Valproic Acid

VALPROIC ACID INTRODUCTION ❖Valproic acid (VPA), a simple branch-chain aliphatic acid, is among the most versatile central nervous system (CNS) active drugs in the pharmacopeia, and whose clinical uses and dosing strategies continue to be explored and refined. ❖It has the widest spectrum of activity compared to the other currently available antiepileptic drugs. It is used for various generalized and focal epilepsy disorders (classic and atypical absence, tonic–clonic, atonic and myoclonic seizures, Dravet syndrome, juvenile myoclonic epilepsy, and focal onset seizures), it is also approved use in bipolar disorder treatment and migraine prophylaxis. ❖Its anti-epileptic activity is due to enhanced inhibitory neurotransmission by γamino butyric acid by VPA is done via increased synthesis, and decreased degradation and turnover. Additionally, anti-seizure effects derive from blockade of voltage-gated sodium channels and calcium channels. INTRODUCTION ❖The unusual nature of VPA is highlighted by: ❖Concentration-dependent protein binding within the therapeutic range, and dose-dependent pharmacokinetic parameters ❖ Large variability in concentration to dose ratio that depends on numerous demographic and clinical factors ❖ A great multitude of metabolic pathways with primary phase 1 and phase 2 reactions whose balance is age dependent and genetically determined ❖ Significant adverse effects that are concentration- or dose dependent. ❖Drug interactions are numerous and mostly feature inhibiting the clearance of other hepatically eliminated drugs via cytochrome p450 and glucuronidation mechanisms. Likewise, other such medicines and genetic polymorphisms may interfere with the clearance of VPA, and increase its adverse event risk profile. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖The generally accepted therapeutic range for total valproic acid steady-state concentrations is 50-100 mcg/mL, although some clinicians suggest drug concentrations as high as 175 mcg/mL with appropriate monitoring of serum concentrations and possible adverse effects. ❖Valproic acid is highly protein bound to albumin with typical values of 90%95%. ❖Plasma protein binding of valproic acid is saturable within the therapeutic range which results in less protein binding and higher unbound fraction of drug at higher concentrations. The concentration-dependent protein binding of valproic acid causes the drug to follow nonlinear pharmacokinetics THERAPEUTIC AND TOXIC CONCENTRATIONS ❖This type of nonlinear pharmacokinetics is fundamentally different than that observed during phenytoin administration. Phenytoin hepatic metabolism becomes saturated which causes Michaelis-Menten pharmacokinetics to take place. As a result, when phenytoin doses are increased total and unbound steady-state concentrations increase more than a proportional amount (eg, when the dose is doubled, serum concentrations may increase 3-5 fold or more). ❖In the case of valproic acid, when the dose is increased total drug steadystate concentration increases less than expected, but unbound steadystate drug concentration increases in a proportional fashion (eg, when the dose is doubled, total serum concentration increases 1.6-1.9 times but unbound steady-state serum concentration doubles). THERAPEUTIC AND TOXIC CONCENTRATIONS ❖ Although total valproic acid concentrations increase in a nonlinear fashion with dosage increases (solid line), unbound, or “free” valproic acid concentrations increase in a linear fashion with dosage increases (dashed line). Valproic acid is a low-extraction ratio drug, and its unbound serum concentrations are only a function of intrinsic clearance (Cl′int). THERAPEUTIC AND TOXIC CONCENTRATIONS ❖The clinical implication of concentration-dependent plasma protein–binding pharmacokinetics is that the clearance of valproic acid is not a constant as it is with linear pharmacokinetics, but is concentration or dose dependent. ❖As the dose or concentration of valproic acid increases, the clearance rate (Cl) increases because more unbound drug is available to hepatic enzymes for metabolism:↑ClH = ↑fBCl′int. This is the reason total steady-state concentrations increase disproportionately after a valproic acid dosage increase: ❖↑Css = [F(⇑D/τ)]/↑ClH, THERAPEUTIC AND TOXIC CONCENTRATIONS ❖When valproic acid dose is increased, the unbound fraction increases and causes an increase in hepatic clearance. ❖Because both dose and hepatic clearance simultaneously increase, total valproic acid concentrations increase, but by a smaller than expected amount ❖Unbound concentrations increase in a proportional amount to dose ❖Insufficient prospective work has been done to