12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
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 with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's anti-nociceptive and antiseizure effects in animals. In animal models of nerve damage, pregabalin has been shown to reduce calcium-dependent release of pro-nociceptive neurotransmitters in the spinal cord, possibly by disrupting alpha2-delta containing-calcium channel trafficking and/or reducing calcium currents. Evidence from other animal models of nerve damage and persistent pain suggest the anti-nociceptive activities of pregabalin may also be mediated through interactions with descending noradrenergic and serotonergic pathways originating from the brainstem that modulate pain transmission in the spinal cord.
While pregabalin is a structural derivative of the inhibitory neurotransmitter gamma-aminobutyric 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. However, in cultured neurons prolonged application of pregabalin increases the density of GABA transporter protein and increases the rate of functional GABA transport. Pregabalin does not block sodium channels, is not active at opiate receptors, and does not alter cyclooxygenase enzyme activity. It is inactive at serotonin and dopamine receptors and does not inhibit dopamine, serotonin, or noradrenaline reuptake.
LYRICA CR has linear pharmacokinetics with dose-proportional increases in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from 82.5–660 mg/day. Following repeated administration, steady state is achieved within approximately 48–72 hours.
LYRICA CR administered once daily following an evening meal has equivalent AUC and lower Cmax relative to a comparative dose of LYRICA administered without food twice daily (Table 5). Variability in Cmax and AUC for LYRICA CR is less than or equal to 25%.
|Note: Geometric mean (%CV) for AUC24, Cmax, Cmin; median (range) for Tmax.|
Abbreviations: AUC24=area under the curve over 24 hours; BID=every 12 hours; Cmax=peak concentrations; Cmin=minimum concentrations; N=Number of subjects ; Tmax=time to peak concentrations.
|Cmax (µg/mL)||2.0 (17)||3.2 (21)|
|Tmax (h)||8.0 (5.0 – 12.0)||0.7 (0.7 – 1.5)|
|AUC24 (µg∙h/mL)||29.4 (17)||31.5 (18)|
|Cmin (µg/mL)||0.44 (24)||0.59 (25)|
Pregabalin is absorbed from the small intestine and proximal colon. LYRICA CR absorption is linear and dose proportional.
The bioavailability of LYRICA CR is reduced if taken on an empty stomach. The AUC is approximately 30% lower when LYRICA CR is administered fasted relative to following an evening meal.
When LYRICA CR is administered following a 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) evening meal, peak plasma concentrations occur within approximately 8 to 10 hours and AUC is approximately 93% to 97% relative to a comparative dose of LYRICA. The rate and extent of LYRICA CR absorption is similar when administered following a 400 to 500 calorie, 30% fat or an 800 to 1000 calorie, 15%, 30%, or 50% fat evening meal.
When LYRICA CR is administered following an 800 to 1000 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal, peak plasma concentrations occur within approximately 12 hours and AUC is 99% relative to a comparative dose of LYRICA. AUC decreases approximately 13% to 25% when LYRICA CR is administered following a 400 to 500 calorie or 600 to 750 calorie (50% carbohydrates, 20% protein, 30% fat) morning meal relative to the 800 to 1000 calorie meal, while Cmax remains the same.
Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 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 mice, rats, and monkeys. 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 radiolabeled pregabalin, approximately 90% of the administered dose was 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 (S-enantiomer) did not undergo racemization to the R-enantiomer in mice, rats, rabbits, or monkeys.
Pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged drug with a mean elimination half-life of 6.3 hours in subjects with normal renal function. Mean renal clearance was estimated to be 67.0 to 80.9 mL/min in young healthy subjects. Because pregabalin is not bound to plasma proteins this clearance rate indicates that renal tubular reabsorption is involved. Pregabalin elimination is nearly proportional to CLcr [see Dosage and Administration (2.5)].
Age: Geriatric Patients
Pregabalin oral clearance tended to decrease with increasing age. This decrease in pregabalin oral clearance is consistent with age-related decreases in CLcr. Reduction of pregabalin dose may be required in patients who have age-related compromised renal function [see Dosage and Administration (2.5)].
