS: HALF-LIFE ❖the half-life of phenytoin is calculated as follows ❖𝑡0.5 = 0.693∗𝑉 𝑉𝑚 𝐾𝑚 + 𝐶 ❖it can be predicted that the half-life of phenytoin will increase as the plasma concentration increases, an observation that has been confirmed. The value and applicability of this observation are very limited, however. ❖The clinical usefulness of the phenytoin half-life is limited because the time required to achieve steady state can be much longer than the usual three to four times the apparent half-life. CLINICAL PHARMACOKINETIC PARAMETERS: HALF-LIFE ❖Likewise, the time required for a plasma concentration to decay following discontinuation of the maintenance dose will be less than predicted by the apparent half-life. ❖The time required to achieve 90% of steady state can be calculated as follows: ❖The t90% is the time required for a patient to achieve 90% of the steady-state plasma concentration on a dosing regimen, given Km, V, and Vm. The units are mg/L for Km, L for V, and mg/day for Vm and dose. CLINICAL PHARMACOKINETIC PARAMETERS: HALF-LIFE ❖The decline of phenytoin concentration after discontinuation of therapy can be described by ❖where C1 is the initial plasma concentration, and C2 is the plasma concentration at the end of the time interval t. When both C1 and C2 are much greater than Km, the rate of metabolism will approach Vm; therefore, the time required to decline from C1 to C2 is primarily controlled by the maximum rate of metabolism (Vm) and the apparent volume of distribution (V). SUMMARY OF KEY PARAMETERS 0.7 SUMMARY OF KEY PARAMETERS ❖Adults with normal liver and renal function as well as normal plasma protein binding (~90%), have an average phenytoin Vmax of 7 mg/kg/d (range: 1.5-14 mg/kg/d) and Km of 4 μg/mL (range: 1-15 μg/mL). ❖The suggested initial dosage rate for extended phenytoin sodium capsules in an adult patient with normal liver and renal function is 4-6 mg/kg/d. ❖Michaelis-Menten parameters for younger children (6 months-6 years) are Vmax = 12 mg/kg/d and Km = 6 μg/mL while for older children (7-16years) Vmax = 9 mg/kg/d and Km = 6 μg/mL. ❖The suggested initial dosage rate for phenytoin suspension in an adolescent patient is 5-10 mg/kg/d. SUMMARY OF KEY PARAMETERS ❖The most difficult and frustrating aspect of phenytoin dosage determination is the 10-15 fold variation in Michaelis-Menten pharmacokinetic parameters which creates a huge amount of variability in dose requirements. ❖An individualized dosage regimen for each patient prescribed phenytoin must be determined to accomplish therapeutic goals. ❖Patients with liver cirrhosis or acute hepatitis have reduced phenytoin clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of CYP2C9 and CYP2C19 available to metabolize the drug and decreases Vmax. The volume of distribution is larger because of reduced plasma protein binding ❖However, the effects that liver disease have on phenytoin pharmacokinetics are highly variable and difficult to accurately predict. It is possible for a patient with liver disease to have relatively normal or grossly abnormal phenytoin clearance and volume of distribution. 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 phenytoin concentrations, it is usually wise to monitor phenytoin concentrations within 2 to 3 days of initiating therapy. This is to ensure that the patient’s metabolism is not remarkably different from that which would be predicted by average literature-derived pharmacokinetic parameters. ❖A second phenytoin concentration would normally be obtained in another 3 to 5 days; subsequent doses of phenytoin can then be adjusted. If the plasma phenytoin concentrations 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 concentrations are generally monitored at 3- to 12-month intervals. TIME TO SAMPLE ❖The time required to achieve steady state with phenytoin can be prolonged. Therefore, plasma levels of phenytoin should be monitored before steady state to avoid sustained periods of low or high phenytoin concentrations. Nevertheless, these