establish the therapeutic range for unbound valproic acid steady-state serum concentrations. As an initial guide, 5% of the lower end and 10% of the upper end of the total concentration therapeutic range is used to construct the preliminary unbound THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Steady-state concentration therapeutic range for valproic acid of 2.5-10 mcg/mL. The percent used for each case is the average unbound fraction of drug at the appropriate concentration. ❖As is the case with phenytoin, measurement of unbound valproic acid serum concentrations should be considered in patients with factors known to alter valproic acid plasma protein binding. These factors fall into three broad categories: (1) lack of binding protein where there are insufficient plasma concentrations of albumin, (2) displacement of valproic acid from albuminbinding sites by endogenous compounds, and (3) displacement of valproic acid from albumin binding sites by exogenous compounds THERAPEUTIC AND TOXIC CONCENTRATIONS ❖In the upper end of the therapeutic range (>75 mcg/mL) some patients will begin to experience the concentration-dependent adverse effects of valproic acid therapy: ataxia, sedation, lethargy, and tiredness. ❖In many individuals, these side effects dissipate with continued dosing, and slow dosage titration may assist in minimizing these adverse reactions in newly treated patients. Other concentration-related side effects of valproic acid therapy include tremor at concentrations >100 mcg/mL, and stupor or coma at concentrations >175 mcg/mL. ❖Additionally, valproic acid–associated thrombocytopenia can usually be limited by a decrease in drug dose CLINICAL MONITORING PARAMETERS ❖The goal of therapy with anticonvulsants is to reduce seizure frequency and maximize quality of life with a minimum of adverse drug effects. While it is desirable to entirely abolish all seizure episodes, it may not be possible to accomplish this in many patients. ❖Patients should be monitored for concentration-related side effects (ataxia, sedation, lethargy, tiredness, tremor, stupor, coma, thrombocytopenia) as well as gastrointestinal upset. ❖Valproic acid serum concentrations should be measured in most patients. Because epilepsy is an episodic disease state, patients do not experience seizures on a continuous basis. Thus, during dosage titration it is difficult to tell if the patient is responding to drug therapy or simply is not experiencing any abnormal central nervous system discharges at that time. Valproic acid serum concentrations are also valuable tools to avoid adverse drug effects. Patients are more likely to accept drug therapy if adverse reactions are held to the absolute minimum. BASIC CLINICAL PHARMACOKINETIC PARAMETERS: BIOAVAILABILITY ❖The oral bioavailability of valproic acid is very good for all dosage forms and ranges from 90% for the extended-release tablets to 100% for the other oral dosage forms. Extended-release tablets produce an AUC that is about 10% less than other oral dosage forms, and drug serum concentrations should be measured for patients converted between extended-release and other oral dosage forms. ❖If a patient is stabilized on an oral valproic acid product, and it is necessary to switch the patient to intravenous drug, the same total daily dose of injectable valproic acid can be given to the individual. Usually, valproic acid doses are not fine tuned to the point of directly accounting for the difference in valproic acid bioavailability. Rather, clinicians are aware that when valproic acid dosage forms are changed, the serum concentration versus time profile may change. Because of this, most individuals recheck valproic acid steadystate serum concentrations after a dosage form change is instituted. BASIC CLINICAL PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION ❖Although lipid soluble by chemistry, V is restricted to 0.1 to 0.4 L/kg. ❖When standardized to body weight, V of VPA is higher in infants and young children because of lower protein binding, with reduced albumin content and altered body composition compared to adolescents and young adults. ❖Valproic acid volume of distribution is assumed to equal 0.15 L/kg for adults and 0.2 L/kg for children under 12 years of age. Thus, for an 80 kg adult patient, the estimated valproic volume of distribution would be 12 L: V = 0.15 L/kg * 80 kg = 12 L. ❖Patients with cirrhosis or renal failure may have larger volumes of distribution. Why? BASIC CLINICAL PHARMACOKINETIC PARAMETERS: CLEARANCE AND METABOLISM ❖Three main routes of metabolism produce about 10 to 20 metabolites for VPA, some purported to have CNS activity during long-term therapy. ❖Glucuronidation