CLINICAL PHARMACOLOGY
Mechanism of Action
LYRICA (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 is unknown, 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 antinociceptive and antiseizure effects
in animal models. In vitro, pregabalin reduces the calcium-dependent release
of several neurotransmitters, possibly by modulation of calcium channel function.
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.
Pharmacokinetics
Pregabalin is well absorbed after oral administration, is eliminated largely by
renal excretion, and has an elimination half-life of about 6 hours.
Absorption and Distribution
Following oral administration of LYRICA capsules under fasting conditions, peak
plasma concentrations occur within 1.5 hours. Pregabalin oral bioavailability is
≥90% and is independent of dose. Following single- (25 to 300 mg) and multiple-dose
(75 to 900 mg/day) administration, maximum plasma concentrations (Cmax)
and area under the plasma concentration-time curve (AUC) values increase linearly.
Following repeated administration, steady state is achieved within 24 to 48 hours.
Multiple-dose pharmacokinetics can be predicted from single-dose data.
The rate of pregabalin absorption is decreased when given with food, resulting in
a decrease in Cmax of approximately 25% to 30% and an
increase in Tmax to approximately 3 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 0.5 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.
Metabolism and Elimination
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 creatinine clearance (CLcr) (see Dosage and
Administration).
Pharmacokinetics in Special Populations
Race
In population pharmacokinetic analyses of the clinical studies in various populations,
the pharmacokinetics of LYRICA were not significantly affected by race (Caucasians,
Blacks, and Hispanics).
Gender
Population pharmacokinetic analyses of the clinical studies showed that the relationship
between daily dose and LYRICA drug exposure is similar between genders.
Renal Impairment and Hemodialysis
Pregabalin clearance is nearly proportional to creatinine clearance (CLcr). Dosage
reduction in patients with renal dysfunction 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, dosing must be modified (see Dosage and Administration).
Elderly
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).
Pediatric Pharmacokinetics
Pharmacokinetics of pregabalin have not been adequately studied in pediatric patients.
Drug Interactions
In Vitro Studies
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 coadministered CYP1A2 substrates (e.g. theophylline, caffeine)
or CYP 3A4 substrates (e.g. midazolam, testosterone) is not anticipated.
In Vivo Studies
The drug interaction studies described in this section were conducted in healthy
adults, and across various patient populations.
Gabapentin
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 coadministration. The extent of pregabalin absorption
was unaffected by gabapentin coadministration, although there was a small reduction
in rate of absorption.
Oral Contraceptive
Pregabalin coadministration (200 mg three times a day) had no effect on the steady-state
pharmacokinetics of norethindrone and ethinyl estradiol (1 mg/35 µg, respectively)
in healthy subjects.
Lorazepam
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.
Oxycodone
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.
Ethanol
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.
Phenytoin, carbamazepine, valproic acid, and lamotrigine
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 three times a day) administration.
Population pharmacokinetic analyses in patients treated with pregabalin and various
concomitant medications suggest the following:
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Therapeutic class |
Specific concomitant drug studied |
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Concomitant drug has no effect on the pharmacokinetics of pregabalin |
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Hypoglycemics
Diuretics
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Glyburide, insulin, metformin
Furosemide
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Antiepileptic Drugs
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Tiagabine
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Concomitant drug has no effect on the pharmacokinetics
of pregabalin and pregabalin has no effect on the pharmacokinetics of concomitant
drug |
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Antiepileptic Drugs
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Carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproic acid
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NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
A dose-dependent increase in the incidence of malignant vascular tumors (hemangiosarcomas)
was observed in two strains of mice (B6C3F1 and CD-1) given pregabalin (200, 1000,
or 5000 mg/kg) in the diet for two years. Plasma pregabalin exposure (AUC) in mice
receiving the lowest dose that increased hemangiosarcomas was approximately equal
to the human exposure at the maximum recommended dose (MRD) of 600 mg/day. A no-effect
dose for induction of hemangiosarcomas in mice was not established. No evidence
of carcinogenicity was seen in two studies in Wistar rats following dietary administration
of pregabalin for two years at doses (50, 150, or 450 mg/kg in males and 100, 300,
or 900 mg/kg in females) that were associated with plasma exposures in males and
females up to approximately 14 and 24 times, respectively, human exposure at the
MRD.
Mutagenesis
Pregabalin was not mutagenic in bacteria or in mammalian cells in vitro,
was not clastogenic in mammalian systems in vitro and in vivo, and
did not induce unscheduled DNA synthesis in mouse or rat hepatocytes.
Impairment of Fertility
In fertility studies in which male rats were orally administered pregabalin (50
to 2500 mg/kg) prior to and during mating with untreated females, a number of adverse
reproductive and developmental effects were observed. These included decreased sperm
counts and sperm motility, increased sperm abnormalities, reduced fertility, increased
preimplantation embryo loss, decreased litter size, decreased fetal body weights,
and an increased incidence of fetal abnormalities. Effects on sperm and fertility
parameters were reversible in studies of this duration (3–4 months). The no-effect
dose for male reproductive toxicity in these studies (100 mg/kg) was associated
with a plasma pregabalin exposure (AUC) approximately 3 times human exposure at
the maximum recommended dose (MRD) of 600 mg/day.
In addition, adverse reactions on reproductive organ (testes, epididymides) histopathology
were observed in male rats exposed to pregabalin (500 to 1250 mg/kg) in general
toxicology studies of four weeks or greater duration. The no-effect dose for male
reproductive organ histopathology in rats (250 mg/kg) was associated with a plasma
exposure approximately 8 times human exposure at the MRD.
In a fertility study in which female rats were given pregabalin (500, 1250, or 2500
mg/kg) orally prior to and during mating and early gestation, disrupted estrous
cyclicity and an increased number of days to mating were seen at all doses, and
embryolethality occurred at the highest dose. The low dose in this study produced
a plasma exposure approximately 9 times that in humans receiving the MRD. A no-effect
dose for female reproductive toxicity in rats was not established.
Human Data
In a double-blind, placebo-controlled clinical trial to assess the effect of pregabalin
on sperm motility, 30 healthy male subjects were exposed to pregabalin at a dose
of 600 mg/day. After 3 months of treatment (one complete sperm cycle), the difference
between placebo- and pregabalin-treated subjects in mean percent sperm with normal
motility was <4% and neither group had a mean change from baseline of more than
2%. Effects on other male reproductive parameters in humans have not been adequately
studied.
Animal Toxicology and/or Pharmacology
Dermatopathy
Skin lesions ranging from erythema to necrosis were seen in repeated-dose toxicology
studies in both rats and monkeys. The etiology of these skin lesions is unknown.
At the maximum recommended human dose (MRD) of 600 mg/day, there is a 2-fold safety
margin for the dermatological lesions. The more severe dermatopathies involving
necrosis were associated with pregabalin exposures (as expressed by plasma AUCs)
of approximately 3 to 8 times those achieved in humans given the MRD. No increase
in incidence of skin lesions was observed in clinical studies.
Ocular Lesions
Ocular lesions (characterized by retinal atrophy [including loss of photoreceptor
cells] and/or corneal inflammation/mineralization) were observed in two lifetime
carcinogenicity studies in Wistar rats. These findings were observed at plasma pregabalin
exposures (AUC) ≥2 times those achieved in humans given the maximum recommended
dose of 600 mg/day. A no-effect dose for ocular lesions was not established. Similar
lesions were not observed in lifetime carcinogenicity studies in two strains of
mice or in monkeys treated for 1 year.