early phenytoin concentrations must be used cautiously in the design of new dosing regimens. ❖In patients receiving oral phenytoin extended absorption dosage form, especially in divided daily doses, the time of sampling within the dosing interval is not critical because the slow absorption of phenytoin minimizes the fluctuations between peak and trough concentrations. Trough concentrations are generally recommended for routine monitoring. ❖Following IV administration, sampling within the first 1 to 2 hours after the end of the infusion should be avoided to ensure complete distribution SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS ❖When given by short-term intravenous infusion or orally, phenytoin follows a onecompartment pharmacokinetic model. ❖ When oral therapy is required, most clinicians utilize an extended phenytoin capsule dosage form that has good bioavailability (F = 1), supplies a continuous release of phenytoin into the gastrointestinal tract, and provides a smooth phenytoin serum concentration time curve that emulates an intravenous infusion after once or twice daily dosing. ❖Because of this, the Michaelis-Menten pharmacokinetic equation that computes the average phenytoin steady-state serum concentration (Css in μg/mL = mg/L) is widely used and allows maintenance dosage calculation. SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS This equation is invalid as a predictor of Css ave when (S)(F)(Dose/τ) is equal to or exceeds Vm. ❖where Vmax is the maximum rate of metabolism in mg/d, S is the fraction of the phenytoin salt form that is active phenytoin (0.92 for phenytoin sodium injection and capsules; 0.92 for fosphenytoin because doses are prescribed phenytoin sodium equivalent or PE, 1.0 for phenytoin acid suspensions and tablets), MD is the maintenance dose of the phenytoin salt contained in the dosage form in mg/d, Css is the phenytoin concentration in mg/L (which equals mcg/mL), and Km is the substrate concentration in mg/L (which equals mcg/mL) where the rate of metabolism = Vmax/2. SELECTION OF APPROPRIATE PHARMACOKINETIC MODEL AND EQUATIONS ❖The equation used to calculate loading doses (LD in mg) is based on a simple one-compartment model: LD = (Css·V)/S, where Css is the desired phenytoin steady-state concentration in μg/mL which is equivalent to μg/L, V is the phenytoin volume of distribution, and S is the fraction of the phenytoin salt form that is active (0.92 for phenytoin sodium injection and capsules; 0.92 for fosphenytoin because doses are prescribed as a phenytoin sodium equivalent or PE, 1.0 for phenytoin acid suspensions and tablets). ❖Intravenous phenytoin sodium doses should be short-term infusions given no greater than 50 mg/min, and intravenous fosphenytoin doses should be short-term infusions given no greater than 150 mg/min PE. EXAMPLE 4 ❖TD is a 50-year old, 75kg (height = 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 concentration equal to 12 μg/ml. The Vmax for a nonobese adult patient with normal liver and renal function is 7 mg/kg/d. Km = 4 mg/L. ❖ANSWER: ❖Vmax = 525 mg/d: Vmax = 7 mg/kg/d • 75 kg = 525 mg/d ❖ mg/day ➔ 525*12/(0.92*(4+12))= 428 mg/day rounded to 400 PSEUDOLINEAR PHARMACOKINETICS METHOD ❖A simple, easy way to approximate new total serum concentrations after a dosage adjustment with phenytoin is to temporarily assume linear pharmacokinetics, then add 15% - 33% for a dosage increase or subtract 15%-33% for a dosage decrease to account for Michaelis-Menten pharmacokinetics: ❖Cssnew = (Dnew/Dold)Cssold, where Cssnew is the expected steady-state concentration from the new phenytoin dose in μg/mL, Cssold is the measured steady-state concentration from the old phenytoin dose in μg/mL, Dnew is the new phenytoin dose to be prescribed in mg/d, and Dold is the currently prescribed phenytoin dose in mg/d ❖ Note: This method is only intended to provide a rough approximation of the resulting phenytoin steady-state concentration after an appropriate dosage adjustment. The