Adjusting phenytoin dosage in complex patients: how to win friends and influence patient outcomes

Adjusting phenytoin dosage in complex patients: how to win friends and influence patient outcomes Brian Hardy, PharmD, FCSHP, FCCP Coordinator Education and Clinical Programs Department of Pharmacy Sunnybrook Health Sciences Centre November 18 th, 2017 1

Presenter Disclosure : Brian Hardy I have no current relationships with commercial entities I have received no speaker s fee for this learning activity 2

Commercial Support Disclosure This learning activity has received no financial or in-kind support from any commercial or other organization 3

Learning Objectives On completion of the workshop participants should be able to: Understand the pharmacokinetic characteristics of phenytoin, and why we monitor serum phenytoin concentrations. Adjust the observed total serum phenytoin concentration in complex patients with low albumin and/or renal dysfunction Design a dosing schedule for a patient receiving phenytoin based on one steady-state serum level using a population-based estimation technique (i.e. Bayesian nomogram). Demonstrate the ability to individualize phenytoin dosage for a specific patient based on two steady-state serum concentrations. 4

Why Monitor Serum Phenytoin Concentrations? Good correlation between the degree of seizure control and serum drug levels Relationship between the type & severity of phenytoin CNS toxicity and serum drug levels Poor correlation between daily dose and achievable steady-state serum drug concentrations Narrow therapeutic index Nonlinear (dose-dependent) kinetics Large inter-subject variability in metabolism Numerous drug-drug interactions 5

Relationship between seizure control and phenytoin serum concentrations Eur Neurol 1979,18:111-115 Therapeutic Range: 10 20 mg/l 6

Why Monitor Serum Phenytoin Concentrations? Good correlation between the degree of seizure control and serum drug levels Strong relationship between the type & severity of phenytoin CNS toxicity and serum drug levels Poor correlation between daily dose and achievable steady-state serum drug concentrations Narrow therapeutic index Nonlinear (dose-dependent) kinetics Large inter-subject variability in metabolism Numerous drug-drug interactions 7

What is the Clinical Presentation of Phenytoin Toxicity? 1. Mild Toxicity (80-120 µmol/l) Far lateral nystagmus 2. Moderate Toxicity (120-160 µmol/l) Ataxia Nystagmus at a 45-degree lateral gaze 3. Severe Toxicity (> 160 µmol/l) Diminished mental capacity Nystagmus, ataxia, involuntary muscular movements, seizures 8

Why Monitor Serum Phenytoin Concentrations? Good correlation between the degree of seizure control and serum drug levels Relationship between the type & severity of phenytoin CNS toxicity and serum drug levels Poor correlation between daily dose and achievable steady-state serum drug concentrations Narrow therapeutic index Nonlinear (dose-dependent) kinetics Large inter-subject variability in metabolism Numerous drug-drug interactions 9

Variation in the percent of patients achieving therapeutic phenytoin concentrations with increasing weight-adjusted dose Baltimore University Park Press: 1972; 227-239 10

Why Monitor Serum Phenytoin Concentrations? Good correlation between the degree of seizure control and serum drug levels Relationship between the type & severity of phenytoin CNS toxicity and serum drug levels Poor correlation between daily dose and achievable steady-state serum drug concentrations Narrow therapeutic index (40 80 µmol/l) Nonlinear (dose-dependent) kinetics Large inter-subject variability in metabolism Numerous drug-drug interactions 11

Pharmacokinetic Drug Interactions: Drug Effects on Phenytoin Decreased Phenytoin Absorption Increased Phenytoin Metabolism Decreased Phenytoin Metabolism Enteral Feeds Charcoal Antacids Folic Acid Alcohol Dexamethasone Low Dose Phenobarbital Topiramate Azoles Oxcarbazepine Chloramphenicol Disulfiram Isoniazid Sucralfate Theophylline Antineoplastics Diazepam Rifampin Nitrofurantoin Carbamazepine Cimetidine Amiodarone Allopurinol Omeprazole Sulfonamides High dose Barbiturates (Clin Pharmacokinet 1990;18:37-60) 12

Pharmacokinetic Drug Interactions: Effects of Phenytoin on Other Drugs Phenytoin is an enzyme inducer and decreases the serum concentrations of: Rivaroxaban Apixaban Ticagrelor Many HIV anti-retroviral drug Oral contraceptives Vitamin D 13

Pharmacokinetic Characteristics of Phenytoin (ADME) 14

Absorption Oral Absorption Bioavailability (85-95%) Parenteral Absorption Intravenous route (40% propylene glycol and 10% alcohol diluent adjusted to a ph of 12 with NaOH, maximum infusion rate of 50 mg/min; not greater than 25 mg/min in the elderly or patients with CVD, limited by compatible iv solutions, use an inline filter) Intramuscular route (erratic absorption) 15

