Carbamazepine

CARBAMAZEPINE INTRODUCTION ❖Carbamazepine is an anticonvulsant compound that is structurally similar to the tricyclic antidepressant agents. ❖ It blocks voltage-dependent sodium channels and is used for the treatment of trigeminal neuralgia, and is used in the treatment of a variety of seizure disorders. ❖It has the Food and Drug Administration (FDA) approval for generalized tonic– clonic (grand mal) and partial (psychomotor, temporal lobe) seizures, bipolar disorders. ❖Carbamazepine is most frequently prescribed for those patients who have failed to respond to other anticonvulsant therapy or for those who have developed significant side effects from other anticonvulsant agents. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖The accepted therapeutic range for carbamazepine is 4-12 mcg/mL when the drug is used for the treatment of seizures. ❖Many patients will develop symptoms of toxicity, including cardiovascular toxicity, such as second- and third-degree heart block, when plasma concentrations exceed 10 mg/L. For this reason, many clinicians prefer to use a therapeutic range of approximately 4 to 8 mg/L, especially in patients on other anticonvulsants. ❖Carbamazepine10, 11epoxide is an active metabolite of carbamazepine that contributes to both the therapeutic and toxic effects of the drug, and can be measured in serum samples at a limited number of epilepsy centers. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Epoxide concentrations tend to be higher in patients taking enzyme inducers and lower in patients taking enzyme inhibitors. The clinician should be aware of conditions that can increase the formation of the 10,11-epoxide such as simultaneous administration of phenytoin, and valproate sodium. ❖The percent of epoxide to parent drug in chronically treated patients averages about 12% for carbamazepine monotherapy, 14% when carbamazepine is taken with phenobarbital, 18% when carbamazepine is taken with phenytoin, and about 25% when carbamazepine is taken with both phenytoin and phenobarbital. ❖In most patients, the carbamazepine to its major metabolite (10,11-epoxide) ratio is relatively constant with serum concentrations of the epoxide metabolite ranging from 15% to 40% of carbamazepine. BASIC CLINICAL PHARMACOKINETIC PARAMETERS ❖In some patients, such as in overdose situations when protein binding is saturated, it might be useful to monitor total carbamazepine and the 10,11-epoxide metabolite because serum concentrations will significantly increase to 50% to 80% of the carbamazepine concentration. ❖In the upper end of the therapeutic range (>8 μg/mL) some patients will begin to experience the concentration related adverse effects of carbamazepine treatment: nausea, vomiting, lethargy, dizziness, drowsiness, headache, blurred vision, diplopia, unsteadiness, ataxia, incoordination. ❖To improve patient acceptance, it is important to initiate and titrate carbamazepine doses at a slow rate to minimize side effects. THERAPEUTIC AND TOXIC CONCENTRATIONS ❖Clinicians should understand that all patients with “toxic” carbamazepine serum concentrations in the listed ranges will not exhibit signs or symptoms of carbamazepine toxicity. Rather, carbamazepine concentrations in the ranges given increase the likelihood that an adverse drug effect will occur. ❖Carbamazepine 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. Carbamazepine serum concentrations are also valuable tools to avoid adverse drug effects ❖Because carbamazepine induces its own hepatic metabolism, it is fairly easy to attain toxic concentrations with modest increases in drug dose before maximal enzyme induction has occurred. DOSAGE FORMS ❖An injectable form of carbamazepine is not available for clinical use. ❖For oral use, the drug is available as immediate release tablets (chewable: 100 mg, regular: 200 mg) ❖Extended release tablets (100, 200, 400 mg), extended release capsules (100, 200, 300 mg), and suspension (100 mg/5 mL). ❖The rapid release dosage forms are erratically absorbed from the gastrointestinal tract resulting in peak concentrations between 2 and 24 hours after a single dose of tablets (average 6 hours). PHARMACOKINETIC PARAMETERS: BIOAVAILABILITY ❖Carbamazepine is a lipid-soluble compound that is slowly and variably absorbed from the gastrointestinal tract. ❖Grapefruit juice increases the bioavailability of carbamazepine by inhibiting CYP3A4 in the gut wall and in the liver. There is evidence that CYP induction/inhibition modulates drug transporter expression of P-glycoprotein, MRP2 (multidrug resistance protein 2), and MRP3 (multidrug resistance protein 3). ❖A high-fat meal has been shown to increase the rate of absorption and elevate the peak concentration while not changing the extent as measured by the area under the curve. PHARMACOKINETIC PARAMETERS: BIOAVAILABILITY ❖The absolute oral bioavailability of commercially available carbamazepine dosage forms for adult epileptics determined using an experimental intravenous injection for comparison is 0.78 ❖Because carbamazepine is slowly absorbed, changes in gastrointestinal function, especially those associated with rapid transit, could decrease its bioavailability and result in variable plasma concentrations of carbamazepine. ❖For clinical purposes, the authors assume the bioavailability factor (F) to be approximately 0.8 for carbamazepine when administered as the oral tablet, chewable tablet, or suspension. PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION AND PROTEIN BINDING ❖On average, the volume of distribution for carbamazepine is approximately 1.1 L/kg. ❖Carbamazepine, a neutral compound, is primarily bound to albumin and αlacid glycoprotein, and has a free fraction (α) of approximately 0.2 to 0.3. ❖ In uremic patients, increases in free carbamazepine concentrations may be seen. Although carbamazepine is bound to plasma proteins, there are very few clinical studies exploring alterations in plasma binding characteristics. ❖Certain stresses and disease states such as trauma, heart failure, and myocardial infarction. carbamazepine binding to AGP can be even larger resulting in an unbound fraction as low as 10%-15%. PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION AND PROTEIN BINDING ❖As an initial guide, 25% of the total carbamazepine therapeutic range has been used to establish a preliminary desirable range for unbound carbamazepine serum concentrations of 1-3 μg/mL. ❖Although carbamazepine is highly plasma protein bound, it is harder to displace this agent to the extent that a clinically important change in protein binding takes place. Generally speaking, a doubling in unbound fraction in the plasma is required to produce such an alteration. ❖As a result of this, the use of unbound carbamazepine serum concentrations are currently limited to those patients that have total concentrations within the therapeutic range but experience adverse effects usually seen at higher concentrations, or those patients that have total concentrations below the therapeutic range but have a therapeutic response usually observed at higher concentrations. PHARMACOKINETIC PARAMETERS: VOLUME OF DISTRIBUTION AND PROTEIN BINDING ❖Loading doses of carbamazepine are not commonly utilized because time must be allowed for concentrations to rise to steady state, because auto-induction alters the pharmacokinetics of carbamazepine. PHARMACOKINETIC PARAMETERS: CLEARANCE ❖Carbamazepine is eliminated almost exclusively by metabolism, with less than 2% of an oral dose being excreted remain unchanged in the urine. ❖Carbamazepine is metabolized in the liver by CYP3A4/5 isoenzymes and induces CYP1A2 (strong), CYP2B6 (moderate), CYP2C8/9 (strong), 2C19 (strong), and CYP 3A4 (strong) to accelerate the hepatic metabolism of other drugs. ❖The average clearance value appears to be approximately 0.064 L/kg/hr in adult patients who have received the drug chronically. ❖Data indicates gender and racial differences account for variability in carbamazepine clearance. Studies indicate that absolute clearance (L/hr/kg) was significantly lower in men as compared to women (0.039 vs. 0.049, p = 0.007) and in African-Americans as compared to Caucasians (0.039 vs. 0.048, p = 0.019). A majority of studies show that apparent CYP3A4 activity is higher in women (and children) PHARMACOKINETIC PARAMETERS: CLEARANCE ❖ In patients who are taking other enzymeinducing antiepileptic drugs concurrently (polytherapy), the clearance is increased to approximately 0.1 L/kg/hr. ❖ The induction of the same system as is used for metabolism is “auto-induction.” This leads to unique pharmacokinetic difficulties until steady-state conditions are reached. ❖ Carbamazepine also induces P-gp production. PHARMACOKINETIC PARAMETERS: CLEARANCE ❖Carbamazepine induces its own metabolism through time- and dose-dependent auto-induction. Therefore, the use of clearance values from single-dose studies is impractical in the calculation of a maintenance dose and may lead to errors. ❖The auto-induction of carbamazepine metabolism has many clinical implications. ❖Due to auto-induction patients cannot initially be placed on the dose of carbamazepine that will ultimately result in a safe and effective outcome. ❖At first, patients are started on ¼ to 1/3 of the desired maintenance dose. This exposes hepatic drug-metabolizing enzymes to carbamazepine and begins the induction process. AUTOINDUCTION ❖The dose is increased by