TDM of Valproic AcidJuntip Kanjanasilp Faculty of Pharmacy Mahasarakham University9 August 2009

Calculate the dose and concentrationAdjust dose and dosage regimensIdentify, resolve and prevent DRPs

CH3CH2CH2CH3CH2CH2CHCOOHValproic acid pKa 4.7

Valproic acidVarious seizure disorders (absence and GTC)Mechanisms: voltage gated Na+ channel Ca2+ channel (T-type) GABA neurotransmitter enzyme glutamic acid decarboxylase GABA enzyme GABA GABA-transaminase succinic semialdehyde dehydrogenase

Valproic acidInitial dose: 15 mg/kg/dHighly bound to serum albuminEnzyme inhibitors

Therapeutic RangesTR: 50-100 mg/LPartial seizure: > 100 mg/L (55-100 mg/L)GTC: > 50 mg/L Generalized seizue: 30-65 mg/LADR: N,V,D, abdominal cramps (6-45%)Wt. gain (8-9%)Alopecia, tremor, thrombocytopenia, hepatotoxicity

Concentration dependentLiver function test (11%)CNS depression (ataxia, depression, lethargy, tiredness)Adrenergic tremor (> 100 mg/L)Thrombocutopenia (6-40%)Stupor, coma (> 175 mg/L)

Idiosyncratic ADRsFatal hepatotoxicityPancreatitisTeratogenicity (1-2%) spina bifidaFolic acid 5 mg/d

BioavailabilityRapidly and completely absorbedOral (fasting) --> Peak: 1-3 hoursMeal (food) --> peak late 6-8 hoursEnteric coated absorbed delayed 3-5 hrs (lag time 2-4 hrs)

TIME TO SAMPLE

Dosage FormValproic acid (sugar coated tablet) 200 mgDepakine Chrono 500 mgsoft gelatin capsules 250 mg Oral solution 200 mg/mLsyrup 250 mg/5 mLdivalproex sodium (Depakote) enteric coated tablets 200 mg (125 mg, 250 mg, 500 mg)Injection vial 400 mg/4 mL

Volume of Distribution (Vd)0.1-0.5 L/kgLow serum albumin/ end stage renal disease variable VdSaturated binding serum albumin: valproic acid > 50 mg/L (80-85 mg/mL)Valproic acid 25-50 mg/L: Vd 0.14 L/kg (assume normal albumin conc. and normal renal function)

Clearance (Cl)Almost entirely : hepatic metabolism

Half-Life (t1/2)4-17 hours (average 6-8 hours)Children and other antiepileptic drugs: reducedShort half-life LD are not givenDosing interval 8-12 hours fluctuation in plasma concentration sustained released

Loading doseChildren:Adult:LD = (0.2 L/kg) X C (mg/L) X BW (kg)LD = (0.15 L/kg) X C (mg/L) X BW (kg)

Key Parameters

Time to sampleMonitor peak and troughUncertain time of peak Only trough 2-4 days following:Initiation of therapyChange dosage regimenAddition of other antiepileptic drugsMeasured Decrease in seizure control or toxicityDiurnal variation

Special PopulationElderly: Decrease protein binding increase unbound Head trauma Decrease protein binding Pregnancy: Increase clearance (3rd trimester) + Vd Total plasma concentration decrease

Drug InteractionLamotrigine decrease dose of lamotrigine 50%Meropenem decrease valproic acid level May be increase renal excretionDisplace albumin binding

Case IChildren 8 y/o, 25 kg maleAbsence seizuresValproic acid 250 mg q 12 hr 1-2 absence seizures/dNo SE.Normal renal and hepatic functionWhat is the expected trough concentration?

Case IAve Cl for children: 13 mL/kg/hrAve Vd 0.14 L/kgCl = (13 mL/kg/hr)(25 kg) = 325 mL/hr or 0.325 L/hrVd = (0.14 L/kg)(25 kg) = 3.5 LElimination rate constant(K) = Cl/Vd= 0.093 hr-1T1/2 = 0.693/K= 7.5 hr

Case IAssume steady stateSalt form(S) and bioavalability(F)= 1.0

Cpss min =(S)(F)(Dose)/Vd(1-e-K)(e-K)

Cpss min = 34.8 mg/L 35 mg/L

Children 8 y/o, 25 kg maleAbsence seizuresValproic acid 250 mg q 12 hr Measured trough conc. 25 mg/L1-2 absence seizures/dNo SE.Normal renal and hepatic functionDecided to increase the trough conc. 50 mg/L

What dose will be required to achieve the target trough conc of 50 mg/L if the dosing interval is decreased from q 12 hr 8 hr?

Cpss max = Cpss min + [(S)(F)(Dose)/Vd]96.4 mg/L

K = [ln (Cp1/Cp2)]/tK = 0.112 hr-1T1/2 = 0.693/K = 6.2 hr

Cl = K*Vd = 0.392 L/hrCpss min =(S)(F)(Dose)/Vd(1-e-K)(e-K)

Dose = 253 mg 250 mg

Female 23 y/o, 70 kgPhenobarbital 60 mg bid 18 mg/L (Css)Phenytoin 300 mg qd 10 mg/L (Css)Poor seizure controlAdd valproic acid 500 mg q 8 hr2 mo later

Complained increased drowsiness Phenobarbital 30 mg/LPhenytoin 6 mg/LValproic acid 75 mg/L

How can the increased phenobarbital concentration be explained?

Valproic acid decreases the clearance of phenobarbital by about 40% decreased dose phenobarbital 40%?

How can the decreased phenytoin concentration be explained?

Competition for plasma protein binding between valproic acid and phenytoinNormal serum albumin and renal function valproic acid conc 70 mg/L 30%-40% decline phenytoin concentrationAcute decline: decrease in the bound concentration; unbound unchangeChronic use: increase unbound phenytoin conc. because inhibition of phenytoin metabolism

Both phenytoin and valproic acid samples should be obtained when valproic acid concentration are at trough

Female 10 y/o, 32 kgValproic acid 750 mg chrono qdCalculate valproic acid level at steady state?

Not expect a great deal of fluctuation with in the dosing interval

Cpss ave = (S)(F)(Dose/)/ClCl = (13 mL/kg/hr)(32 kg) = 416 mL/hr = 0.416 L/hr

Cpss ave = (1)(1)(750 mg/ 24 hr)/ 0.416 L/hr = 75.1 mg/L