Phenobarbital Pharmacokinetic Dosing Information

FDA-Approved Indications: Febrile seizures and all types of epilepsy except absence seizures.

Non-FDA Approved Indications:

• Preterm neonatal seizures due to intracranial hemorrhage
• Essential tremors in adults
• Traumatic brain injury

Bioavailability (F):

• IM, IV, Oral = 1
• Rectal = 0.9

Salt (S): Injection 0.91; capsules, tablets, elixir = 1

Route of Administration: IV, IM, oral, rectal (Injectable usually used)

Absorption: Slow but complete absorption unaffected by food.

Distribution: Phenobarbital has low lipid solubility. Maximum brain-to-plasma concentrations occur after 60 minutes when IV loading doses are given. Effective brain concentrations are achieved within minutes.

Peak Concentrations:

• Oral: ~ 2 hours
• IM: 3 hours
• IV: Immediate
• Rectal: Quicker than oral

Protein Binding:

• Neonates < 2 weeks: 37%
• Infants ≥ 2 weeks, children and adults: 51%
• Note: Protein binding may be decreased in renal failure accompanied by acidosis

Metabolism: Extensively metabolized without first-pass effects to inactive metabolites through N-glucoside and cytochrome P4502C9 and 2C19 metabolism. Low hepatic extraction ratio and changes in liver blood flow should not affect clearance.

Excretion: Unchanged drug renal excretion is urine flow and pH-dependent. Normally 20-40% is excreted unchanged in the urine and can be increased by combined diuresis and alkalization of urine. Hepatic clearance and renal clearance usually offset each other when there is a decline in one or the other.

Breast Milk: Levels are approximately 40% of maternal serum levels which may produce therapeutic levels and toxicity in a nursing infant.

Dialysis Removal:

• Non-high flux hemodialysis: ~ 30%
• High flux hemodialysis: ~ 50%
• Peritoneal dialysis: Possibly 8-15% removal
• Note: Renal replacement therapies remove phenobarbital and require multiple daily doses to maintain therapeutic levels due to high clearance

Volume of Distribution (V_d):

• Neonates less than 2 weeks: 0.96 L/kg
• Infants & children 2 weeks - 19 years: 0.63 L/kg
• Adults greater than 19 years: 0.61 L/kg

Clearance (L/hr/kg):

Clearance increases rapidly in the first 10 postnatal days. Clearance (L/hr/kg) declines from 1 year to 17 years of age. Increasing urine or plasma pH may increase clearance as phenobarbital is a weak acid.

Note: These values do not match those calculated from the dosage guidelines below. Due to scarcity of published pharmacokinetic studies and the prolonged half-life of phenobarbital, serial levels at weekly intervals are recommended to guide dosage until steady state is achieved.

• Neonates and infants less than 1 year: 0.0047 L/hr/kg
• Children 1 - 19 years: 0.0082 L/hr/kg
• Adults 19 - 65 years: 0.0056 L/hr/kg
• Geriatrics > 65 years: 0.0024 L/hr/kg

K (1/hours): Volume of distribution and clearance dependent (K = Clearance / V_d)

Half-life (hours): Half-life is dependent on volume of distribution and clearance

Dosage Forms: Injection, tablets, capsules, and elixir

Usual Interval: Once-daily usually in the evening, but may be divided. Bedtime dosing may help reduce sedative side effects.

To minimize side effects, the dose is usually started at 25% of the final dose, and increased 25% each week until the goal dose is reached.

Important: As phenobarbital's half-life is very long, if a loading dose is not given, it will take 2-3 weeks or longer to achieve steady state levels.

General Range: 10-40 mcg/mL (Note: side effects, CNS depression and ataxia, may appear at the upper end of range)

Indication-Specific Targets:

• Febrile Convulsions: 16-30 mg/L
• Hypoxic Ischemic Seizures in Neonates: > 30 mg/L then 20-30 mg/L after 24-48 hours
• Generalized Tonic-Clonic Seizure: 10-25 mg/L
• Refractory Status Epilepticus: ≥ 70 mg/L
• Cerebral Salvage from Hypoxic or Traumatic Brain Injury for Barbiturate Coma: > 75 mg/L

Post-Loading Peak: A peak 2-3 hours post loading dose, to allow distribution to complete, may be used to evaluate the need for further loading.

Routine Monitoring: Trough levels are recommended for monitoring so levels can be compared over time. Due to the long half-life, samples should be drawn for up to 3-4 weeks to determine the steady state level.