Population pharmacokinetic analyses of the clinical studies showed that the relationship between daily dose and LYRICA CR drug exposure is similar between genders.
In population pharmacokinetic analyses of the clinical studies of LYRICA and LYRICA CR, the pharmacokinetics of pregabalin were not significantly affected by race (Caucasians, Blacks, and Hispanics).
Pregabalin clearance is nearly proportional to CLcr. Dosage reduction in patients with reduced renal function is necessary. Pregabalin is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, plasma pregabalin concentrations are reduced by approximately 50%. For patients on hemodialysis, treatment with LYRICA CR is not recommended [see Dosage and Administration (2.5)].
Drug Interaction Studies
In Vitro Studies
In vitro studies showed that pregabalin is unlikely to be involved in significant pharmacokinetic drug interactions. Pregabalin, at concentrations that were, in general, 10-times those attained in clinical trials, does not inhibit human CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 enzyme systems. In vitro drug interaction studies demonstrate that pregabalin does not induce CYP1A2 or CYP3A4 activity. Therefore, an increase in the metabolism of co-administered CYP1A2 substrates (e.g., theophylline, caffeine) or CYP3A4 substrates (e.g., midazolam, testosterone) is not anticipated.
In Vivo Studies
With the exception of erythromycin, the interactions of LYRICA CR with co-administration of other drugs have not been systematically evaluated.
Additional studies have been performed with LYRICA [see Drug Interactions (7)]. No pharmacokinetic interactions were observed between LYRICA and carbamazepine, ethanol, gabapentin, lamotrigine, lorazepam, oral contraceptive, oxycodone, phenobarbital, phenytoin, topiramate, and valproic acid. A similar lack of pharmacokinetic interactions would be expected to occur with LYRICA CR.
The drug interaction studies described in this section were conducted in healthy adults, and across various patient populations.
Multiple-dose administration of erythromycin (500 mg every 6 hours for 18 hours) in healthy subjects resulted in a 17% decrease in AUC of LYRICA CR (330 mg single dose).
Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of ethanol single-dose pharmacokinetics and single-dose administration of ethanol (0.7 g/kg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with ethanol. No clinically important effects on respiration were seen [see Drug Interactions (7)].
The pharmacokinetic interactions of pregabalin and gabapentin were investigated in 12 healthy subjects following concomitant single-dose administration of 100-mg pregabalin and 300-mg gabapentin and in 18 healthy subjects following concomitant multiple-dose administration of 200-mg pregabalin every 8 hours and 400-mg gabapentin every 8 hours. Gabapentin pharmacokinetics following single- and multiple-dose administration were unaltered by pregabalin co-administration. The extent of pregabalin absorption was unaffected by gabapentin co-administration, although there was a small reduction in rate of absorption.
Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of lorazepam single-dose pharmacokinetics and single-dose administration of lorazepam (1 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with lorazepam. No clinically important effects on respiration were seen [see Drug Interactions (7)].
Pregabalin co-administration (200 mg 3 times a day) had no effect on the steady-state pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively) in healthy subjects.
Multiple-dose administration of pregabalin (300 mg twice a day) in healthy subjects had no effect on the rate and extent of oxycodone single-dose pharmacokinetics. Single-dose administration of oxycodone (10 mg) had no effect on the steady-state pharmacokinetics of pregabalin. Additive effects on cognitive and gross motor functioning were seen when LYRICA was co-administered with oxycodone. No clinically important effects on respiration were seen [see Drug Interactions (7)].
Carbamazepine, Lamotrigine, Phenobarbital, Phenytoin, Topiramate and Valproic Acid
Steady-state trough plasma concentrations of phenytoin, carbamazepine, and carbamazepine 10,11 epoxide, valproic acid, and lamotrigine were not affected by concomitant pregabalin (200 mg 3 times a day) administration.
Population pharmacokinetic analyses in patients treated with pregabalin and various concomitant medications suggest the following:
|Therapeutic class||Specific concomitant drug studied|
|Concomitant drug has no effect on the pharmacokinetics of pregabalin|
|Hypoglycemics||Glyburide, insulin, metformin|
|Concomitant drug has no effect on the pharmacokinetics of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant drug|
|Antiepileptic Drugs||Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid|