Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Anti-epileptics, other anti-epileptics. ATC code: N03AX16 
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 (2- protein) of voltage-gated calcium channels in the central nervous system.
Clinical efficacy and safety

Neuropathic pain
Efficacy has been shown in trials in diabetic neuropathy, post herpetic neuralgia and spinal cord injury. Efficacy has not been studied in other models of neuropathic pain.


Pregabalin has been studied in 10 controlled clinical trials of up to 13 weeks with twice a day dosing (BID) and up to 8 weeks with three times a day (TID) dosing. Overall, the safety and efficacy profiles for BID and TID dosing regimens were similar.

In clinical trials up to 12 weeks for both peripheral and central neuropathic pain, a reduction in pain was seen by Week 1 and was maintained throughout the treatment period.

In controlled clinical trials in peripheral neuropathic pain 35% of the pregabalin treated patients and 18% of the patients on placebo had a 50% improvement in pain score. For patients not experiencing somnolence, such an improvement was observed in 33% of patients treated with pregabalin and 18% of patients on placebo. For patients who experienced somnolence the responder rates were 48% on pregabalin and 16% on placebo.

In the controlled clinical trial in central neuropathic pain 22% of the pregabalin treated patients and 7% of the patients on placebo had a 50% improvement in pain score.

Fibromyalgia
Pregabalin as monotherapy has been studied in 5 placebo-controlled studies, three of 12 weeks fixed dose duration, one of 7 weeks fixed dose duration and a 6 month study demonstrating long term efficacy. Pregabalin treatment in all fixed dose studies produced a significant reduction in pain associated with fibromyalgia at doses from 300 to 600 mg/day (BID).
In the three 12 week fixed dose studies, 40% of pregabalin treated patients experienced a 30% or more improvement in pain score versus 28% of the patients on placebo; 23% of treated patients experienced a 50% or more improvement in pain score versus 15% of the patients on placebo.

Pregabalin produced significantly superior global assessment scores via the Patient Global Impression of Change (PGIC) in the three 12 week fixed dose studies as compared to placebo treatment. (41% patients feeling very much or much improved on pregabalin versus 29% on placebo). As measured by Fibromyalgia Impact Questionnaire, (FIQ), pregabalin produced a statistically significant improvement in function versus placebo treatment in 2 out of the 3 fixed dose studies in which it was evaluated.

Pregabalin treatment produced significant improvements in patient reported sleep outcomes in the 4 fixed dose studies as measured by MOS-SS Sleep disturbance subscale (Medical Outcomes Study Sleep Scale), MOS-SS overall sleep problem index, and the daily sleep quality diary.

In the 6 month study, improvement in pain, global assessment (PGIC), function (FIQ total score) and sleep (MOS-SS Sleep disturbance subscale) were maintained for pregabalin treated patients for a significantly longer period compared to placebo.

Pregabalin 600 mg/day showed an additional improvement in patient reported sleep outcomes as compared to 300 and 450 mg/day; mean effects on pain, global assessment, and FIQ were similar at 450 and 600 mg/day, although the 600mg per day dose was less well tolerated.

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. The adverse events observed in a pharmacokinetic and tolerability study that enrolled patients from 3 months to 16 years of age (n=65) with partial onset seizures were similar to those observed in adults. Results of a 12-week placebo-controlled study of 295 paediatric patients aged 4 to 16 years and a 14-day placebo-controlled study of 175 paediatric patients aged 1 month to younger than 4 years of age performed to evaluate the efficacy and safety of pregabalin as adjunctive therapy for the treatment of partial onset seizures and two1 year open label safety studies in 54 and 431 paediatric patients respectively, from 3 months to 16 years of age with epilepsy indicate that the adverse events of pyrexia and upper respiratory infections were observed more frequently than in adult studies of patients with epilepsy (see sections 4.2, 4.8 and 5.2).