a similar amount every 2-3 weeks until the total desired daily dose is ultimately given. This gradual exposure of carbamazepine allows liver enzyme induction and carbamazepine clearance increases to occur over a 6-12 week time period. ❖Therapeutic effect and steady-state carbamazepine serum concentrations can be assessed 2-3 weeks after the final dosage increase. ❖Autoinduction continues to occur in patients who are stabilized on a carbamazepine dose but require a dosage increase. AUTOINDUCTION ❖It appears that a 2-3 week time period is also needed under chronic dosing conditions for maximal autoinduction to occur after a dosage increase. The effects of autoinduction are reversible even when doses are held for as few as 6 days ❖After a few doses of carbamazepine, enough autoinduction has occurred that clearance increases, half-life decreases, and drug accumulation slows down. With additional exposure of liver tissue to carbamazepine, clearance continues to increase and half-life continues to shorten. As a result of these pharmacokinetic changes, carbamazepine concentrations decline and ultimately stabilize in accord with the new clearance and half-life values. Maximal autoinduction usually occurs 2-3 weeks after dosing commenced. Because of the autoinduction phenomenon, the ultimate desired maintenance dose cannot be started with the first dose. Additional autoinduction occurs with subsequent increases in dose. HALF-LIFE (T½) ❖Steady-state data suggest a half-life of approximately 15 hours in adult patients receiving carbamazepine monotherapy, and approximately 10 hours in patients receiving other enzyme-inducing antiepileptic drugs (e.g., phenytoin, phenobarbital) concurrently. ❖However, steady-state data suggest a half-life of approximately 15 hours in adult patients receiving carbamazepine monotherapy, and approximately 10 hours in patients receiving other enzyme-inducing antiepileptic drugs (e.g., phenytoin, phenobarbital) concurrently. ❖Children metabolize carbamazepine more rapidly than adults do with reported steady-state half-lives of 4 to 12 hours. EFFECTS OF DISEASE STATES AND CONDITIONS ON PHARMACOKINETICS AND DOSING ❖Patients with liver cirrhosis or acute hepatitis have reduced carbamazepine clearance because of destruction of liver parenchyma. This loss of functional hepatic cells reduces the amount of CYP3A4 available to metabolize the drug and decreases clearance. ❖The volume of distribution may be larger because of reduced plasma protein binding. ❖Protein binding may be reduced and unbound fraction maybe increased due to hypoalbuminemia and/or hyperbilirubinemia (especially albumin <3 g/dL and/or total bilirubin >2 mg/dL). However, the effects that liver disease has on carbamazepine pharmacokinetics are highly variable and difficult to accurately predict. It is possible for a patient with liver disease to have relatively normal or grossly abnormal carbamazepine clearance and volume of distribution. ❖ As an example, a liver disease patient who has relatively normal albumin and bilirubin concentrations can have a normal volume of distribution for carbamazepine. EFFECTS OF DISEASE STATES AND CONDITIONS ON PHARMACOKINETICS AND DOSING ❖An index of liver dysfunction can be gained by applying the Child-Pugh clinical classification system ❖A Child-Pugh score greater than 8 is grounds for a decrease of 25%-50% in the initial daily drug dose for carbamazepine. As in any patient with or without liver dysfunction, initial doses are meant as starting points for dosage titration based on patient response and avoidance of adverse effects. ❖Carbamazepine serum concentrations and the presence of adverse drug effects should be monitored frequently in patients with liver cirrhosis. EFFECTS OF DISEASE STATES AND CONDITIONS ON PHARMACOKINETICS AND DOSING ❖Elderly and younger epileptic patients have similar carbamazepine clearances. ❖ However, older patients may be more sensitive to the central nervous system adverse effects of carbamazepine, and a lower starting dose of 100 mg/d is often used in elderly patients to avoid these problems. ❖During the third trimester of pregnancy, oral clearance of carbamazepine may decrease and require dosage adjustment. ❖Doses of carbamazepine do not require adjustment for patients with renal failure, and the drug is not removed by dialysis. ❖Breast milk concentrations of carbamazepine are about 60% of concurrent serum concentrations. TIME TO SAMPLE ❖Obtaining carbamazepine plasma samples within the first few weeks of therapy may be useful to establish a relationship between carbamazepine concentration and a patient’s clinical response. ❖However, these data should be interpreted cautiously if one is attempting to predict the