Source: Health Products Regulatory Authority (ZA) Revision Year: 2023 Publisher: Forrester Pharma (Pty) Ltd, 2 Waterford Mews, Waterford Place, Century City, 7441, Cape Town, South Africa
A 2.5 Central nervous system depressants: Anticonvulsants, including anti-epileptics
Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics
ATC code: N03AX16
Pregabalin is a gamma-aminobutyric acid (GABA) analogue ((S)3(aminomethyl)-5-methylhexanoic acid).
Pregabalin binds, in vitro, to an auxiliary subunit (α2-δ protein) of voltage-gated calcium channels in the central nervous system, potently displacing [3H]gabapentin. In animal models it was shown that binding of pregabalin to the α2δ site is required for analgesic activity. In addition, pregabalin reduces the release of several neurotransmitters, including glutamate, noradrenaline and substance P. The significance of these effects for the clinical pharmacology of pregabalin is not known.
Pregabalin does not interact with either GABAA or GABAB receptors; it is not converted metabolically into GABA or a GABA agonist; it is not an inhibitor of GABA uptake or degradation. Pregabalin prevents pain-related behaviours of neuropathic and postsurgical pain, including hyperalgesia and allodynia.
Pregabalin is 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.
In animals, pregabalin crosses the blood brain barrier and the placenta, and is present in breast milk. 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.
Pregabalin undergoes negligible metabolism. Following a dose of radio-labelled 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 is no indication of racemisation of pregabalin S-enantiomer to the R-enantiomer.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged medicine. Pregabalin mean elimination half-life is 6,3 hours. Pregabalin plasma clearance and renal clearance are directly proportional to creatinine clearance (see Special patient groups, Renal impairment). Dosage adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see section 4.2, Table 1).
Pregabalin pharmacokinetics are linear over the recommended daily dose range. Intersubject 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.
Gender does not have a clinically significant influence on the plasma concentrations of pregabalin.
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, dosage reduction in patients with renal impairment and dosage supplementation following haemodialysis are necessary (see section 4.2, Table 1).
No specific pharmacokinetic studies were carried out in patients with impaired liver function. Since pregabalin does not undergo significant metabolism and is excreted predominantly as unchanged medicine in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.
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 section 4.2, Table 1).
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