C3.1 R4(e): Perform & document a pharmacokinetic interpretation (OTHER drug)

Interpretation #1 of SB:

MAR 1/ 17 (1000hr) Clinical Pharmacy Note RE: Valproic Acid Level

ID: 24 yo female, 40kg with atypical Angelman’s Syndrome, admitted for uncontrolled status epilepticus

S/O:
Currently on VPA 250mg via G-tube AM and 500mg via G-tube PM. During hospital stay, was started on valproic acid and given varying doses at different times as detailed below:

  • Feb 25, 2350hr: 800mg IV → Feb 26, 250hr: 400mg IV
  • Feb 27, 1130hr: 750mg via G-tube and 2200hr: 500mg via G-tube
  • Feb 28, 800hr: (↓) 250mg via G-tube
    → level taken 30 mins prior to 2100hr dose of 500mg: 277 umol/L (target: 350-700)

Previous levels:
Feb 26, 448hr: 815 umol/L (random level)
Feb 26, 1255hr: 629 umol/L (10 hr post-dose)
Other labs: Alb (Feb 26) : 32 g/L; PLTs (Feb 28): 114 (↓142 from 26th); eGFR: >150mL/min (stable), LFTs WNL

  • Difficult to assess safety of valproic acid as patient is non-verbal and RASS -3
  • Unclear to neurology if any EEG changes with short episodes of grinning but thought to have no epileptiform activity on EEG for the past 24 hours

A:

  • Trough level taken appropriately 30 mins prior to dose, and subtherapeutic
  • Not a true steady state level of current dose
  • Potential drug interaction with topiramate: ↓ levels of topiramate and valproic acid and ↑ risk of encephalopathy, hyperammonemia, ↓ platelets

P:

  • Discussed with neurology and plan is to wean off valproic acid after extubation or sooner. No changes to other anti-epileptics (clobazam, topiramate, levetiracetam)
  • Continue to monitor for AEs while on valproic acid, such as tremors, confusion, drowsiness, nausea, diarrhea and thrombocytopenia

Reflection and feedback:

  • Important to provide own assessment of appropriateness and efficacy of VPA and all notes regarding levels → at this point in time, it seemed that valproic acid while appropriate may not be doing much for epilepsy management as levels are currently sub-therapeutic

Progression in hospital: Valproic acid was titrated down to 250mg via G-tube BID, and levetiracetam was increased from 1000mg BID to 1500mg BID. On Mar 2, epileptologist (who was following SB as out-patient) noted EEG changes consistent with seizures. Parents are also observing seizures (presenting as arrhythmic mouth opening and grinning). Valproic acid load was given, maintenance dose was increased and propofol (previously weaned off) was restarted. Valproic peak level (2hrs post IV load dose was given, daily valproic acid levels prior to AM dose, and ammonia levels were ordered.


Interpretation #2 of SB:

Mar 3, 2017 (1000hr) Clinical Pharmacy Note RE: Valproic Acid Levels

ID: 24 yo female, 40kg admitted with status epilepticus
HPI: EEG changes found to be reflective of seizure activity and valproic acid was increased and propofol restarted

S/O:
Valproic acid dose changes since last note:

  • Feb 28: 250mg G-tube AM, 500mg G-tube PM
  • Mar 1: 250mg G-tube AM, 250mg G-tube PM
  • Mar 2: 250mg G-tube at 800hr
    → 600mg IV loading dose at 1200hr and VPA ↑ to 750mg BID at 600hr and 1800hr
  • Valproic acid levels:
    • 2 hours post loading dose: 543 umol/L
    • 30 mins pre AM 750mg dose: 295 umol/L
  • Ammonia levels: Mar 2: 54 umol/L → Mar 3: 44 umol/L
  • LFTs (last done on Feb 26): WNL
  • RASS -4 and still on propofol → difficult to assess efficacy and safety of valproic acid

A:

  • Valproic acid appropriate for seizures and currently titrating up to therapeutic levels
  • Recent ↑ in VPA is appropriate as peak level post load was only in therapeutic range for a trough level
  • Steady state of valproic acid (half life: 9-19 hrs) tends to take 2-4 days
  • Ammonia is elevated but not significantly. VPA-associated hyperammonemia is typically associated with ammonia levels of 75-283 umol/L. Hyperammonemia can also be asymptomatic

