520: Pharmacokinetic Applications of Antiepileptic an Antipsychotic Medications

Learning Objectives

• Discuss favorable pharmacokinetic characteristics of antiepileptic drugs

• Recognize the unique pharmacokinetic properties of different antiepileptic and antipsychotic drugs and strategies for therapeutic drug monitoring

• Develop an appropriate dosing regimen for phenytoin, carbamazepine, valproic acid, and lithium

• Illustrate how pharmacokinetic principles are integrated into long-acting injectable antipsychotics

What are Pharmacokinetic characteristics of the Ideal AED?

• Good bioavailability (F) → To avoid high doses to achieve desired therapeutic outcomes 

• Minimal protein binding → To avoid protein binding displacement interactions 

• Linear pharmacokinetics →  To allow for simpler dosing and prescribing 

• Renal elimination → To avoid pharmacokinetic variability and active metabolites 

• No drug interactions → To not worry about co-administration of other medications 

• Half-life of 12-24 hours → To allow for once or twice daily dosing, improving patient compliance.

What is the MOA of phenytoin?

Block voltage-dependent sodium channels at high firing frequencies

What are the dosage forms of Phenytoin?

• Phenytoin sodium:

  • 100mg, 200mg, 300mg ER capsule, 50mg/ml IV solution (max=50mg/min)

• Phenytoin acid:

  • 50mg chewable tablet, 125mg/5ml oral suspension

• Fosphenytoin:

  • 50mg PE/ml IV solution (max= 150mg PE/min)

• Salt correction:

  • 0.92 for phenytoin sodium

What are some PK parameters of phenytoin?

• Vd: 0.8 L/kg 

• Half-life: 9-36 hours 

• Protein binding: 90% 

• Excretion: 95% liver (metabolized by CYP 2C9 and 2C19) 

• Target range: 10-20 mg/L 

• Enzymatic activity: Broad-spectrum inducer (most inducing AED) 

• Follows Michaelis Menten kinetics (zero-order or nonlinear)

What are the toxicity ranges of Phenytoin?

• >15mg/L: somnolence 

• >20 mg/L: nystagmus, diplopia 

• >30mg/L: ataxia,slurred speech 

• >40mg/L: confusion, lethargy, coma 

• >50mg/L: drug induced seizures

Describe the interpatient variability of phenytoin

Study done among 100 patients, everyone gets 300mg Phenytoin

Serum concentrations were all over the place (some low, some high). This led to the connection of Phenytoin following non-linear kinetics

What are Michaelis-Menten kinetics?

Non-linear kinetics - mathematical model that describes how the rate of an enzyme-catalyzed reaction depends on the concentration of a substrate

What’s the deal with phenytoin concentration vs dose?

• For phenytoin, capacity for metabolism by CYP2C9 becomes saturated 

• Therefore, ↑ Dose =↓ Clearance = ↑t1/2 

• ↑ in dose results in greater than proportional ↑ in concentrations 

• A slight increase in dose may lead to a considerable increase in plasma concentrations

  • Phenytoin has a narrow therapeutic window

What’s the relationship between phenytoin and albumin? Which form of drug can produce clinical effects? (bound or unbound)

• Phenytoin is highly bound (~90%) to albumin 

  • Only unbound drug can produce clinical and adverse effects 

  • Variability in the fraction unbound drug can have a significant impact on its pharmacological effect

What are disease states and conditions that alter phenytoin plasma protein binding?

• 1) Insufficient Albumin Concentration (Hypoalbuminemia) 

  • Liver disease 

  • Nephrotic syndrome 

  • Pregnancy 

  • Cystic fibrosis 

  • Burns 

  • Trauma 

  • Malnourishment 

  • Elderly

• 2) Displacement By Endogenous Compounds 

  • Hyperbilirubinemia 

  • Jaundice 

  • Liver disease

  • Renal dysfunction

• 3) Displacement By Exogenous Compounds

  • Drug interactions 

  • Warfarin 

  • Valproic acid 

  • Aspirin (>2 g/d) 

  • NSAIDs with high albumin binding

These conditions increase Phenytoin’s fraction unbound (f_u)

What are the therapeutic/toxic ranges of total and free Phenytoin?

