TDM of drugs used in seizure disorders
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The document discusses therapeutic drug monitoring of carbamazepine, which is used to treat seizures. It provides the usual dosage ranges and therapeutic ranges for carbamazepine treatment. The pharmacokinetics of carbamazepine are described, including absorption, distribution, metabolism by CYP3A4, and excretion. Sampling times and techniques are outlined, along with dosing strategies and factors that influence carbamazepine levels like drug interactions and age.
![Dr.
Ramesh
Bhandari
DOSING STRATEGIES
Variability in the pharmacokinetic of carbamazepine makes dosage prediction
difficult.
According to NONMEM analysis following equation can be used alone or in
combination.
1. Cl/F (L/hr) = [(0.0134 X ABW) + 3.58]
2. If the patient is also receiving phenytoin, the Cl/F determined above is
multiplied by 1.42.
3. If the patient is also receiving phenobarbitone, the Cl/F determined above is
multiplied by 1.17.
4. If the patient is 70 years of age, the Cl/F determined above is multiplied by
0.749.](https://image.slidesharecdn.com/14-210527100553/85/TDM-of-drugs-used-in-seizure-disorders-11-320.jpg)
TDM of drugs used in seizure disorders
- 1. TDM OF DRUGS USED IN SEIZURE DISORDERS DR. RAMESH BHANDARI ASST. PROFESSOR DEPARTMENT OF PHARMACY PRACTICE KLE COLLEGE OF PHARMACY, BELAGAVI
- 2. Dr. Ramesh Bhandari TDM OF CARBAMAZEPINE The Food and Drug Administration (FDA) approved carbamazepine for the treatment of partial seizures with complex symptomology, generalized tonic-clonic seizures, and mixed seizure patterns in adults and children. It is also approved for the treatment of trigeminal and glossopharyngeal neuralgia in adults and may be useful in the treatment of other types of neuropathy. Originally, carbamazepine was marketed for the treatment of trigeminal neuralgia and was later found to be effective for the treatment of seizures. It is ineffective in absence or myoclonic seizures and can worsen or precipitate absence seizures.
- 3. Dr. Ramesh Bhandari USUAL DOSE RANGE Carbamazepine is unique in that it induces its own metabolism (autoinduction), which complicates dosing. Autoinduction takes approximately 3–5 weeks on a fixed dosing regimen. Note: Metabolism of carbamazepine is subject to enzyme induction and inhibition, the maintenance dosage will depend on presence or absence of other drugs that may induce or inhibit hepatic enzymes. Dosage form Age Groups Initial dose Maximum maintenance dose Oral Children <6 Yrs 10-20 mg/kg/day 35 mg/kg/day Children 6-12 Yrs 100 mg twice daily 1000 mg/day Children 12-15 Yrs 200 mg twice daily 1000 mg/day Adult >15 Yrs 200 mg twice daily 1600 mg/day
- 4. Dr. Ramesh Bhandari THERAPEUTIC RANGE 4-12 mg/L for treatment of seizures, psychiatric disorders and trigeminal neuralgia.
- 5. Dr. Ramesh Bhandari General pharmacokinetic parameters for Carbamazepine Absorption: Immediate release tablets: 85-90 % Oral suspension – 85-90 % Extended release tablets and capsule: 85-90 % Concurrent administration with food affects the rate but not the amount of absorption. Immediate release tablets, extended release tablets and the suspension should be administered with meal. linear relationship: 600-1400 mg/day Exhibit saturable absorption: >20 mg/kg
- 6. Dr. Ramesh Bhandari General pharmacokinetic parameters for Carbamazepine Distribution: Animal studies suggests that carbamazepine achieve higher concentration in organs of high blood flow (Eg: liver, kidney and brain). Carbamazepine rapidly crosses the placenta and accumulates in fetal tissues with higher concentration in liver and kidney than brain and lungs. The carbamazepine concentration in breast milk is about 25-60 % of the concentration in the mothers plasma.
- 7. Dr. Ramesh Bhandari General pharmacokinetic parameters for Carbamazepine Drug can be detected in CSF, Brain, Duodenal fluids, Bile and Saliva. Carbamazepine binds to albumin and alpha-1-acid glycoprotein. Binding in slightly less in neonates. Age Category Volume of Distribution (L/kg) Protein Binding (%) Neonates 1.5 65-70 Children 1.9 75 Adults >15 Yrs 0.6-2 75
- 8. Dr. Ramesh Bhandari General pharmacokinetic parameters for Carbamazepine Elimination: Carbamazepine doesn’t undergo first pass metabolism. It is metabolized by oxidation, hydroxylation, direct conjugation with glucuronic acid and sulphur conjugation pathways. Most important metabolite is 10, 11-epoxide which appears to be active and may contribute to the efficacy and toxicity of carbamazepine. CYP3A4 enzyme is responsible for catalysing 10,11-oxidation of carbamazepine in the human liver.
- 9. Dr. Ramesh Bhandari General pharmacokinetic parameters for Carbamazepine Excretion: The metabolites and small percentage of unchanged drug are excreted in urine(72%), feces (28%). Clearance of the 10,11-epoxide metabolite is higher than parent drug. Age Clearance (L/hr/kg) Children (Initial) 0.12-0.32 Children (Chronic dosing) 0.05-0.4 Adults >15 Yrs 0.01-0.03 (Initial) 0.05-0.1 (Chronic)
- 10. Dr. Ramesh Bhandari SAMPLING TIME AND TECHNIQUES Although drug can be detected in saliva and CSF but utility of these samples are limited but should be restricted to saliva sampling when blood sample cannot be obtained. Half life of carbamazepine is 25-43 hour with single dose and 6.1 hour with chronic fixed dosing. Sampling time for carbamazepine depends on the duration of treatment. Trough concentration measurement is an appropriate for the evaluation of efficacy and steady state concentration.
- 11. Dr. Ramesh Bhandari DOSING STRATEGIES Variability in the pharmacokinetic of carbamazepine makes dosage prediction difficult. According to NONMEM analysis following equation can be used alone or in combination. 1. Cl/F (L/hr) = [(0.0134 X ABW) + 3.58] 2. If the patient is also receiving phenytoin, the Cl/F determined above is multiplied by 1.42. 3. If the patient is also receiving phenobarbitone, the Cl/F determined above is multiplied by 1.17. 4. If the patient is 70 years of age, the Cl/F determined above is multiplied by 0.749.
- 12. Dr. Ramesh Bhandari PHARMACODYNAMIC MONITORING Concentration related efficacy: < 4 mg/L: Little therapeutic benefit 4-12 mg/L: Optimum therapeutic range for monotherapy > 9 mg/L: Possible side effects of nystagmus, diplopia, drowsiness and ataxia. > 12 mg/L: Side effects common
- 13. Dr. Ramesh Bhandari DRUG – DRUG INTERACTION Drugs that are inhibitors of the CYP3A4 isoenzyme will decrease the clearance of carbamazepine due to decreased metabolism. Carbamazepine is reported to be an inhibitor of CYP2C19 as it can increase concentrations of phenytoin, selegiline and clomipramine. Drugs that are inducers of the CYP450 system, will increase the clearance of carbamazepine due to enhanced metabolism.
- 14. Dr. Ramesh Bhandari DOSE ADJUSTMENT Adjust the dose proportionately according to the desired serum concentration. Linear Pharmacokinetic Methods: New Dose = New desired concentration Old concentration X Old Dose