Pseudolinear Pharmacokinetics method should never be used to compute a new dose based on measured and desired phenytoin concentrations. EXAMPLE 5 ❖TD is a 50yearold, 75kg (height = 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 concentration equals 6.2 μg/mL. His dosage is changed to 500 mg/day. Computed expected steady state concentration based on the new regimen EXAMPLE 5 ❖Using pseudolinear pharmacokinetics, the resulting total steady-state phenytoin serum concentration would be estimated as: ❖Cssnew = (Dnew/Dold)Cssold = (500 mg/d/400 mg/d)*6.2 μg/mL = 7.8 μg/mL. ❖Because of Michaelis-Menten pharmacokinetics, the serum concentration would be expected to increase 15%, or 1.15 times, to 33%, or 1.33 times, greater than that predicted by linear pharmacokinetics: ❖Css = 7.8 μg/mL * 1.15 = 9.0 μg/mL and Css = 7.8 μg/mL *1.33 = 10.4 μg/mL. Thus, a dosage increase of 100 mg/d would be expected to yield a total phenytoin steady-state serum concentration between 9 and 11 μg/mL. ❖A steady-state trough total phenytoin serum concentration should be measured after steadystate is attained in 7-14 days. Phenytoin serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenytoin toxicity. USE OF PHENYTOIN SERUM CONCENTRATIONS TO ALTER DOSES ❖Due to the large amount of pharmacokinetic variability among patients, it is likely that doses computed using patient population characteristics will not always produce phenytoin serum concentrations that are expected or desirable. ❖Because of pharmacokinetic variability, the Michaelis-Menten pharmacokinetics followed by the drug, the narrow therapeutic index of phenytoin, and the desire to avoid adverse side effects of phenytoin, measurement of phenytoin serum concentrations is conducted for almost all patients to insure that therapeutic, nontoxic levels are present. ❖ In addition to phenytoin serum concentrations, important patient parameters (seizure frequency, potential phenytoin side effects, etc) should be followed to confirm that the patient is responding to treatment and not developing adverse drug reactions. USE OF PHENYTOIN SERUM CONCENTRATIONS TO ALTER DOSES ❖A variety of methods are used to estimate new maintenance doses or Michaelis-Menten parameters when one steady-state phenytoin serum concentration is available, such methods include the Vozeh-Sheiner method. ❖If two or more steady-state phenytoin serum concentrations are available from two or more daily dosage rates, it may be possible to calculate and use pharmacokinetic parameters to alter the phenytoin dose (see next slides). ❖Finally, computerized methods that incorporate expected population pharmacokinetic characteristics (Bayesian pharmacokinetic computer programs) can be used in difficult cases where serum concentrations are obtained at suboptimal times or the patient was not at steady-state when serum concentrations were measured. An additional benefit of this method is that a complete pharmacokinetic workup (Vmax, Km, V) can be done with one or more measured concentrations. VOZEH-SHEINER OR ORBIT GRAPH ❖A graphical method that employs population Michaelis-Menten information using Bayes theorem can also be used to adjust phenytoin doses using a single steady-state total concentration. ❖This method employs a series of orbs encompassing 50%, 75%, 85%, etc of the population parameter combinations for Vmax and Km on the plot suggested by Mullen for use with multiple steady-state/ dosage pairs ❖The use of the population’s parameter orbs allows the plot to be used with one phenytoin steady-state concentration/dose pair USING THE ORBIT GRAPH (1)Plot the rate of administration ➔ the daily dose of acid phenytoin (mg/kg/day) on the vertical axis (2)Plot the steady state concentration (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. 