• Therapeutic Range

  • Total: 10-20 mcg/mL

  • Free: 1-2 mcg/mL

• Toxic Range

  • Total: >30 mcg/mL

  • Free: >2.5mcg/mL

Describe TDM for Phenytoin (total vs free serum concentrations)

• Total phenytoin serum concentrations = mainstream way for routine therapeutic drug monitoring purposes.

• Unbound phenytoin serum concentrations (free phenytoin) should be measured in patients with factors known to alter phenytoin plasma protein binding.

Which equation can we use to correct phenytoin for low albumin?

• The Sheiner-Tozer Equation normalizes total phenytoin concentrations reliably in patients with low albumin concentrations 

  • No correction is needed for albumin >3.2 g/dL.

Which equation can we use to correct phenytoin for renal failure?

• In advanced renal failure, there is reduced phenytoin binding to albumin

• In patients with Creatinine Clearance <25 ml/min, and adjustment of 0.1 is used

What does the Michaelis-Menten dosing method estimate?

In adults with normal liver, renal, and plasma protein binding:

• Maximum rate of metabolism (mg/d) or Vmax = 7 mg/kg/d

  • Substrate Concentration or Km = 4 μg/mL

• ↓ Dose by 25-50% in patients with significant hepatic dysfunction

What is the V_d for phenytoin (Michaelis-Menten dosing)?

• V_d for phenytoin = 0.7 L/kg 

• For obese individuals (>30% ideal body weight): 

  • V_d = 0.7 L/kg * [IBW + 1.33(TBW − IBW) ]

How do we dose Phenytoin in healthy patients? (Michaelis-Menten dosing method)

• Loading Dose = (Vd * Css)/S 

  • Css= target phenytoin concentration in μg/mL 

  • S = fraction of the phenytoin salt form that is active phenytoin

    • 0.92 phenytoin sodium injection, capsules, and fosphenytoin;

    • 1.0 for phenytoin acid suspensions and tablets

• Maintenance Dose:

What is the MOA of Valproic acid?

• May enhance GABA transmission in specific circuits

• Blocks voltage-dependent sodium channels

What are PK parameters of VPA?

• Vd: 0.2 L/kg

• Half-life: 6-18 hours

• Protein binding: 90%

• Excretion: 98% liver

• Target range: 50-125 mg/L

• Clearance: low clearance due to protein binding

• Enzymatic activity: Broad-spectrum inhibitor (CYP 2C9)

How does protein binding displacment affect the pharmacologic effect of valproic acid?

• Similar to phenytoin, valproic acid is highly protein bound → binding is concentration dependent and saturable.

• The concentration-dependent protein binding of valproic acid causes the drug to follow nonlinear pharmacokinetics.

What’s the relationship between valproic and phenytoin?

Valproic acid displaces phenytoin from its plasma albumin binding sites, increasing the free fraction of phenytoin

• As valproic acid concentrations increase, enzyme inhibition of phenytoin occurs via CYP2C9, thus decreasing the clearance of phenytoin 

  • When co-administered with phenytoin, valproic acid can increase the free fraction of phenytoin by up to 60%, increasing its pharmacologic effects

• Phenytoin is a potent inducer of CYP 2C9 and UDPglucuronosyltransferases (UGT), which ↑ Cl of valproic acid 

  • The increased metabolism of valproic acid might ↑ the serum concentration of hepatotoxic valproate metabolites, increasing the risk for hyperammonemia.

What is the interaction between VPA & carbapenem?

• Carbapenems: 

  • 1) Inhibit of the xenobiotic p-glycoprotein in erythrocytes, trapping VPA in erythrocytes 

  • 2) inhibit the intestinal absorption of VPA 

  • 3) directly inhibit the VPA-recovering enzyme glucuronidyl-hydrolase, thereby increasing excretion

Big interaction between carbapenems and VPA

What is Carbamazepine’s MOA?

• Related to structure of TCA

• Block voltage-dependent sodium channels at high firing frequencies

What are PK parameters of Carabmazepine?

