Clinical Pharmacokinetics BPharm
Phenytoin
Ahmad Kamal Ariffin bin Abdul Jamil
BSc BPharm(USM) MPharm Clinical Pharmacy (USM)
Clinical Pharmacy Lecturer
Aimst University
Learning outcomes :
At the end of the lecture, students should be able to:
1.Understand the pharmacokinetic profile of phenytoin.
2.Understand the pharmacokinetic monitoring aspects of phenytoin.
3.Interprete the TDM results and make appropriate recommendation to
doctors & other healthcare professionals.
4.Integrate the above aspects to solve real cases…
Phenytoin is primarily used as anticonvulsant and is occasionally used
in the treatment of certain types of cardiac arrhythmias.Phenytoin
(PHT) is a hydantoin-derivative anticonvulsant
Indicated for :
Treatment of tonic-clonic & complex partial seizure
Seizure prophylaxis following neurosurgery
Usual dose: 200 to 400 mg/day
If rapid therapeutic effect is required: LD 15mg/kg PO or IV
Individualizing the dose of phenytoin is beset by 2 major problems
Metabolic capacity
Binding of phenytoin for
to plasma proteins is phenytoin is limited:
decreased in patients Modest change in
with renal failure or dose
hypoalbuminemia
Disproportionate
changes in CPss
Bioavailability & salt factor
PHT
Vd
PHT is a relatively lipid-soluble drug
Obese patients have a larger Vd
V obese(L) = 0.65L/kg x [(IBW) + 1.33(ABW – IBW)]
Clearance ( Cl )
5 to 10 mg/L can be therapeutic for some patients
< 5 mg/L are not likely to be effective
Sampling Time
Loading dose
12 - 24 hours after administration
Maintenance dose
IV/Oral : Just before next dose
Time to monitor serum
concentration
(at steady state)
After LD
12 hours after completion of IV LD
24 hours after administration of an oral loading dose
Without LD : 8 – 10 days (after the initiation or a change in the
regimen)
Time to steady state
• No Loading Dose : 7 - 14 days
• With Loading Dose (oral ): 24 hours
Blood sampling time
• Maintenance dose: to confirm therapeutic response
• Steady state level: ≥ 5 days after initiate or change
dose
• Pre-level: ½ hr before next dose
• Every 7 to 14 days in acute care setting
• Stable patient: every 3 to 6 months
PHT administration
How to administer the LD?
Phenytoin Na injection contains propylene glycol, a cardiac depressant
Infuse too fast
Bradycardia & hypotension
Infusion rate: ≤ 50 mg/min for adult
1-3 mg/kg/min for neonates and pediatrics
Dilution
Adding phenytoin to dextrose or dextrose-containing IV infusions is
NOT RECOMMENDED due to a lack of solubility and the chance of
precipitation.
Phenytoin sodium should be diluted in normal saline(NS 0.9%), to a
final concentration no less than 5mg/ml.
Do NOT refrigerate phenytoin sodium once diluted.
Non-linear PK
Elimination
PHT is cleared primarily (>95%) by hepatic metabolism
However, the clearance is capacity limited (concentration-dependent
clearance)
As the concentration ↑ , the Cl will ↓
Therefore, PHT demonstrates a non-linear pharmacokinetic (Michaelis-
Menten) profile
Pharmacodynamic Monitoring
Efficacy – Objective & subjective
Toxicity
Drug interactions
ADRs
Drug Interactions
Formulae
LD formula * ( same )
Incremental loading dose * ( same )
R = maintenance dose (in mg/d)
Css = Desired concentration at steady state (in mg/L)
Vm = Maximum rate (or velocity) of metabolism (in mg/d)
Km = Plasma concentration at which metabolism is occurring at
half the maximum rate (in mg/L)
PHT level in low albumin level but
normal renal function
PHT level in low albumin level
&reduced renal function ( Cr Cl <
10ml/min )
Cases
#1
• Mr JHS, a 45-year-old, 75 kg, 5 feet 4 inch male, has
history of epilepsy. He was on phenytoin capsule 100
mg tds since 3 months ago.
• Last night, Mr JHS has an episode of tonic-clonic
seizure & was admitted to the hospital.
• A TDM was done & the phenytoin level was 3.08
mg/L. Kindly interpret the result.
Pt obese ??
