Clin Pharmacokinet 2010; 49 (10): 661-669

REVIEW ARTICLE 0312-5963/10/0010-0661/$49.95/0

ª 2010 Adis Data Information BV. All rights reserved.

A Comparison of the Pharmacokinetics

and Pharmacodynamics of Pregabalin
and Gabapentin
Howard N. Bockbrader, David Wesche, Raymond Miller, Sunny Chapel, Nancy Janiczek and Paula Burger
Pfizer Global Research & Development, Ann Arbor, Michigan, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 661
1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
1.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 662
1.2 Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 663
1.3 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 664
1.4 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
1.5 Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
1.6 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 665
2. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
2.1 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
2.2 Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
2.3 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667
3. Discussion and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 667

Abstract Pregabalin and gabapentin share a similar mechanism of action, inhibiting calcium influx and subsequent
release of excitatory neurotransmitters; however, the compounds differ in their pharmacokinetic and phar-
macodynamic characteristics. Gabapentin is absorbed slowly after oral administration, with maximum
plasma concentrations attained within 3–4 hours. Orally administered gabapentin exhibits saturable
absorption – a nonlinear (zero-order) process – making its pharmacokinetics less predictable. Plasma con-
centrations of gabapentin do not increase proportionally with increasing dose. In contrast, orally
administered pregabalin is absorbed more rapidly, with maximum plasma concentrations attained within
1 hour. Absorption is linear (first order), with plasma concentrations increasing proportionately with
increasing dose. The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases
from 900 to 3600 mg/day, while the absolute bioavailability of pregabalin remains at ‡90% irrespective of the
dosage. Both drugs can be given without regard to meals. Neither drug binds to plasma proteins. Neither
drug is metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs.
Both drugs are excreted renally, with elimination half-lives of approximately 6 hours.
Pregabalin and gabapentin both show dose-response relationships in the treatment of postherpetic
neuralgia and partial seizures. For neuropathic pain, a pregabalin dosage of 450 mg/day appears to reduce
pain comparably to the predicted maximum effect of gabapentin. As an antiepileptic, pregabalin may be
more effective than gabapentin, on the basis of the magnitude of the reduction in the seizure frequency. In
conclusion, pregabalin appears to have some distinct pharmacokinetic advantages over gabapentin that may
translate into an improved pharmacodynamic effect.
662 Bockbrader et al.

−
O + (s) pain and as adjunctive therapy for adults with partial seizures,
+ H3N
H3N − with or without secondary generalization. Subsequent approv-
−
O
O als in the EU were granted for neuropathic pain (peripheral or
O central) and for generalized anxiety disorder. In the US, the FDA
Gabapentin Pregabalin approved pregabalin in 2005 for the management of neuro-
pathic pain associated with diabetic peripheral neuropathy and
+
postherpetic neuralgia in adults, and as adjunctive therapy for
O H3N (s)
+
adults with partial-onset seizures. In June 2007, pregabalin was
H3N
−
O − C also approved by the FDA for management of fibromyalgia.
O
GABA O This review explores some differences in the pharmacokine-
L-leucine tics and pharmacodynamics of pregabalin and gabapentin, which
Fig. 1. Chemical structures of gabapentin, pregabalin, g-aminobutyric acid might render one medication advantageous over the other in
(GABA) and L-leucine. some clinical settings. The medical literature was searched through
MEDLINE, using the drug names as search terms, with re-
Pregabalin and gabapentin are members of a unique class of search in humans receiving preference to animal or in vitro re-
compounds characterized by their high-affinity binding to the search. We used information from published abstracts and
a2d protein, an auxiliary subunit of voltage-gated calcium chan- clinical study protocols to complement peer-reviewed articles as
nels in central nervous system neuronal tissues.[1] Both drugs required to more fully explain a topic. Additionally, we devel-
reduce the release of neurotransmitters from brain tissues. Al- oped a dose-response model for pregabalin and gabapentin in
though the mechanism of action of pregabalin and gabapentin the treatment of postherpetic neuralgia, using a pooled analysis
is not fully understood, studies with these compounds in ge- of four studies of pregabalin and two studies of gabapentin, and
netically modified mice (modified to alter the binding affinity of a dose-response model in the treatment of epilepsy, using three
these ligands to the a2d subunit) have indicated that selective studies of pregabalin and six studies of gabapentin.
binding to the a2d subunit is necessary for both pregabalin and
gabapentin and their associated antinociceptive, anticonvul-
sant and anxiolytic-like effects.[2-4] Structure-activity studies of
1. Pharmacokinetics
a variety of compounds that are structurally related to gaba-
pentin and pregabalin have supported the premise that both Pregabalin and gabapentin have undergone extensive re-
high-affinity binding and transport of the compounds into the search to determine their absorption, distribution, metabolism
brain compartment are required for pharmacological action.[5] and elimination properties.
Pregabalin and gabapentin are non-natural, branched-
chain amino acids (figure 1). Both are chemical analogues of g- 1.1 Absorption
aminobutyric acid (GABA); however, neither drug has activity in
GABAergic neuronal systems.[6-8] Functionally, they are simi- Pregabalin and gabapentin immediate-release formulations
lar to the essential, metabolizable, branched-chain amino acid, readily disintegrate; the drugs are highly soluble in aqueous
leucine, with regard to competitive binding to a2d subunit types media (table I). Doses of the capsule (pregabalin and gaba-
1 and 2[9] and facilitated movement across cellular membranes pentin) and tablet (gabapentin) formulations are bioequivalent
by system-L transporters.[5] Each of these characteristics is a to solution doses. There are significant differences in the
necessary, but individually insufficient, requirement for the absorption properties of these two drugs. The system-L trans-
pharmacological activity of this class of compounds.[5] porter family facilitates large, neutral, amino acid transport
Gabapentin was originally approved in the UK in 1993 and (LAT), including phenylalanine, leucine, isoleucine and va-
is currently marketed in more than 100 countries for treatment line,[11] as well as intestinal absorption of both gabapentin and
of epilepsy and neuropathic pain disorders. Gabapentin is ap- pregabalin. Preclinical studies have suggested that gabapentin
proved in the US for adjunctive treatment of partial seizures is transported solely by the LAT1 transporter,[12] resulting in
and for treatment of postherpetic neuralgia. Pregabalin was dose-limited absorption, presumably because of saturation of
approved in 2004 by the European Agency for the Evaluation the facilitated transport process.[11,13,14] Pregabalin absorption
of Medicinal Products (now known as the European Medicines seems to be mediated by an additional pathway, thus allowing
Agency) for treatment of adults with peripheral neuropathic for near-complete, non-saturable absorption into the blood-

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
Pregabalin and Gabapentin: PK and PD 663

stream.[15] In vitro studies have suggested that pregabalin and Pregabalin

10 Gabapentin
gabapentin have different capacities and rates of uptake by the
L-type transport system in Caco-2 cells.[16] 8
The maximum rate of absorption of pregabalin is approxi-
mately 3-fold greater than that of gabapentin. In healthy