• Vd: 0.6-2L/kg

• Half-life: 9-15 hours

• Protein binding: 75%

• Excretion: 99% liver

• Target range: 4-12 mg/L

• Rapid absorption and distribution

• Enzymatic activity: metabolized by CYP 3A4; Broadspectrum inducer of CYP 1A2, 2C9, 3A4

• Autoinduction

Toxicity of Carbamazepine

• Diplopia, nystagmus, blurred vision, ataxia, dizziness, sedation, hyponatremia

• Black-box warning for severe dermatologic reactions.

• HLA B*1502 allele testing should be done in Asian patients prior to starting

What’s special about Carbamazepine’s metabolism?

• It induces its own metabolism (autoinduction) via CYP3A4

• Onset is as early as 24 hours, but may take 1-5 weeks for completion 

  • Due to autoinduction, clearance ↑, therefore half-life ↓

• Patients are typically started on 25-33% of the desired maintenance dose

  • Maximal autoinduction continues for 2-3 weeks after starting

  • Dose is increased q2-3 weeks until the total desired dose is achieved.

How should Carbamazepine therapy be initiated?

• Initiate therapy at low dose → gradually increase every 2-3 weeks during the initial 4-6 weeks based on adverse effects and therapeutic response

• A trough serum concentration should be measured after steady-state is attained in 3-4 weeks

Describe pseudolinear PK of Carbamazepine

To approximate new total serum concentrations (after a dose change), assume linear PK using this equation:

• For dose increases → Subtract 10-20% to Css_new

• For dose reductions → Add 10-20% to Css_new

A patient is on carbamazepine for partial seizures and reports compliance. He has been on 400 mg twice daily(800 mg/d) for 1 month, and his carbamazepine total concentration equals 3.8 μg/mL. What would his new expected concentration be if his dose is increased by 200mg?

• Css_new = (D_new/D_old)Css_old = (1000 mg/d / 800 mg/d) * 3.8 μg/mL = 4.8 μg/mL.

• Due to autoinduction, the serum concentration would be expected to decrease by 10-20%.

• Css = 4.8 μg/mL x 0.90 = 4.3 μg/mL — Css = 4.8 μg/mL x 0.80 = 3.8 μg/mL

Therefore, a 200mg increase would result in a Css_new of 3.8-4.3 μg/mL

What’s special about Lithium?

The PK follows a 2 compartment model

• Does not bind to any proteins, almost exclusively excreted through the kidneys (much of which is excreted unchanged)

What is Lithium’s MOA?

Alters sodium transport in nerve and muscle cells resulting in intraneuronal metabolism of catecholamines

Describe the PK of Lithium:

• 2-compartment model

  • 1) initial rapid serum concentration decline (2-3 hrs)

  • 2) Long distribution phase (6-10 hrs)

• Due to the long distribution phase, serum concentrations should be obtained at least 12 hours after a dose. 

  • Steady-state lithium concentrations should be obtained after 1-2 weeks. 

• Lithium is not metabolized ➔ eliminated renally as free cation (80% reabsorbed in the proximal tubules with sodium) 

• Follows linear pharmacokinetics, so a simple dosage ratio can be used to change lithium doses: 

What are factors that increase Lithium clearance?

• Acute mania (can decrease by 50%) 

• High-sodium diet 

• Pregnancy 

• Daytime (30% due to circadian rhythm) 

• Caffeine

In what scenario would we want to double the Lithium dose?

When a patient presents with acute mania

• Acute mania can decrease Lithium CL by 50%

What are factors that decrease Lithium clearance?

• Dehydration (vomiting, diarrhea) 

• Low-sodium diet 

• Renal failure 

• Nephrogenic diabetes insipidus 

• Medications 

  • Concomitant use of thiazide diuretics, ACE inhibitors, ARBs, NSAIDs

Which drugs decrease Lithium clearance when used concomitantly?

Thiazide diuretics, ACE inhibitors, ARBs, NSAIDs

How do we calculate lithium dosing?