BMI = ____kg/m2 ABW/IBW x 100 = 75/59.2 x 100 = 127% (>20% )
IBW = 50 + 2.3 (inch > 5 feet)
= 50 + 2.3 (4) = 59.2kg
Vm = (8.45mg/kg/d)(59.2kg)
= 500.24 mg/d
R = 300 mg/d (100 mg tds)
Phenytoin Na capsule (S = 0.92)
Therefore, R = (300 mg/d)(0.92) = 276 mg/d of phenytoin
Css = (276 mg/d)(6.72 mg/L) / (500.24 – 276) mg/d
= 8.72 mg/L
***
Non-compliance (level = 3.08 mg/L)
Maintenance dose was sub-therapeutic (expected level = 8.72 mg/L)
The physician planned to give a IV loading dose to control Mr JHS’s
seizure.
Calculate an appropriate incremental loading dose
Mr JHS’s seizure was under controlled after the LD. Calculate an
appropriate maintenance dose for Mr JHS
#2
MC, a 37 year-old male, had been taking 300 mg/d of phenytoin
capsule; however, his dose was increased to 400 mg/d because his
seizures were poorly controlled and because his plasma concentration
was only 9 mg/L at steady state.
Currently, he complains of minor CNS side effects and his reported
steady state plasma phenytoin concentration is 20 mg/L.
Calculate a new daily dose of phenytoin that will result in a steady state
level of 15 mg/L.
R1 = 300 mg/d, C1 = 9 mg/L
R2 = 400 mg/d, C2 = 20 mg/L
Purpose of TDM: recommend the dose based on patient’s
individualized pharmacokinetic parameter
Population data (Vm = 8.45 & Km = 6.72) is NOT suitable for this
patient.
To calculate Mr MC’s SPECIFIC Vm & Km based on the TDM results
R1 = 300mg PHT Na x 0.92 = 276mg PHT
R2 = 400mg PHT Na x 0.92 = 368mg PHT
Vm = 276 ( 9 + Km ) /9 - ( 1 )
Vm = 368 ( 20 + Km )/20 - ( 2 )
(1)=(2)
12.27 Km = 91.97
Km = 7.496 mg/L = 7.5 mg/L
Vm = 368 ( 20 + 7.5 ) / 20 = 506mg PHT
New regimen to achieve Css = 15 mg/L
R = VmCss / Km + Css
= (506 mg/d)(15 mg/L) / (7.5 + 15)mg/L
= 337.33 mg/d PHT
= 366.67 mg PHT Na
Give 360 mg/d PHT Na ( practical dose )
#2
Madam HY, a 55-year-old, 58 kg female, has chronic kidney disease and
a seizure disorder. She undergoes hemodialysis treatment three times a
week, has a serum albumin of 2.9 g/dL, and takes 300 mg/d of
phenytoin capsule.
A TDM was done and her reported steady-state plasma phenytoin
concentration is 3.2 mg/L.
Interpret the TDM result. Should daily PHT dose be increased?
C reported = 3.2 mg/L Ξ ? Cnormal binding
C reported = total PHT concentration reported by
laboratory (represents decrease plasma protein
binding) when Alb LOW*
Cnormal binding = total PHT concentration that
would be observed if patient had normal protein
binding (90% bound)
C normal binding ?
C normal binding = C reported
[(0.432)(albumin in g/dL / 4.4g/dL)] + 0.1
= 3.2 mg/L / [(0.432)(2.9/4.4)] + 0.1
= 3.2 / 0.3847
= 8.32 mg/L
Mdm HY’s measured concentration of 3.2 mg/L is comparable to a
concentration of 8.32 mg/L (subtherapeutic level) in a patient with
normal plasma binding.
- Need to adjust the dose
To achieve Cp,ss = 15.0 mg/L
R = (498.92 mg/d)(15.0) / (6.72 + 15.0)
= 344.55 mg/day of PHT
÷ 0.92 = 374.52 mg/day of PHT Na
Give 360 mg/day
Recommendation: the measured concentration of 3.2 mg/L is
comparable to a concentration of 8.32 mg/L (subtherapeutic level) in a
patient with normal plasma binding.
Suggest to increase the dose to 360 mg/d and recheck the level after 1
week.
Time to withhold PHT when toxic
level
Case
Jessie is a 28 yo 55 kg male pt, suffering from epilepsy. He was
treated with 300 mg ON capsule phenytoin. Suddenly he had
lethargy and slurred speech and came to A/E after having
mild nystagmus.
TDM Phenytoin level was taken and the level was 35
mg/L.Calculate time to withhold the dose.
Vd = 0.65 x 55 = 35.75L
Cp measured = 35 mg/L, Cp desired = 15 mg/L
Vm = 8.45 mg /kg/day x 55kg = 464.75mg/day
Km = 6.72 mg/L
Time = _______ days