Initiation Monitoring: Weekly levels on initiation may be helpful to ensure levels do not go above the desired range.

A linear one-compartment open model is adequate for dosage predictions. When levels are at steady state, doses can be adjusted proportionally to the desired concentration.

Concentration-Dependent Side Effects:

• Sedation, impaired cognition
• Decreased neonatal feeding, respirations, and muscle tone
• Sedation, slowness, and ataxia
• Coma

Non-Concentration-Dependent Side Effects:

• Folate deficiency
• Fetal vitamin K deficit from maternal phenobarbital therapy
• Gingival hyperplasia
• Vitamin D deficiency
• Shoulder-hand syndrome
• Hepatotoxicity

Important: Phenobarbital is a potent inducer of p-glycoprotein and CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP3A4, CYP2D6 enzymes.

Decreased Clearance (Clearance Multipliers):

• Carbamazepine: 0.91 (in those > 65 years old)
• Chloramphenicol: 0.6
• Phenytoin: 0.8 (in those > 65 years)
• Valproic Acid: 0.5-0.7 (2000 mg daily and 1000 mg daily)

Increased Clearance (Clearance Multipliers):

• Pyridoxine: 1.4
• Rifampin: > 1
• Thioridazine/Mesoridazine/Phenothiazines: 1.3
• Alkalinization of urine and forced diuresis: > 1

Decreased Clearance:

• Cirrhosis
• Severe renal failure
• Hepato-renal syndrome

Increased Clearance:

• Continuous renal replacement therapy (large increase in clearance)
• Hemodialysis (30% removal)
• Peritoneal dialysis (7.5-15% removal)
• Pregnancy

Body Mass Index (BMI):

BMI = Actual Body Weight(kg) / (Height in meters)²

Ideal Body Weight (Devine Formula):

IBW(kg) Adult Males (18 years and older) = 50 kg + 2.3 × (Height in inches greater than 60 inches)

IBW(kg) Adult Females (18 years and older) = 45.5 kg + 2.3 × (Height in inches greater than 60 inches)

Fat-Free Mass (Janmahasatian Formula):

FFM(kg) Adult Males = [9270 × Actual Body Weight(kg)] / [6680 + (216 × BMI)]

FFM(kg) Adult Females = [9270 × Actual Body Weight(kg)] / [8780 + (244 × BMI)]

Body Surface Area (meters²):

BSA (m²) = [(Weight in kg)^0.425] × [(Height in centimeters)^0.725] × (71.84/10000)

Dosing Weight:

Dosing Weight(kg) = Total body weight for V_d and clearance calculation

Note: Little to no data is available for obese patients (one case study report: Wilkes, L., Danziger, L.H. & Rodvold, K.A. Phenobarbital Pharmacokinetics in Obesity. Clin. Pharmacokinet. 22, 481–484 (1992)). A cautious approach to dosing and monitoring is recommended in obesity.

Clearance:

Clearance(L/hr) = Clearance(L/hr/kg) × Dosing Weight(kg)

Volume of Distribution:

V_d(L) = V_d(L/kg) × Dosing Weight(kg)

Elimination Rate Constant:

K(1/hours) = Clearance(L/hr) / V_d(L)

Maintenance Dose:

Maintenance Dose(mg) = [Cp_average(mg/L) × Tau(Hours) × Clearance(L/hr)] / (Fraction × Salt)

Steady State Average Concentration:

Cpss_average(mg/L) = [Salt × Fraction × Dose(mg)] / [Clearance(L/hr) × Tau(hours)]

Steady State Maximum Concentration:

Cpss_maximum(mg/L) = [Salt × Fraction × Dose(mg)] / [V_d(L) × (1 - exp(-K × Tau))]

Steady State Minimum Concentration:

Cpss_minimum(mg/L) = Cp_maximum(mg/L) × exp(-K × Tau)

Time to Level from Start of Dosing:

Time(days) = -ln(1 - (level / Css_average)) / (K(1/hours) × 24)

Time to Fraction of Steady State:

Time(days) = -ln(1 - (Fraction of Steady State to Achieve)) / (K(1/hours) × 24)

Time from Known Level to Fraction of Steady State:

Time(days) = ln[(1 - (Fraction of Steady State to Achieve)) / (1 - (Current Level / Steady State Level))] / (K × 24)

Concentration After N Doses:

Cp(mg/L) = [S × F × Dose(mg) × (1 - Exp(-K × N × Tau)) × Exp(-K × T)] / [V_d(L) × (1 - Exp(-K × Tau))]

where N equals number of doses given