Clinical Pharmacokinetics of Carbamazepine Dr. Muslim Suardi Faculty of Pharmacy University of Andalas 2013

Carbamazepine Partial or secondarily generalized seizures An iminostilbene derivative related to the tricyclic antidepressants that is used in the treatment of: Tonic-clonic (grand mal) Partial or secondarily generalized seizures

THERAPEUTIC & TOXIC CONCENTRATIONS Therapeutic range for CAR is 4–12 µg/mL for the treatment of seizures. CAR plasma protein binding (PPB) is quite variable among individuals because it is bound to both albumin & α1-acid glycoprotein (AGP). In normal patients, PPB is 75–80%, free fraction of drug of 20–25%.

CLINICAL MONITORING PARAMETERS Goal of anticonvulsants therapy is to reduce seizure frequency & maximize quality of life with a minimum of ADR. While it is desirable to entirely abolish all seizure episodes, it may not be possible to accomplish this in many patients.

CLINICAL MONITORING Patients should be monitored for conc-related side effects: Nausea, vomiting, lethargy, dizziness, Drowsiness, headache, blurred vision, Diplopia, unsteadiness, ataxia, Incoordination)

BASIC CLINICAL Pk PARAMETERS CAR is primarily eliminated by hepatic metabolism (99%) mainly via the CYP3A4 enzyme system. Altogether metabolites have been identified with CAR- 10, 11-epoxide being the major species. Epoxide metabolite is active & probably contributes to both the therapeutic & toxic side effects observed during therapy.

EFFECTS OF DISEASE STATES & CONDITIONS ON Pk & DOSING

DRUG INTERACTIONS CAR is a potent inducer of hepatic drug metabolizing enzyme systems Other antiepileptic drugs that have their Cl increased & Css decreased by CAR-related enzyme induction include: Felbamate, lamotrigine, PHENY, primidone, VAL Tiagabine, topiramate

DRUG INTERACTIONS CAR increases the Cl & decreases Css of many other drugs including: Oral contraceptives, Calcium channel blockers, Tricyclic antidepressants, Cyclosporin, Tacrolimus, Theophylline, Warfarin.

DRUG INTERACTIONS CAR Cl & CAR Css: PHENY & PHENO CAR CL & CAR Css: Cimetidine, macrolide antibiotics, azole antifungals, fluoxetine, fluvoxamine, nefazodone, cyclosporine, diltiazem, verapamil, indinavir, & ritonavir

DRUG INTERACTIONS Adm of single doses of CAR with grapefruit juice both AUC & Cmax of CAR by about 40%. Adm of single doses of CAR with grapefruit juice both AUC & Cmax of CAR by about 40%.

INITIAL DOSAGE DETERMINATION METHODS A simple partial seizures, LK, 51yo, 75-kg (5 ft 10 in) male who requires therapy with oral CAR. Normal liver function. Suggest an initial CAR dosage regimen designed to achieve a CAR Css equal to 6–8µg/mL.

Estimate CARBAMAZEPINE Dose According to Disease States & Condition Present in the Patient. The suggested initial dosage rate for immediate-release CAR tablets in an adult patient is 200 mg 2X daily (400 mg/d). This dose would be titrated upward in 200-mg increments every 2–3 weeks while monitoring for adverse & therapeutic effects.

Continued CAR Csr should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of CAR toxicity.

Continued The goal of therapy includes maximal suppression of seizures, avoidance of side effects, & a target drug range of 800–1200 mg/d. A SS trough total CAR Csr should be measured after SS is achieved in 2–3 weeks at the highest dosage rate attained.