Distribution and Protein Binding Apparent volume of distribution (0.6-1.2 L/kg) (we will use 1.0) Plasma protein binding (88-92%) (we will use 90%) Factors altering protein binding Decreased serum albumin concentration Burns Cirrhosis Nephrotic syndrome Pregnancy Cystic fibrosis Apparent decrease in affinity for serum albumin Renal failure Jaundice (severe) Other highly protein-bound drugs (displacers) 16

Metabolism Biotransformation to inactive metabolites by CYP2C9 and CYP2C19 Saturable hepatic enzymes within the therapeutic range (capacity-limited metabolism) Non-linear pharmacokinetics (Michaelis-Menten kinetics) Less than 5% is excreted unchanged renally Large intra-subject variability in metabolism 17

Phenytoin Non-Linear Kinetics Brian: Insert Diagram here 18

Michaelis-Menten Kinetics R = Vmax x Css Km + Css R = Vmax Km x (R/Css) Where: R (mg/day), Vmax (mg/day), Km (mg/l), Css (mg/l) 19

Concepts of Clearance and Half-Life CL = Vmax / (Km + C(t)) = R / Css T ½ = 0.693 x (Vd/CL) = 0.693 x Vd (Km + C (t)) Vmax 20

Brian: Insert Diagram here 21

Select Conditions Affecting the Metabolism of Phenytoin Condition or Disease Example Vmax increased Enzyme induction Concurrent administration of phenobarbital or carbamazepine Vmax decreased Hepatic cirrhosis Decreased enzyme activity is assumed to be the major effect Km increased Km decreased Competitive inhibition Decreased plasma protein binding Concurrent administration of cimetidine or chloramphenicol Decreased serum albumin or presence of displacers such as valproic acid or salicylate 22

Time to a Steady-State Plateau t 90% = Km x Vd ((2.303 x Vmax) (0.9 x R)) (Vmax R) 2 Where: R (mg/day), Vmax (mg/day), Km (mg/l), Vd (L), t 90% (days) 23

Time to Plateau Brian: Insert Diagram here 24

Adjustment of a Observed Total Phenytoin Concentration for Decreased Albumin and/or Renal Function Hypoalbuminemia: Cadjusted = Cobserved (What is Cadjusted?) 0.9 * (albumin/4.4) + 0.1 Severe Renal Disease: Reduce target concentration by one-half See equivalent target concentration ranges - Figure (next slide) Renal Disease and Hypoalbuminemia: Cadjusted = Cobserved 0.1 * (albumin) + 0.1 (or Liponi Method) Where albumin is in g/dls; g/l (SI Units) / 10 = g/dl 25

Phenytoin Concentrations that are Equivalent to 10-20 µg/ml for Patients with Diminished Renal Function The values reflect average binding data: No correction is made for serum albumin. Brian: Insert Diagram here Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 1984; 34:395-397 26

Estimation of free fraction (f) in Patients with Combined Renal Dysfunction and/or Low Albumin f = 1 1 + nka (P) Cadjusted = Cobserved x (f / 0.1) Where f = free fraction P = Protein = albumin (g/dl); g/l (SI units)/10 = g/dl n = # of binding sites and Ka = the binding affinity constant nka = product of the binding parameters (dl/g) 27

Estimation of free fraction (f) in Patients with Combined Renal Dysfunction and/or Low Albumin Brian: Insert Diagram here 28

Exercise #1 Adjustment of the observed total serum phenytoin concentration based on decreased albumin levels and/or renal dysfunction A 66 year old male (weight 76 kg) with an observed total serum phenytoin level of 80 µmol/l, albumin of 36 mg/l and serum creatinine of 120 µmol/l is exhibiting signs of CNS toxicity. 1. Estimate the free fraction (f) of phenytoin in this patient. 2. What is the adjusted total serum phenytoin concentration (Cadjusted) in this patient? 29

Exercise #1 Adjustment of the observed total serum phenytoin concentration based on decreased albumin levels and/or renal dysfunction Estimate the free fraction (f) of phenytoin in this patient 1. Creatinine Clearance (CrCL) estimate: CrCl (ml/min)(male) = (140-age) (TBW (kg) x 60) 50 x SCr (µmol/l) = (140 66) (76 x 60) 50 x 120 = 56 ml/min 2. Estimate the nka (binding affinity) parameter (see Table) 30

Exercise #1 Adjustment of the observed total serum phenytoin concentration based on decreased albumin levels and/or renal dysfunction 31