to VPA-glucuronide is responsible for 40% to 50% of the disposition of VPA, predominantly using UGT1A3 and UGT2B7. ❖Mitochondrial β-oxidation accounts for 30% to 40%, the cytochrome p450 system (mainly CYP2C9) a more minor 10% that produces hydroxylated metabolites and unsaturated moieties. ❖Clearances of VPA on monotherapy are within typical ranges of 10 to 25 mL/hr/kg in children with elimination half-lives ranging from 6 to 12 hours ❖Clearances of VPA on monotherapy are within typical ranges of 6 to 12 mL/kg/hr in adults with elimination half-lives ranging from 8 to 20 hours BASIC CLINICAL PHARMACOKINETIC PARAMETERS: CLEARANCE AND METABOLISM ❖The half-life may be shorter when protein binding is lower, depending on whether expansion of V offsets the increase in total Cl. ❖Larger clearance and shorter half-life are expected when enzyme-inducing co-medications are prescribed. ❖Increased intrinsic clearance of VPA is also recognized in traumatic brain injury. ❖Unfortunately, there is no good way to estimate the elimination characteristics of liver metabolized drugs using an endogenous marker of liver function in the same manner that serum creatinine and estimated creatinine clearance are used to estimate the elimination of agents that are renally eliminated. BASIC CLINICAL PHARMACOKINETIC PARAMETERS: CLEARANCE AND METABOLISM ❖Because of this, a patient is categorized according to the disease states and conditions that are known to change valproic acid clearance, and the clearance previously measured in these studies is used as an estimate of the current patient’s clearance. ❖For example, for a 70 kg adult patient with liver cirrhosis or acute hepatitis, valproic acid clearance would be assumed to equal 3-4 mL/h/kg: 70 kg * 3.5 mL/h/kg = 245 mL/h or 0.245 L/h. To produce the most conservative valproic acid doses in patients with multiple concurrent disease states or conditions that affect valproic acid pharmacokinetics, the disease state or condition with the smallest clearance should be used to compute doses. ❖This approach will avoid accidental overdosage as much as currently possible. aVolume of distribution may be increased in infants, elderly, liver and renal disease, hypoalbuminemia, or with displacers of VPA binding. is decreased in the elderly, neonates and infants, functional liver disease, drugs that impair intrinsic clearance, or compete for glucuronidation; presence of poor function allelic polymorphisms of CYP2C9 or UGT. cClearance may be increased in patients receiving co-therapy with enzyme-inducing antiepileptic agents or other drugs that induce p450 or glucuronidation, or in patients with polymorphisms imparting higher than normal metabolic enzymatic function. Free drug clearance may be decreased at higher VPA concentrations. Higher clearance is seen in patients with traumatic brain injury in the absence of liver impairment. dProtein binding is concentration dependent within the therapeutic range; the fraction unbound increases with higher VPA levels and with drugs and free fatty acids that displace VPA from albumin binding sites. Protein binding will be lower in disease states where poor synthesis (liver disease, malnutrition, elderly, critical illness) or increased losses (nephrotic syndrome, other renal diseases, protein-losing enteropathy, critical illness) of albumin exist. VPA, valproic acid. bClearance DRUG INTERACTIONS ❖Valproic acid is a potent inhibitor of hepatic drug metabolizing enzyme systems and glucuronidation and other antiepileptic drugs that have their clearance rates decreased and steady-state concentrations increased by valproic acid–related enzyme inhibition include clonazepam, carbamazepine, phenytoin, primidone, lamotrigine, and ethosuximide. ❖Valproic acid therapy also decreases the clearance and increases steady-state concentrations of other drugs including zidovudine, amitriptyline, and nortriptyline. ❖As a general rule, when valproic acid is added to a patient’s drug regimen, an adverse effect due to one of the other drugs must be considered as a possible drug interaction with valproic acid. DRUG INTERACTIONS ❖Additionally, other drugs can affect valproic acid clearance and steady-state serum concentrations. Phenytoin, lamotrigine, rifampin, and carbamazepine can increase valproic acid clearance and decrease valproic acid steady-state serum concentrations. ❖ Cimetidine, chlorpromazine, and felbamate are examples of drugs that decrease valproic acid clearance and increase valproic acid steady-state concentrations. ❖Carbapenem antibiotics decrease valproic acid concentrations to the extent that of loss of seizure control has occurred in some epileptic patients ❖Because valproic