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Pharmacology: Pharmacodynamics: The active substance, pregabalin, is a gamma=aminobutyric acid analogue [(5)-3-(aminomethyl)-5-methylhexanoic acid].
Mechanism of action: Pregabalin binds to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system.
Clinical efficacy and safety: Neuropathic pain: Efficacy has been shown in diabetic neuropathy, post herpetic neuralgia and spinal cord injury. Efficacy has not been studied in other models of neuropathic pain.
Epilepsy: Adjunctive Treatment: Pregabalin has been studied with either BID or TID dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens are similar. A reduction in seizure frequency was observed by Week 1.
Paediatric population: The efficacy and safety of pregabalin as adjunctive treatment for epilepsy in paediatric patients below the age of 12 and adolescents has not been established.
Monotherapy (newly diagnosed patients): Pregabalin and lamotrigine were similarly safe and well tolerated.
Generalised Anxiety Disorder: Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) has been observed.
Pharmacokinetics: Pregabalin steady-state pharmacokinetics are similar in healthy volunteers, patients with epilepsy receiving anti-epileptic drugs and patients with chronic pain.
Absorption: Pregabalin is rapidly absorbed when administered in the fasted state, with peak plasma concentrations occurring within 1 hour following both single and multiple dose administration. Pregabalin oral bioavailability is estimated to be ≥90% and is independent of dose. Following repeated administration, steady state is achieved within 24 to 48 hours. The rate of pregabalin absorption is decreased when given with food resulting in a decrease in Cmax by approximately 25-30% and a delay in tmax to approximately 2.5 hours. However, administration of pregabalin with food has no clinically significant effect on the extent of pregabalin absorption.
Distribution: In humans, the apparent volume of distribution of pregabalin following oral administration is approximately 0.56 l/kg. Pregabalin is not bound to plasma proteins.
Biotransformation: Pregabalin undergoes negligible metabolism in humans.
Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug.
Pregabalin mean elimination half-life is 6.3 hrs. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance. Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary.
Linearity/non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
Gender: Gender does not have a clinically significant influence on the plasma concentrations of pregabalin.
Renal Impairment: Pregabalin clearance is directly proportional to creatinine clearance. In addition, pregabalin is effectively removed from plasma by haemodialysis (following a 4 hour haemodialysis treatment plasma pregabalin concentrations are reduced by approximately 50%). Because renal elimination is the major elimination pathway, dose reduction in patients with renal impairment and dose supplementation following haemodialysis is necessary.
Hepatic Impairment: Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
Paediatric population: After oral administration of pregabalin in pediatric patients in the fasted state, in general, time to reach peak plasma concentration was similar across the entire age group and occurred 0.5 hours to 2 hours post dose.
Pregabalin Cmax and AUC parameters increased in a linear manner with increasing dose within each age group. The AUC was lower by 30% in paediatric patients below a weight of 30 kg due to an increased body weight adjusted clearance of 43% for these patients in comparison to patients weighing ≥30 kg.
Pregabalin terminal half-life averaged about 3 to 4 hours in paediatric patients up to 6 years of age, and 4 to 6 hours in those 7 years of age and older.
Population pharmacokinetic analysis showed that creatinine clearance was a significant covariate of pregabalin oral clearance, body weight was a significant covariate of pregabalin apparent oral volume of distribution, and these relationships were similar in paediatric and adult patients.
Elderly: Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with decreases in creatinine clearance associated with increasing age. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function.
Breast-feeding mothers: Lactation had little to no influence on pregabalin pharmacokinetics.
Pregabalin was excreted into breast milk with average steady-state concentrations approximately 76% of those in maternal plasma. The estimated infant dose from breast milk (assuming mean milk consumption of 150 ml/kg/day) of women receiving 300 mg/day or the maximum dose of 600 mg/day would be 0.31 or 0.62 mg/kg/day, respectively. These estimated doses are approximately 7% of the total daily maternal dose on a mg/kg basis.