Exercise #1 Adjustment of the observed total serum phenytoin concentration based on decreased albumin levels and/or renal dysfunction 2. Estimate the nka (binding affinity) parameter: For Group II (CrCl 50 79 ml/min) the nka estimate = 1.6 dl/g 3. Conversion of Albumin concentration: Protein = Albumin = 36mg/L (SI units) = 3.6 mg/dl = P 4. Free fraction estimation: f = 1 = 1 = 0.148 1 + nka (P) 1 + (1.6 x 3.6) 5. Cadjusted = Cobserved x (f / 0.1) = 80 µmol/l x (0.148/0.1) = 118 µmol/l 32

Methods of Dosage Adjustment Based on Css Levels 1. Adjustment based on a population estimate of Km and one Css level (equation) 2. Adjustment based on probable values of Vmax and Km and one Css level (Bayesian prediction) 3. Adjustment based on two Css levels at different daily doses (equation) 33

Adjustment based on a population estimate of Km and one Css phenytoin level Equation: Vmax = R + Km x (R/Css) Given: Km = 4 mg/l R = 300 mg/day Css = 8 mg/l (32 µmol/l) Solve for Vmax = R + Km x (R/Css) = 300 + 4 x (300/8) = 450 mg/day Then: R = Vmax x Css = 450 x 15 = 355 mg/day Km + Css 4 + 15 Where: Css (desired) = 15 mg/l (60 µmol/l) Dose rounded to 360 mg (3 x 100mg & 2 x 30 mg) 34

Adjustment based on probable values of Vm and Km and one Css level - Bayesian Nomogram Brian: Insert Diagram here Observed total phenytoin steady-state level on 300mg/day (300mg/70kg = 4.29 mg/kg/day) was 8 mg/l Estimated dose required for target level of 15mg/L is 5.2 mg/kg/day (~ 360 mg/day) 35

Adjustment based on two Css levels at different doses Equation: R = Vmax - Km * (R/Css) Given: R (mg/day) Css (mg/l) R/Css (L) 300 8 37.5 500 25 20 Find: R (mg/day) producing a desired Css = 15 mg/l (60 µmol/l) 36

Adjustment based on two Css levels at different doses Solution: Km = -slope = - Y2 Y1 = - 500-300 = 11.4 mg/l X2 X1 20-37.5 Vmax = R + Km (R/Css) = 300 + 11.4 (300/8) = 727.5 mg/day For Css (desired) = 15 mg/l (60 µmol/l) R = Vmax x Css = 727.5 x 15 = 413.4 mg Km + Css 11.4 + 15 Round dose to commercially available dosage: 400mg (4 x 100 mg) 37

Exercise #2 Adjustment based on probable values of Vmax and Km and one Css level - Bayesian Nomogram A 23 year old man (75 kg) presented to the ER on 17-10-08 @ 0600h with severe head trauma following a MVA. The patient has no significant past medical history, serum creatinine 85 µmol/l, albumin 35 g/l, normal LFTs. An oral maintenance dose of 300 mg phenytoin sodium was started 11 weeks ago and a steady-state serum phenytoin trough level (@ 0800h on 17-10-09) was 22 µmol/l (therapeutic range 40-80 µmol/l). 1. Estimate the Vmax and Km for this patient from the Bayesian nomogram. 2. Estimate the daily dosage of phenytoin required to achieve a target phenytoin serum concentration at steady-state of 60 µmol/l. 3. Estimate the time to 90% of steady-state following initiating the suggested new daily dose. 4. Write a TDM consult note for this patient. 38

Exercise #2 Adjustment based on probable values of Vmax and Km and one Css level - Bayesian Nomogram 1. Estimate the Vmax and Km for this patient from the Bayesian nomogram Given: phenytoin sodium dosage = 300 mg/75 kg/day = 4 mg/kg/day observed serum level = 22 µmol/l X 0.25 mg/l = 5.5 mg/l 39

Exercise #2 Adjustment based on probable values of Vmax and Km and one Css level - Bayesian Nomogram 1. Estimated Km = 5 mg/l and Estimated Vmax = 7.25 mg/kg/day = 544 mg/day 2. Recommended dose (R) to achieve 15 mg/l (60 µmol/l) R = 5.6 mg/kg/day = 420 mg/day ~ 400 mg/day 3. Time to steady-state on the new daily dose: Time (90%) = Km x Vd (2.3 Vmax 0.9 R), where Vd = 1.0 L/kg (75 L) (Vmax R) 2 Time (90%) = (5 x 75)(2.3 x 544 0.9 x 400) = 16.1 days ~ 16 days (544-400) 2 40