longterm relationship between a carbamazepine dosing regimen and plasma levels. ❖ Once steady state has been achieved, the time of sampling within a dosing interval is somewhat arbitrary given the long half-life and relatively short dosing interval for carbamazepine. It is important to establish a fixed relationship between drug intake and blood sampling. ❖The most sensible time to take routine samples is in the early morning (trough) before the first dose of medication is administered, or later in the day, prior to the next dose. Such samples will reflect the trough concentration and are comparable from day to day. INITIAL DOSAGE DETERMINATION ❖Children under 6 years of age 1. Initially 5mg/kg/d (at night) or 2.5mg/kg twice daily 2. Increased as necessary by 2.5 – 5mg/kg every 3 – 7 days 3. Usual maintenance dose 5mg/kg 2 – 3 times daily 4. Doses up to 20mg/kg daily have been ❖Children 6–12 years old 1. Initially 200 mg/d (divided in two doses) 2. This dose would be titrated upward in 100-mg increments every 2–3 weeks while monitoring for adverse and therapeutic effects 3. A target drug range of 400–800 mg/d. INITIAL DOSAGE DETERMINATION ❖Adults and Older Children >12 years old 1. Initially 400 mg/d (divided in two doses) 2. This dose would be titrated upward in 200-mg increments every 2–3 weeks while monitoring for adverse and therapeutic effects 3. A target drug range of 800–1200 mg/d. ❖If the patient has significant hepatic dysfunction (Child-Pugh score ≥8), maintenance doses prescribed using this method should be decreased by 25– 50% EXAMPLE 1 ❖KL is a 51 year-old, 75kg male with simple partial seizures who requires therapy with oral carbamazepine. He has normal liver function. Suggest an initial carbamazepine dosage regimen designed to achieve a steady-state carbamazepine concentration equal to 6-8 μg/mL. EXAMPLE 1 ❖The suggested initial dosage rate for immediate-release carbamazepine tablets in an adult patient is 200 mg twice daily (400 mg/d). This dose would be titrated upward in 200mg increments every 2-3 weeks while monitoring for adverse and therapeutic effects. The goal of therapy includes maximal suppression of seizures, avoidance of side effects, and a target drug range of 800-1200 mg/d. ❖A steady-state trough total carbamazepine serum concentration should be measured after steady-state is achieved in 2-3 weeks at the highest dosage rate attained. Carbamazepine 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 carbamazepine toxicity. EXAMPLE 2 ❖UO is a 10 year old, 40kg male with simple partial seizures who requires therapy with oral carbamazepine. He has normal liver function. Suggest an initial carbamazepine dosage regimen designed to achieve a steady-state carbamazepine concentration equal to 6-8 mcg/mL. EXAMPLE 2 ❖The suggested initial dosage rate for immediate release carbamazepine tablets for a child in this age range is 100 mg twice daily (200 mg/d). This dose would be titrated upward in 100mg increments every 2-3weeks while monitoring for adverse and therapeutic effects. The goal of therapy includes maximal suppression of seizures, avoidance of side effects, and a target drug range of 400800 mg/d. ❖A steady-state trough total carbamazepine serum concentration should be measured after steady-state is achieved in 2-3 weeks at the highest dosage rate attained. Carbamazepine 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 carbamazepine toxicity. EXAMPLE 3 ❖N.S., a 36-year-old, 60 kg female, is to be started on carbamazepine as an anticonvulsant agent. How would you initiate therapy? Explain your rationale. Estimate amount needed at steady state and then propose how to start the patient on therapy. Calculate a daily dose that will produce an average steady-state plasma concentration of approximately 6 mg/L. EXAMPLE 3 ❖Do not give a loading dose of carbamazepine because of auto-induction. ❖(S) is 1.0, bioavailability is assumed 0.8 and an average clearance value of 3.84 L/hr (0.064 L/kg/hr × 60 kg). ❖MD= Cssavg*CL*τ/S*F ➔ 3.84*6*24/0.8= 691.2 mg/day ❖This dose is that which would be required to achieve the steady-state level of 6 mg/L after auto-induction of carbamazepine metabolism had taken place. For this reason, N.S. should be started on a lower daily dose initially and increased at 1- to 2-week intervals based on her clinical response. The usual initial daily dose for adult patients is 200 by mouth twice daily, with increases of approximately 200 mg/day every 14 to 21 days. When discontinuing treatment, reduce the dose gradually to avoid the risk of seizure. EXAMPLE 4 ❖The decision is made to add valproic acid to attempt better control of the seizures. N.S. returns 2 weeks later to clinic. The patient complains that