Pharmacotherapeutic Group: Antiepileptics, other antiepileptics. ATC Code: N03AX16.
Pharmacology: The active substance, pregabalin, is a gamma-aminobutyric acid analogue [(S)-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.
Evidence from animal models with nerve damage has shown that pregabalin reduces calcium dependent release of pro-nociceptive neurotransmitters in the spinal cord possibly by disrupting calcium trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage suggests the antinociceptive activities of pregabalin may also be mediated through interactions with the descending noradrenergic and serotonergic pathways.
Pharmacokinetics: Pregabalin steady-state pharmacokinetics are similar in all patient groups.
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: Pregabalin has been shown to cross the blood brain barrier in mice, rats, and monkeys. Pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats. 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. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0.9% of the dose. There was no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.
Elimination: Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug. Pregabalin mean elimination half-life is 6.3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see Pharmacology: Pharmacokinetics: Renal impairment as follows). Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see Table 1 under Dosage & Administration).
Linearity/non-linearity: Pregabalin pharmacokinetics are linear over the recommended daily dose range. Inter-subject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. Therefore, there is no need for routine monitoring of plasma concentrations of pregabalin.
Pharmacokinetics in special patient groups: 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 (see Table 1 under Dosage & Administration).
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.
Older people (over 65 years of age): 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 (see Table 1 under Dosage & Administration).