Exercise #2 Adjustment based on probable values of Vmax and Km and one Css level - Bayesian Nomogram 4. THERAPEUTIC DRUG MONITORING (PHENYTOIN) CONSULT This 23 year old man (75 kg) presented to the ER on 17-10-08 @ 0600h with severe head trauma following a MVA. The patient has no significant past medical history, serum creatinine 85 µmol/l, albumin 35 g/l, normal LFTs. An oral maintenance dose of 300 mg phenytoin sodium was started 11 weeks ago and a steady-state serum phenytoin trough level (@ 0800h on 17-10-09) was 22 µmol/l (therapeutic range 40-80 µmol/l). Based on the above serum level and Bayesian estimates, this patient has phenytoin pharmacokinetics characterized by a Vmax and Km of 544 mg/day and 4.5 mg/l, respectively. These calculated estimates are similar to those expected for young adults. Based on these pharmacokinetic parameters, we suggest an oral phenytoin sodium capsule dosage of 400 mg/day to achieve anticipated steady-state phenytoin trough serum levels of ~ 60 µmol/l. Repeat steady-state levels could be obtained after 16 days on the recommended dosage just prior to the morning dose. We will continue to follow this patient with you. Thank you for this consult. Jane Smith, BScPhm Pharmacy Ext. 4500 41

Exercise #3 Adjustment of phenytoin based on two Css levels at different daily doses (equations) A 65 year old woman (52 kg) with a 25 year history of epilepsy is presently on the following anticonvulsants: phenytoin acid 500 mg daily and carbamazepine 400 mg bid. At an outpatient visit on 17-08-25, a routine serum phenytoin trough level of 18 µmol/l was measured. At that time the patient was receiving phenytoin 300 mg daily and reaffirmed that she was being compliant. The daily dosage was increased on 17-08-28 to 500 mg. A repeat steady-state serum phenytoin level of 86 µmol/l was measured on 17-10 -17 when the patient complained of dizziness. 1. Estimate this patients Vmax and Km values using the 2 sets of levels. 2. Calculate the daily dosage of phenytoin to achieve a level of 60 µmol/l. 3. Estimate the time to 90% of steady-state on the recommended dosage. 4. Write a TDM consult for this patient. 42

Exercise #3 Adjustment of phenytoin based on two Css levels at different daily doses (equations) Given: R (mg/day) Css (µmol/l) Css (mg/l) R/Css (L) 300 18 4.5 66.67 500 86 21.5 23.26 R = Vmax Km (R/Css) 1. Estimate this patients Km and Vmax values using the 2 sets of levels Km = -slope = - Y2 Y1 = - (500-300) = 4.61 mg/l X2 X1 (23.26-66.67) Vmax = R + (Km x (R /Css)) = 300 + (4.61 x 66.67) = 607 mg/day 43

Exercise #3 Adjustment of phenytoin based on two Css levels at different daily doses (equations) 2. Calculate the daily dosage of phenytoin to achieve a level of 60 µmol/l. For a desired Css = 15 mg/l R = Vmax x Css = (607)(15) Km + Css (4.61 + 15) = 464 mg ~ 460 mg R = Sodium phenytoin capsules (4 x 100 mg + 2 x 30 mg) 44

Exercise #3 Adjustment of phenytoin based on two Css levels at different daily doses (equations) 3. Estimate the time to 90% of steady-state on the recommended dosage. Time to 90% steady-state: T 90% = Km x Vd (2.3 Vmax 0.9 R) (Vmax R) 2 Where Vd = volume of distribution = 1.0 L/kg = 52 kg R = 460 mg/day T 90% = (4.61)(52)(2.3 x 607 0.9 x 460) = 10.9 days (~11 days) (607 460) 2 45

Exercise #3 Adjustment of phenytoin based on two Css levels at different daily doses (equations) 4. THERAPEUTIC DRUG MONITORING (PHENYTOIN) CONSULT This 65 year old woman (52 kg) with a 25 year history of epilepsy is presently on the following anticonvulsants: phenytoin acid 500 mg daily and carbamazepine 400 mg bid. At an outpatient visit on 17-08-25, a routine serum phenytoin trough level of 18 µmol/l was measured. At that time the patient was receiving phenytoin 300 mg daily and reaffirmed that she was being compliant. The daily dosage was increased on 17-08-28 to 500 mg. A repeat steady-state serum phenytoin level of 86 µmol/l was measured on 17-10-17 when the patient complained of dizziness. Based on the two sets of levels, this patient has calculated phenytoin disposition constants Km and Vmax of 4.6 mg/l and 607 mg/day, respectively. We recommend a daily phenytoin sodium dosage of 460 mg (4 x 100 mg + 2 x 30 mg) to achieve steady-state phenytoin levels of 60 µmol/l (therapeutic range 40-80 µmol/l). A repeat serum phenytoin trough level should be obtained after 11 days when the new steadystate is achieved. Thank you for this consult. Jane Smith, BScPhm Pharmacy Ext. 4500 46