acid is highly protein bound, plasma protein–binding drug interactions can occur with other drugs that are highly bound to albumin. ❖Aspirin, warfarin, and phenytoin all have plasma protein–binding drug interactions with valproic acid, and these drugs have higher unbound fractions when given concurrently with valproic acid. THERAPEUTIC DRUG MONITORING ❖VPA levels are best obtained at steady-state for patients on maintenance therapy for epilepsy, to assure compliance and correlation with clinical benefit, and avoid potential concentration-related toxicities. ❖Repeat measurements of VPA levels should be done when toxicity occurs, when the dose is changed, when anticipated pharmacokinetic drug interactions exist, and when efficacy is lost. ❖Levels may also be obtained upon admission to the hospital for recurrence or breakthrough seizures, and after loading doses are given to assure achievement of the target concentration. THERAPEUTIC DRUG MONITORING ❖For practical purposes, if trough concentrations are monitored consistently in the individual patient, then the concentration to dose ratio is useful and can be compared on different doses, and the relationship between serum concentration and effectiveness can be accurately evaluated. ❖Unbound drug concentration measurement of VPA, using ultrafiltration methods, may be needed when correlation to effect or toxicity is elusive, or if liver or renal disease, traumatic brain injury, hypoalbuminemia, or protein binding displacement is present, and especially if a combination of bindingaltering factors exists. ❖Elevated unbound VPA Css may better reflect and predict neurotoxicity symptoms in patients with hypoalbuminemia when total VPA Css is within the therapeutic range. EXAMPLE 1 ❖KL is a 51 year-old, 75 kg male with tonic-clonic seizures who requires therapy with oral valproic acid. He has normal liver function and takes no medications that induce hepatic enzymes. ❖Suggest an initial valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration equal to 50 μg/mL. EXAMPLE 1 1. Estimate CL and VD according to disease states and conditions present in the patient ❖The clearance rate for an adult patient not taking other drugs that induce hepatic drug metabolism is 6-12 mL/h/kg. ❖Using a value of 10 mL/h/kg, the estimated clearance would equal 0.75 L/h: ❖Cl = 75 kg *10 mL/h/kg = 750 mL/h or 0.75 L/h. ❖Using 0.15 L/kg, the estimated volume of distribution would be 11 L: 75 kg *0.15 L/kg = 11 L. 2. Estimate half-life and elimination rate constant. ❖Once the clearance and volume of distribution estimates are identified for the patient, they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0.693 • V)/Cl = (0.693 • 11 L)/0.75 L/h = 10 h, k = 0.693/t1/2 = 0.693/10 h = 0.069/H EXAMPLE 1 ❖3. Compute dosage regimen. ❖Oral enteric-coated divalproex sodium tablets will be prescribed to this patient (F = 1). ❖The dosage equation for oral valproic acid is: ❖D = (Css * Cl * τ)/F = (50 mg/L* 0.75 L/h * 12 h)/1 = 450 mg, rounded to 500 every 12 hours. ❖A steady-state trough valproic acid serum concentration should be measured after steady-state is attained in 3-5 half-lives. ❖Since the patient is expected to have a half-life equal to 10 hours, the valproic acid steady-state concentration could be obtained any time after the second day of dosing (5 half-lives= 5 * 10 h = 50 h). Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. EXAMPLE 2 ❖UO is a 10-year old, 40-kg male with absence seizures who requires therapy with oral valproic acid. He has normal liver function and currently takes carbamazepine. Suggest an initial valproic acid dosage regimen designed to achieve a steady-state valproic acid concentration equal to 50 mcg/mL. EXAMPLE 2 ❖1. Estimate CL and VD according to disease states and conditions present in the patient. Using a value of 25 mL/h/kg, the estimated clearance would equal 1 L/h: Cl = 40 kg*25 mL/h/kg = 1000 mL/h or 1 L/h. Using 0.2 L/kg, the estimated volume of distribution would be 8 L: 40 kg * 0.2 L/kg = 8 L. ❖2. Estimate half-life and elimination rate constant. ❖Once the correct clearance and volume of distribution estimates are identified for the patient, they can be converted into the valproic acid half-life (t1/2) and elimination rate constant (k) estimates using the following equations: t1/2 = (0.693 • V)/Cl = (0.693*8 L)/1 L/h = 6 h, k = 0.693/t1/2 =0.693/6 h = 0.116/h. EXAMPLE 2 ❖3. Compute dosage regimen. ❖Oral valproic acid syrup will be prescribed to this patient (F = 1). ❖The dosage equation for oral valproic acid is: D = (Css * Cl * τ)/F = (50 mg/L*1 L/h * 8 h)/1 = 400 mg, or 400 mg every 8 h. ❖A steady-state trough valproic acid serum concentration should be measured after steadystate is attained in 3-5 half-lives. ❖Since the patient is expected to have a half-life equal to 6 hours, the valproic acid steadystate concentration could be obtained any time after the first day of dosing (5 half-lives = 5*6 h = 30 h). Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. PSEUDOLINEAR PHARMACOKINETICS METHOD ❖A simple, easy way to approximate new total serum concentrations after a dosage adjustment with valproic acid is to temporarily assume linear pharmacokinetics, then subtract 10%-20% for a dosage increase or add 10%-20% for a dosage decrease to account for nonlinear, concentration dependent plasma protein binding pharmacokinetics ❖Note: This method is only intended to provide a rough approximation of the resulting valproic acid total steady state concentration after an appropriate dosage adjustment has been made. Of course, as expected, unbound steady state concentrations increase or decrease in a linear fashion with dose EXAMPLE 3 ❖KL is a 51-year-old, 75-kg (5 ft 10 in) male with tonic-clonic seizures who requires therapy with oral valproic acid. After dosage titration, the patient was prescribed 500 mg every 12 hours of enteric-coated divalproex sodium tablets (1000 mg/d) for 1 month, and the steady-state valproic acid total concentration equals 38 μg/mL. What would be the expected concentration if the dose was increased to 2000 mg/day? EXAMPLE 3 ❖Using pseudolinear pharmacokinetics, the resulting total steady-state valproic acid serum concentration would equal D 2000 Cssnew = New ⋅ Cssold = ∗ 38 = 76 mg/d DOld 1000 ❖Because of nonlinear, concentration-dependent protein binding pharmacokinetics, the total steady-state serum concentration would be expected to be 10% less, or 0.90 times, to 20% less, or 0.80 times, than that predicted by linear pharmacokinetics: EXAMPLE 3 Css = 76 μg/mL * 0.90 = 68.4 μg/mL and Css = 76 μg/mL *0.80 = 60.8 μg/mL. ❖Thus, a dosage rate of 2000 mg/d would be expected to yield a total valproic acid steady-state serum concentration between 60.8–68.4 μg/mL. ❖A steady-state trough total valproic acid serum concentration should be measured after steady-state is attained in 1-2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. EXAMPLE 4 ❖UO is a 10 year old, 40 kg male with absence seizures who requires therapy with oral valproic acid. He has normal liver function. After dosage titration, the patient was prescribed 400 mg three times daily (1200 mg/d) of valproic acid syrup for 1 month, and the steadystate valproic acid total concentration equals 130 μg/mL. The patient is assessed to be compliant with his dosage regimen. If the dose is changed to 250 mg three times daily. Predict the new concentration at steady state. EXAMPLE 4 ❖Using pseudolinear pharmacokinetics, the resulting total steady-state valproic acid serum concentration would equal DNew 750 Cssnew = ⋅ Cssold = ∗ 130 = 81.25 mg/d DOld 1200 ❖Because of nonlinear, concentration-dependent protein binding pharmacokinetics, the total steady-state serum concentration would be expected to be 10% more, or 1.1 times, to 20% more, or 1.2 times, than that predicted by linear pharmacokinetics: EXAMPLE 4 Css = 81.25 μg/mL *1.1= 89.4 μg/mL and Css = 81.25 μg/mL *1.2= 97.5 μg/mL. ❖Thus, a dosage rate of 2000 mg/d would be expected to yield a total valproic acid steady-state serum concentration between 89.4–97.5 μg/mL. ❖A steady-state trough total valproic acid serum concentration should be measured after steady-state is attained in 1-2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. EXAMPLE 5 ❖B.I. has his seizures controlled while in the intensive care unit on a dose of VPA of 500 mg every 8 hours, but spikes a fever and has an elevated neutrophil count. He has a history of documented urinary tract infections, with extended-spectrum β-lactamases producing Escherichia coli is placed on meropenem 1,000 mg every 8 hours on suspicion of recurrence. Two days later, he has a breakthrough tonic–clonic seizure, and a stat mid-interval VPA level comes back at 25 mg/L. All of the doses are checked, and another serum sample is sent for verification, and it results as 19 mg/L. A 1,000 mg loading dose is given, and the maintenance dose is increased to 750 mg every 8 hours. The next morning, B.I. has another brief breakthrough seizure, and the VPA level sent is 25 mg/L. Rapid calculation demonstrates a clearance value that is not physiologically plausible. What accounts for the repeated low levels? EXAMPLE 5 ❖A major pathway of VPA metabolism is via glucuronidation, and deglucuronidation by hydrolysis may contribute active drug back into the circulation. The carbapenem antibiotics (e.g., imipenem, doripenem, meropenem) all