P: Discussed with doctor

  • Continue current VPA dose and daily VPA levels
  • Monitor for AEs of VPA: drowsiness, tremors, N/V/D, thrombocytopenia
  • Monitor ammonia and LFTs daily while in ICU
  • Monitor for valproate-induced hyperammonemic encephalopathy: confusion, lethargy, vomiting, increased seizure frequency

Reflection and Feedback:

  • Important to understand and assess appropriateness of what is happening for patient prior to assessing the level
  • Questions to ask yourself while assessing drug levels:
    • In what situations should a peak level be ordered (esp, for a drug where monitoring is usually done with trough levels)?
      → In this case, varying doses have been given and patient has been on a relatively low dose of VPA, so a peak level was done post-dose to see if it was in therapeutic range. If peak level is sub-therapeutic, current dose is probably not sufficient. If peak level is therapeutic or above therapeutic level, the appropriateness of current dose is more difficult to assess.
    • If a peak level is warranted, when should it be ordered?
      → Consider: volume of distribution and required time for the drug to distribute throughout the body
    • How often should you monitor levels?
      → Consider: urgency, severity of clinical situation, and what will help dictate therapy and dose adjustments
    • What are the pharmacokinetics of the drug you are monitoring? And, how does it affect your interpretation of the levels?

Follow-up:

Mar 6, 2017

S/O:
Propofol increased to 100 mcg/kg/min IV infusion (FYI: feeds had to be decreased as feeding “fat” with propofol) 
Valproic Acid doses since last note:

  • Mar 3: (pre-AM level: 295 umol/L) 750mg Gtube at 600hr, 600mg IV at 1025hr, 750mg Gtube at 1800hr
  • Mar 4: (pre-AM level: 260 umol/L) 750mg Gtube at 600hr, 500mg IV at 1200hr, 750mg Gtube at 1800hr
  • Mar 5: (pre-AM level: 282 umol/L) 750mg G tube at 600hr, 500mg IV at 1200hr, (↑) 1000mg Gtube at 1800hr
  • Mar 6: (pre-AM level: 358 umol/L) 1000mg Gtube at 600hr and 1800hr

Neurology to d/w EEG and assess if any seizures on the weekend. Plan is to wean off propofol. Continue daily VPA levels – unlikely to be therapeutic with 1g BID as therapeutic level reached with multiple IV loading doses.


Valproic Acid:chemically related to free fatty acids and is used in the treatment of generalized, partial, and absence (petit mal) seizures. Has a broad spectrum of activity

Pharmacokinetics:

  • Kinetics: NON-linear
    • Due to concentration-dependent protein binding of valproic acid
  • Distribution: CSF at concentration similar to unbound concentration in plasma
    (i.e. ~10% of total plasma concentration)

    • Vd = 0.15L/kg
  • Protein binding (concentration dependent): 80-90%
    • Decreased in elderly and patients with hepatic or renal impairment
    • Due to concentration-dependent protein binding: may take several week to achieve a therapeutic effect despite already reaching therapeutic range at ss
  • Metabolism: extensively hepatic
  • Bio-availability:
    • Depakote ER: ~90% relative to IV and ~89% relative to delayed release formulation
  • Time to peak:
    • Depakote tablet and sprinkle capsules: ~ 4 hrs
    • Depakote ER: 4-17 hrs
    • Epival: 4 hrs
  • Half-life elimination:
    • Adults: 9-19 hours

Levels:

  • Trough within 30 mins prior to dose
  • Sampling should ideally be done prior to same dose, preferably AM dose – due to effects of diurnal variation on clearance
  • Initially after reading steady state (usually 2-4 days) and after each dosing adjustment at steady state

Free VPA levels: indicated if:

  • Total VPA dose is >60mg/kg/day (max dose)
    OR
  • Seizure-free at a total level of <350 umol/L and need to determine whether a dosage increase is necessary
    OR
  • exhibiting signs of toxicity at a dosage of <60mg/kg/day
    OR
  • unique subpopulation (e.g. pregnant female, patient on multiple anticonvulsant therapy, etc)

Other monitoring:

  • Adverse reactions: tremors, confusion, drowsiness, insomnia, nausea, vomiting, diarrhea
  • Hepatotoxicity (LFTs), CBCs (dose-related thrombocytopenia), Ammonia (if suspect encephalopathy) – ammonia should be sent on ice and stat!

References:

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