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. B A EXAMPLE 6 ❖TD is a 50-yearold, 75kg (height = 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 concentration equals 6.2 μg/mL. The patient is assessed to be compliant with his dosage regimen. Suggest an initial phenytoin dosage regimen designed to achieve a steady-state phenytoin concentration equal to 10 μg/mL. EXAMPLE 6 ❖Using the orbit graph, the serum concentration/dose information is plotted (note: phenytoin dose = 0.92 * phenytoin sodium dose = 0.92 * 400 mg/d = 368 mg/d; 368 mg/d/75 kg = 4.9 mg/kg/d). ❖According to the graph, a dose of 5.5 mg/kg/d of phenytoin is required to achieve a steady-state concentration equal to 10 μg/mL. This equals an extended phenytoin sodium capsule dose of 450 mg/d, administered by alternating 400 mg/d on even days and 500 mg/d on odd days: (5.5 mg/kg/d * 75 kg)/0.92 = 448 mg/d, rounded to 450 mg/d. ❖A steady-state trough total phenytoin serum concentration should be measured after steady-state is attained in 7-14 days. Phenytoin serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenytoin toxicity EXAMPLE 7 ❖GF is a 35-year-old, 55kg 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 concentration equals 10.7 μg/mL. The patient is assessed to be compliant with her dosage regimen. Suggest an initial phenytoin dosage regimen designed to achieve a steady-state phenytoin concentration of 18 μg/mL EXAMPLE 7 ❖Using the orbit graph, the serum concentration/dose information is plotted (note: phenytoin dose = 0.92 • phenytoin sodium dose = 0.92 * 300 mg/d = 276 mg/d; 276 mg/d/55 kg = 5.0 mg/kg/d). ❖According to the graph, a dose of 5.7 mg/kg/d of phenytoin is required to achieve a steady-state concentration equal to 18 μg/mL. This equals an extended phenytoin sodium capsule dose of 350 mg/d, administered by alternating 300 mg/d on even days and 400 mg/d on odd days: (5.7 mg/kg/d * 55 kg)/0.92 = 341 mg/d, rounded to 350 mg/d. ❖A steady-state trough total phenytoin serum concentration should be measured after steady-state is attained in 7-14 days. Phenytoin serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of phenytoin toxicity. DOSAGE ADJUSTMENT WITH TWO OR MORE CSS OBSERVATIONS (MULLEN METHOD) ❖This method assists in determination of dosage adjustments when two or more Css values at different doses are available. ❖This dosage approach uses the same dose/concentration plot as that described for the Vozeh-Sheiner or Orbit Graph method, but the population orbs denoting the Bayesian distribution of Vmax and Km parameters are omitted ❖The estimate of Vmax and km is not based on the probability contours but on the intersection points of the lines for each Css dose pair DOSAGE ADJUSTMENT WITH TWO OR MORE CSS OBSERVATIONS (MULLEN METHOD) ❖As before, the graph is divided into two sectors. On the left side of the x-axis, a steadystate total phenytoin concentration is plotted. On the yaxis, the phenytoin dosage rate (in mg/kg/d of phenytoin; S = 0.92 for phenytoin sodium and fosphenytoin PE dosage forms) is plotted. ❖ A straight line is drawn between these two points and extended into the right sector. This process is repeated for all steadystate dose/concentrations pairs that are available. ❖The intersection of these lines in the right sector provides the Michaelis-Menten constant values for the patient. If a line parallel to the y-axis is drawn down to the x-axis from the intersection point, Km (in mcg/mL) is obtained. DOSAGE ADJUSTMENT WITH TWO OR MORE CSS OBSERVATIONS (MULLEN METHOD) ❖Similarly, if a line parallel to the x-axis is drawn to the left to the y-axis from the intersection point, an estimate of Vmax (in mg/kg/d) is obtained. To compute the new phenytoin dose, the intersection point and the desired steady-state phenytoin total concentration (on the left portion of the x-axis) are connected by a straight line. ❖The intersection of this line with the y-axis is the new phenytoin dose required to achieve the new phenytoin concentration. If needed, the phenytoin dose is converted to phenytoin sodium or fosphenytoin amounts. DOSAGE ADJUSTMENT WITH 2 OR MORE CSS OBSERVATIONS EXAMPLE 8 ❖TD is a 50–year old, 75kg (height = 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 