Source: Health Products Regulatory Authority (ZA) Publisher: Strides Pharma SA (Pty) Ltd, 106 16<sup>th</sup> Road, Building 2, Midrand, 1685, South Africa
Pharmacological classification: A 2.5 Central nervous system depressants -Anticonvulsants, including anti-epileptics
Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics
ATC code: N03AX16
The active substance, pregabalin, is a gamma-aminobutyric acid (GABA) analogue ((S)3(aminomethyl)-5-methylhexanoic acid).
Pregabalin binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin has not been fully elucidated, results from animal studies suggest that binding to the alpha2-delta subunit may be involved in pregabalin’s anti-nociceptive effects.
While pregabalin is a structural derivative of the inhibitory neurotransmitter gammaaminobutyric acid (GABA), it does not bind directly to GABAA, GABAB, or benzodiazepine receptors, does not augment GABAA responses in cultured neurons, does not alter rat brain GABA concentration or have acute effects on GABA uptake or degradation. Pregabalin prevents pain-related behaviours in animal models of neuropathic and post-surgical pain, including hyperalgesia and allodynia.
Following oral administration of pregabalin capsules under fasting conditions, peak plasma concentrations occur within 1 hour. 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 relevant effect on the total absorption of pregabalin. Therefore, pregabalin can be taken with or without food.
Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0,56 L/kg. Pregabalin is a substrate for system L transporter which is responsible for the transport of large amino acids across the blood brain barrier. Although there are no data in humans, pregabalin has been shown to cross the blood brain barrier in animal studies. In addition, pregabalin has been shown to cross the placenta in rats and is present in the milk of lactating rats.
Pregabalin undergoes negligible metabolism in humans. Following a dose of radiolabelled pregabalin, approximately 98% of the radioactivity recovered in the urine as unchanged pregabalin. The N-methylated derivative of pregabalin, the major metabolite of pregabalin found in urine, accounted for 0,9% of the dose. In preclinical studies, Pregabalin (Senantiomer) did not undergo racemisation to the R-enantiomer.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged medicine with a mean elimination half-life of 6,3 hours. Pregabalin elimination is nearly proportional to creatinine clearance. Dosage adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see section 4.2).
Pregabalin pharmacokinetics are linear over the recommended daily dosage range. Intersubject pharmacokinetic variability for pregabalin is low (<20%). Multiple dose pharmacokinetics are predictable from single-dose data. There is therefore no need for routine plasma concentrations monitoring of pregabalin.
Studies have shown that 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, dose reduction in patients with renal impairment and dosage supplementation following haemodialysis is necessary (see section 4.2).
There have been no specific pharmacokinetic studies conducted in patients with hepatic impairment. Pregabalin is predominantly excreted unchanged in the urine by renal elimination, and it is therefore unlikely that hepatic impairment will have significant effects on pregabalin plasma concentrations.
Pregabalin clearance tends to decrease with increasing age. This decrease in pregabalin 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).
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