recently, she is sleepy and “feels funny.” A carbamazepine concentration is drawn and reported to be 9 mcg/mL. What is your explanation? ❖ANSWER: ❖Owing to the addition of valproic acid, a CYP3A4 enzyme inhibitor, the metabolism of carbamazepine is decreased which in turn increases carbamazepine serum concentrations as well as the carbamazepine 10,11-epoxide, which also has some activity. This leads to the increased serum concentration, and because the epoxide has activity, it can cause further sedation than was seen on the lower dose of carbamazepine. After serum levels have stabilized, the body may adjust to the higher level and her sleepiness will become less of a noticeable side effect. EXAMPLE 4 ❖In addition, valproic acid can inhibit the metabolism of carbamazepine via CYP3A4 and can displace carbamazepine from protein binding sites, thus increasing the free fraction of carbamazepine. ❖Valproic acid can increase the formation of the epoxide metabolite, which may also be picked up by the assay (about 7%) for carbamazepine. These factors can lead to an increase in carbamazepine’s serum concentration, which could result in side effects such as drowsiness. PSEUDOLINEAR PHARMACOKINETICS METHOD ❖A simple, easy way to approximate new total serum concentrations after a dosage adjustment with carbamazepine 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 autoinduction pharmacokinetics: ❖ Cssnew = (Dnew/Dold)Cssold, where Cssnew is the expected steady-state concentration from the new carbamazepine dose in mcg/mL, Cssold is the measured steady-state concentration from the old carbamazepine dose in mcg/mL, Dnew is the new carbamazepine dose to be prescribed in mg/d, and Dold is the currently prescribed carbamazepine dose in mg/d. ❖Note: This method is only intended to provide a rough approximation of the resulting carbamazepine steady-state concentration after an appropriate dosage adjustment, such as 100-200 mg/d, has been made. The Pseudolinear Pharmacokinetics method should never be used to compute a new dose based on measured and desired carbamazepine concentrations. EXAMPLE 4 ❖KL is a 51 year old, 75-kg male with simple partial seizures who requires therapy with oral carbamazepine. He has normal liver function. After dosage titration, the patient was prescribed 200 mg of carbamazepine tablets in the morning, 200 mg in the afternoon, and 400 mg at bedtime (800 mg/d) for 1 month, and the steadystate carbamazepine total concentration equals 3.8 μg/mL. The patient is assessed to be compliant with his dosage regimen. ❖Predict carbamazepine concentration following increasing the daily dose to 1000 mg/day EXAMPLE 4 ❖Using pseudolinear pharmacokinetics, the resulting total steadystate carbamazepine serum concentration would equal: ❖Cssnew = (Dnew/Dold)*Cssold = (1000/800)*3.8 μg/mL = 4.8 μg/mL. ❖Because of autoinduction pharmacokinetics, the serum concentration would be expected to increase 10% less, or 0.90 times, to 20%, or 0.80 times, less than that predicted by linear pharmacokinetics: Css = 4.8 μg/mL • 0.90 = 4.3 μg/mL and Css = 4.8 μg/mL • 0.80 = 3.8 μg/mL. Thus, a dosage increase of 200 mg/d would be expected to yield a total carbamazepine steadystate serum concentration between 3.8 and 4.3 μg/mL. ❖A steadystate trough total carbamazepine serum concentration should be measured after steadystate is attained in 2-3 weeks. Carbamazepine 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 carbamazepine toxicity. EXAMPLE 5 ❖UO is a 10 year-old, 40kg male with simple partial seizures who requires therapy with oral carbamazepine. He has normal liver function. After dosage titration, the patient was prescribed 200 mg of carbamazepine tablets three times daily (600 mg/d) for 1 month, and the steady-state carbamazepine total concentration equals 5.1 mcg/mL. ❖Predict carbamazepine concentration following increasing the daily dose to 800 mg/day EXAMPLE 5 ❖Using pseudolinear pharmacokinetics, the resulting total steady-state carbamazepine serum concentration would equal: ❖Cssnew = (Dnew/Dold)Cssold = (800 mg/d/600 mg/d) 5.1 μg/mL = 6.8 μg/mL. ❖Because of autoinduction pharmacokinetics, the serum concentration would be expected to increase 10% less, or 0.90 times, to 20%, or 0.80 times, less than that predicted by linear pharmacokinetics: Css = 6.8 μg/mL • 0.90 = 6.1 μg/mL and Css = 6.8 μg/mL • 0.80 = 5.4 μg/mL. Thus, a dosage increase of 200 mg/d would be expected to yield a total carbamazepine steady-state serum concentration between 5.4 and 6.1 μg/mL. ❖A steady-state trough total carbamazepine serum concentration should be measured after steady-state is attained in 2-3weeks. ❖Carbamazepine 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 carbamazepine toxicity.