steadystate phenytoin total concentration equals 6.2 μg/mL. The dosage was increased to 500 mg/d of extended phenytoin sodium capsules for another month, the steady state phenytoin total concentration equals 22.0 μg/mL, 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 steadystate phenytoin concentration within the therapeutic range. EXAMPLE 8 ❖Using the graph, the serum concentration/dose information is plotted (note: phenytoin dose = 0.92 * phenytoin sodium dose = 0.92 * 400 mg/d = 368 mg/d, ➔ 368 mg/d/75 kg = 4.9 mg/kg/d ❖phenytoin dose = 0.92 * phenytoin sodium dose = 0.92 * 500 mg/d = 460 mg/d, ➔460 mg/d/75 kg = 6.1 mg/kg/d. ❖According to the graph, a dose of 5.5 mg/kg/d of phenytoin is required to achieve a steadystate concentration equal to 11.5 μg/mL. ❖This equals an extended phenytoin sodium capsule dose of 450 mg/d, administered by alternating 400 mg/d on even days and 500 mg/d on odd days: (5.5 mg/kg/d*75 kg)/0.92 = 448 mg/d, rounded to 450 mg/d. Vmax = 6.8 mg/kg/d and Km = 2.2 μg/mL for this patient EXAMPLE 8 ESTIMATION OF MICHAELIS–MENTEN PARAMETERS AT STEADY STATE Phenytoin ❖At steady state input =output ESTIMATION OF MICHAELIS–MENTEN PARAMETERS FROM TWO STEADY-STATE DRUG CONCENTRATIONS IN PATIENTS ❖The rate of drug metabolism will vary depending on the concentration of drug Cp as well as on the metabolic rate constants KM and Vmax of the drug in each individual. ❖To determine KM and Vmax, two different dose regimens are given at different times, until steady state is reached. The steady-state drug concentrations are then measured by assay. At steady state, the rate of drug metabolism is assumed to be the same as the rate of drug input, thus equation 1 can be written as shown below. ❖Note: steady state will not be reached if the drug input rate, is greater than the Vmax; instead, drug accumulation will continue to occur without reaching a steady-state plateau Dosing rate(amount per unit of time) = VmC SS Km + C SS ESTIMATION OF MICHAELIS–MENTEN PARAMETERS FROM TWO STEADY-STATE DRUG CONCENTRATIONS IN PATIENTS ❖Two dosing rates resulted in the following steady state conc: Dosing rate Css R1(F*S*Ra1) Css1 R2(F*S*Ra2) Css2 ❖Estimate Vmax and Km ESTIMATION OF MICHAELIS–MENTEN PARAMETERS FROM TWO STEADY-STATE DRUG CONCENTRATIONS IN PATIENTS Vmax Css1 R1 =  Vmax Css1 = R1  K m + R1  Css1 K m + Css1 Vmax Css2 R2 =  Vmax Css2 = R2  K m + R2  Css2 K m + Css2 Two equations with two unknowns ESTIMATION OF MICHAELIS–MENTEN PARAMETERS FROM TWO STEADY-STATE DRUG CONCENTRATIONS IN PATIENTS ❖Solving the previous equations yields ❖Km = (R2-R1)/[(R1/C1)-(R2/C2)] ❖Vm can be then can be easily calculated by substitution the value of Km, R1, C1 in the previous equation EXAMPLE 9 ❖GF is a 35-year-old, 55-kg female with tonic-clonic seizures who requires therapy with phenytoin. She has normal liver and renal function. The patient was prescribed 300 mg/d of phenytoin sodium capsules for 1 month, and the steady-state phenytoin total concentration equals 10.7 μg/mL. 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 concentration was 15.8 μg/mL. The patient is assessed to be compliant with her dosage regimen. Suggest a new sodium phenytoin dosage regimen designed to achieve a steady-state phenytoin concentration of 20 μg/mL (assume F=1, S=0.92) EXAMPLE 9 R1* Km + R1* CSS (1) = Vm * CSS (1) R1 = 300 mg / day, C SS (1) = 10.7 mg / L R 2 * Km + R 2 * CSS (2) = Vm * CSS (2) R 2 = 350 mg / day, C SS (2) =15.8 mg / L 300 * 0.92 * Km + 300 * 0.92 *10.7 = Vm *10.7  25.8 * Km + 276 = Vm (1)    350 * 0.92 * Km + 350 * 0.92 *15.8 = Vm *15.8  20.4 * Km + 322 = Vm (2) Eqn (1)- Eqn(2): 5.5 * Km − 46 = 0 50 Km = = 8.5 mg / L 5.4 Eqn (1): Vm = 20.4 * Km + 322 = 495 mg / day EXAMPLE 9 ❖Calculate RM’s a new daily dose of sodium phenytoin that will result in a steady state level of about 20 mg/L VmCSS 495 * 20 Dosing rate = = = 347.4 mg / day Km + C SS 8.5 + 20 Dosing rate=S*F*R=347.4 mg /day The dose of sodium phenytoin is 347.4/0.92=378 mg of sodium phenytoin.