feature inhibition of the VPA-glucuronidase enzyme acylpeptide hydrolase, located in the cytosol of the liver and kidney, which blocks the deglucuronidation of VPA and enhances the urinary elimination of VPA-glucuronide. ❖This increases the apparent clearance dramatically, and VPA levels fall more than 50%, even for increased dosing, hence precipitating seizures in those vulnerable to breakthrough. Even increases in dose may not sustain a therapeutic level or outcome, and other antimicrobials, susceptibility permitting, or additional AEDs may be required. EXAMPLE 5 ❖Despite the relatively short half-lives of the carbapenems, the effect on blocking deglucuronidation lasts for several days, and levels may take a week or more to return to pre-carbapenem values. ❖Meropenem and ertapenem show greater decreases in VPA levels in patients than with imipenem. ❖Care must be taken to reduce the dose of VPA back to the baseline VPA doses that had been significantly raised in an attempt to obtain therapeutic concentrations, because once the interaction reverses, the VPA levels may rise dramatically to levels promoting toxicity. ❖Perhaps more concerning is the convenient use of parenteral meropenem to treat various community infections in the nonhospital setting, thereby increasing the risk of breakthrough seizure activity in a less monitored location. EXAMPLE 6 ❖B.I.’s seizures are eventually controlled on a regimen of depakote delayedrelease tablets of 500 mg orally every 8 hours, with a steady-state trough concentration of 50 mg/L. He is diagnosed with depression, and fluoxetine is added to his regimen. He is seen in clinic a month later, and it is noted that his nutrition has been poor and that he has lost 7 kg. His depression is slightly improved, but a noticeable tremor of his right hand is present, and he is sleepy during the day. His labs show that his albumin is low at 2.8 g/dL, his ammonia level has risen to 98 µmol/L, and his follow-up trough VPA level is now 70 mg/L. What assessment can be made regarding any changes in the pharmacokinetics of VPA and associated toxicity findings? EXAMPLE 6 ❖B.I.’s VPA revised Cl can be calculated from the trough level. Because the time to maximum concentrations (Tmax) with the delayed-release tablets is approximately 8 hours, the fluctuation in between peak and trough concentrations with every 8hour dosing is minimal, and, therefore, the trough concentration can be considered an average steady state. The revised clearance before adding fluoxetine can then be calculated using the following equation: S∗F∗X0 500 𝐿 ❖CL = = = 1.25 𝐶𝑠𝑠𝑎𝑣𝑔∗𝜏 50∗8 ℎ ❖The revised clearance after adding fluoxetine: S∗F∗X0 500 𝐿 ❖CL = = = 0.89 𝐶𝑠𝑠𝑎𝑣𝑔∗𝜏 70∗8 ℎ EXAMPLE 6 ❖With the 40% increase in steady-state blood level to 70 mg/L, B.I.’s VPA clearance is reduced to 0.893 L/hr, or 11.90 mL/hr/kg, a decrease of 28.6%. ❖Fluoxetine can moderately inhibit CYP2C9 metabolism, an important pathway in the metabolism of VPA, thus limiting its intrinsic clearance. ❖However, the total concentration measured is not outside the therapeutic range, or consistent with levels that dose-related toxicities, although individual sensitivities should be clinically considered. Concentration-dependent protein binding is evident within the therapeutic range, and considering that the hypoalbuminemia is present in BI, an assessment of the free concentration given reduced binding capacity may be useful in sorting out these apparent concentration-related toxicities. EXAMPLE 6 ❖There are a number of equations and graphic relationships that illustrate the nonlinearity of the relationship between free and total (free + bound) concentrations. A simple linearized version of this nonlinear relationship is given in the following equation: ❖Fraction unbound= 0.0015*Ctotal ➔ 0.0015*70=0.105= 10.5% ❖Free concentration= Total concentration*Fu =70*0.105 ➔ 7.35 mg/L ❖The therapeutic range of free VPA is 2.5 to 10 mg/L (based on the normal fu of 0.05 to 0.1). EXAMPLE 6 ❖With B.I.’s hypoalbuminemia, the free fraction is increased when the binding capacity (i.e., albumin concentration) diminishes. For total VPA concentrations less that 75 mg/L, an accurate corrected level can be calculated using : ❖Percent free=130.2*e(-0.72*ALB), where ALB is the albumin concentration in g/dL. ❖Percent free=130.2*e(-0.72*2.8)=17.34% ❖Free concentration=Total concentration * free fraction=70*0.1734=12.14 mg/L ❖For B.I. at an albumin concentration of 2.8 g/dL, the percent free is estimated to be 17.34%, and, therefore, the free concentration = 0.1734 × 70 mg/L = 12.14 mg/L, which exceeds the therapeutic range for free drug, and can explain the adverse effects seen in this patient.