Transcript Clinical Pharmacokinetics of Carbamazepine

Clinical Pharmacokinetics
of Carbamazepine
Dr. Muslim Suardi
Faculty of Pharmacy
University of Andalas
2013
Carbamazepine
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 concrelated 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 CARrelated 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 200mg 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.