In the 12-week placebo-controlled study, paediatric patients (4 to 16 years of age) were assigned to pregabalin 2.5 mg/kg/day (maximum, 150 mg/day), pregabalin 10 mg/kg/day (maximum, 600 mg/day), or placebo. The percentage of subjects with at least a 50% reduction in partial onset seizures as compared to baseline was 40.6% of subjects treated with pregabalin 10 mg/kg/day (p=0.0068 versus placebo), 29.1% of subjects treated with pregabalin 2.5 mg/kg/day (p=0.2600 versus placebo) and 22.6% of those receiving placebo.

In the 14-day placebo-controlled study, paediatric patients (1 month to younger than 4 years of age) were assigned to pregabalin 7 mg/kg/day, pregabalin 14 mg/kg/day, or placebo. Median 24-hour seizure frequencies at baseline and at the final visit were 4.7 and 3.8 for pregabalin 7 mg/kg/day, 5.4 and 1.4 for pregabalin 14 mg/kg/day, and 2.9 and 2.3 for placebo, respectively. Pregabalin 14 mg/kg/day significantly reduced the log-transformed partial onset seizure frequency versus placebo (p=0.0223); pregabalin 7 mg/kg/day did not show improvement relative to placebo.

In a 12-week placebo-controlled study in subjects with Primary Generalized Tonic-Clonic (PGTC) seizures 219 subjects (aged 5 to 65 years, of which 66 were aged 5 to 16 years) were assigned to pregabalin 5 mg/kg/day (maximum 300 mg/day), 10 mg/kg/day (maximum 600 mg/day) or placebo as adjunctive therapy. The percentage of subjects with at least a 50% reduction in PGTC seizure rate was 41.3%, 38.9% and 41.7% for pregabalin 5 mg/kg/day, pregabalin 10 mg/kg/day and placebo respectively.

Generalised Anxiety Disorder
Pregabalin has been studied in 6 controlled trials of 4-6 week duration, an elderly study of 8 week duration and a long-term relapse prevention study with a double-blind relapse prevention phase of 6 months duration.

Relief of the symptoms of GAD as reflected by the Hamilton Anxiety Rating Scale (HAM-A) was observed by Week 1.

In controlled clinical trials (4-8 week duration) 52% of the pregabalin treated patients and 38% of the patients on placebo had at least a 50% improvement in HAM-A total score from baseline to endpoint.

In controlled trials, a higher proportion of patients treated with pregabalin reported blurred vision than did patients treated with placebo which resolved in a majority of cases with continued dosing. Ophthalmologic testing (including visual acuity testing, formal visual field testing and dilated funduscopic examination) was conducted in over 3600 patients within controlled clinical trials. In these patients, visual acuity was reduced in 6.5% of patients treated with pregabalin, and 4.8% of placebo-treated patients. Visual field changes were detected in 12.4% of pregabalin-treated, and 11.7% of placebo-treated patients. Funduscopic changes were observed in 1.7% of pregabalin-treated and 2.1% of placebo-treated patients.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties
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 preclinical studies, 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. In preclinical studies, 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 section 5.2 Renal impairment).

Dose adjustment in patients with reduced renal function or undergoing haemodialysis is necessary (see section 4.2 Table 1).



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.

Gender
Clinical trials indicate that 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 section 4.2 Table 1).

Hepatic impairment
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 drug in the urine, impaired liver function would not be expected to significantly alter pregabalin plasma concentrations.


Paediatric population
Pregabalin pharmacokinetics were evaluated in paediatric patients with epilepsy (age groups: 1 to 23 months, 2 to 6 years, 7 to 11 years and 12 to 16 years) at dose levels of 2.5, 5, 10 and 15 mg/kg/day in a pharmacokinetic and tolerability study.
After oral administration of pregabalin in paediatric 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 postdose.

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.
Pregabalin pharmacokinetics in patients younger than 3 months old have not been studied (see sections 4.2, 4.8 and 5.1).

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 (see section 4.2 Table 1).

Breast-feeding mothers
The pharmacokinetics of 150 mg pregabalin given every 12 hours (300 mg daily dose) was evaluated in 10 lactating women who were at least 12 weeks postpartum. 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.