• 1) Calculate patient’s CrCl

• 2) Determine lithium clearance in L/day

  • Lithium Clearance (mL/min) = 20% of CrCl = 0.2 (CrCl)

    • Expressed as liters/day → 0.288 * CrCl

      • **In acute mania, Lithium CL = 0.432 (CrCl)

• 3) Calculate maintenance dosing (C_ss)

  • C_ss = [F(D/τ)] / Cl 

    • Or D/τ = (Css x Cl) / F

  • F = 1 for oral lithium

  • D is the lithium dose in mmol

  • τ is the dosage interval in days  

  • Cl is lithium clearance in L/d

• Everytime we dose lithium, we convert into mg of Lithium carbonate

What is the conversion factor of lithium to lithium carbonate?

Conversion factor is 300mg Lithium carbonate = 8.12 mmol Li+

What are target Lithium concentrations?

For acute mania → 0.8 - 1 mmol/L

For long term maintenance → 0.6 - 0.8 mmol/L

Which long-acting injectable antipsychotics can be used for schizophrenia and bipolar I disorder?

Schizophrenia:

• Paliperidoen

• Risperidone

• Olanzapine

• Aripiprazole

Bipolar I Disorder:

• Paliperidone

• Risperidone

• Aripiprazole

Describe the PK of Aripiprazole monohydrate (Abilify Maintena)

Absorption:

• Initial absorption period takes quite amount of time →

• Must bridge therapy with oral aripiprazole for 2 weeks when starting injection

• Rate of absorption is higher with deltoid injection vs gluteal muscle (t_max 4 days vs 7 days)

  • Gluteal muscle takes longer to get to steady state

• Highly protein bound (>85%)

Elimination

• Super long half-life, stays in body for 30 - 46 days

  • Watch out for drug interactions bc it stays in system for so long

• Steady state reached by 4th month

• Metabolized by CYP3A4 + 2D6

What did Aripiprazole lauroxil (Aristada) improve on compared to Abilify?

Serves as a prodrug for Aripiprazole → Has active metabolites

• Stays in body for much longe, can be dosed every 2 months

• Instead of bridging therapy with PO aripiprazole for 2 weeks, Aristada only requires a one-time 30mg PO dose + 1^st Aristada injection

• T_1/2 = 57 days

But, similar to Abilify once we start, there’s no going back. Watch out for DIs because it stays in our system for so long

What are pros of using long-acting anti-psychotic injections?

• Improves medication adherence by reducing the need for daily oral dosing 

• Provides consistent medication levels, reducing symptom fluctuations and relapse risk

• Less frequent administration (e.g., monthly or every few months)simplifies treatment regimen.

• Allows healthcare providers to monitor adherence and treatment progress during injection visits. 

• Discreet administration may reduce stigma 

• May reduce hospitalization costs by preventing relapses through better adherence. 

• Suitable for patients with difficulty swallowing pills or complex medication schedules. 

What are cons of using long-acting antipsychotic injections?

• Requires regular healthcare visits for injections, which may be inconvenient for some patients. 

• May take longer to adjust dose or switch medications due to prolonged drug release. 

• Injections can be painful or cause discomfort at the injection site. 

• Side effects (e.g., weight gain, sedation, or movement disorders) may persist longer due to extended drug release. 

• Some patients may feel stigmatized by receiving injections in clinical settings. 

• Higher upfront costs compared to oral medications; insurance coverage varies. 

• Less flexibility in stopping treatment quickly if side effects or adverse reactions occur.

What are drug interactions are present with LAIs?

• Aripiprazole LAIs (Abilify Maintena, Aristada)

  • Metabolized by CYP3A4 and CYP2D6

• Risperidone and Paliperidone LAIs (Risperdal Consta, Invega Sustenna):

  • Metabolized by CYP2D6

• Olanzapine LAI (Zyprexa Relprevv):

  • Metabolized by CYP1A2 and CYP2D6

Which LAIs need renal or hepatic adjustments?

• Paliperidone LAIs rely on renal clearance; severe impairment requires dose reductions (e.g., 25-50% lower)

• Hepatic impairment affects metabolism of risperidone or olanzapine LAIs

What ADRs are seen with LAIs?

LAIs can enhance CNS depression or extrapyramidal symptoms (EPS) when combined with other sedatives or dopaminergics.