Cmin,ss (µg/mL)
6
subjects, pregabalin is rapidly absorbed, with peak blood con-
centrations attained within 1 hour.[17] The rate of gabapentin
4
absorption is relatively slow, with peak plasma concentrations
occurring around 3 hours postdose.[14] The rate and extent of
2
absorption are influenced by the absence or presence of the
transporter(s) along the gastrointestinal tract, which facilitates
the passage of each of these compounds from the intestinal 0
0 600 1200 1800 2400 3000 3600 4200 4800
lumen to the systemic circulation. Colonic intubation studies[18] Dosage (mg/d)
have indicated that systemic absorption of gabapentin occurs
Fig. 2. Mean (– SD) steady-state minimum plasma drug concentration
primarily in the small intestine, with minimal absorption in the (Cmin,ss) values in healthy subjects given pregabalin or gabapentin every
colon, which limits gabapentin absorption. In contrast, sys- 8 h.[14,20]
temic absorption of pregabalin occurs over a longer segment of
the gastrointestinal tract. In addition to absorption in the small 1.2 Bioavailability
intestine, colonic intubation studies have indicated that pre-
gabalin absorption extends into the ascending portion of the With regard to the fraction of the dose absorbed, the lowest
colon.[19] gabapentin dose studied (100 mg every 8 hours) is associated
In 33 healthy subjects, pregabalin displayed linear pharma- with absolute bioavailability of approximately 80%. This value
cokinetics over its recommended dose range of 75 to 900 mg/ was shown to decrease with increasing dose to an average
day (figure 2), as reflected in dose proportionality observed of 27% absolute bioavailability for a 1600 mg dose every
for the plasma concentration and the area under the plasma 8 hours.[11,21] In contrast, oral bioavailability of pregabalin
concentration-time curve (AUC). Gabapentin, in contrast, dis- averaged ‡90% across the full dose range of 75 to 900 mg/day
plays saturable absorption, which decreases with increasing studied.[22] The maximum plasma drug concentration (Cmax)
dose, as tested in 96 healthy subjects.[14,20] Mean gabapentin and AUC – both measures of exposure – increase linearly with
steady-state minimum plasma concentration (Cmin,ss) values dosages ranging from 75 to 900 mg/day. This range includes
increase with increasing dose, but the increase is not dose and exceeds the efficacious dosage range (150–600 mg/day)
proportional. This observation is consistent with the in vitro studied in phase III pregabalin trials. The variability (co-
Caco-2 experiments, which predicted a nonlinear absorption efficient of variation) in the pregabalin Cmax and AUC values is
profile for gabapentin and a more linear relationship for generally 10–15%,[20] whereas the variability in the estimates for
pregabalin.[16] gabapentin is generally 20–30%. The saturable absorption
process and the interindividual variability in this process con-
tribute significantly to the higher variability observed with
Table I. Summary of the physical chemistry properties of gabapentin and
pregabalin[10]
gabapentin.[23] For gabapentin, the time to reach the Cmax
following drug administration (tmax) is a function of the dose
Property Gabapentin Pregabalin
administered, with low doses of 100 mg having a tmax of »1.7
Molecular weight (g/mol) 171.24 159.22
hours, and the tmax increases to 3–4 hours following higher
pKa 3.7 4.2
single doses. In contrast, the tmax of pregabalin is considerably
pKb 10.7 10.6 shorter – generally averaging £1 hour following single-dose
Aqueous solubility (mg/mL) >100 32.1 administration of 1–300 mg.[24,25]
Log Pa -1.25 -1.35 Both gabapentin and pregabalin can be administered with-
Intestinal transport System-L amino System-L amino out regard to food, but differences in absorption during the fed
acid transporter 1 acid transporter(s) and fasting states distinguish the two drugs (table II). For ga-
a pH 7.4 phosphate buffer. bapentin, a standard meal and a high-fat meal both result in an
pKa = acid dissociation constant; pKb = base dissociation constant. approximate 10% increase in the Cmax and AUC, with no signi-

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
664 Bockbrader et al.

Table II. Gabapentin and pregabalin pharmacokinetic parameter values following administration to fasting subjects and subjects fed a standard or high-fat
breakfast. (Adapted from Bockbrader et al.,[20] with permission. Copyright ª 2010 by Sage Publications. Reprinted by Permission of SAGE Publications.)
Parameter Fed (test)a Fasting (reference)a Ratio (%) [90% CI]b
Gabapentin
Standard breakfast (n = 12)
Cmax (mg/mL) 3.78 3.49 108.0 [88.9, 131.0]
tmax (h) 3.3 3.5 94.3 [NA]


AUC1 (mg h/mL) 39.6 36.7 108.0 [91.8, 126.0]
High-fat breakfast (n = 12)
Cmax (mg/mL) 3.06 2.82 108.0 [97.8, 120.0]
tmax (h) 3.6 3.3 109.0 [NA]


AUC1 (mg h/mL) 29.9 27.2 110.0 [98.6, 123.0]
Pregabalin
Standard breakfast (n = 11)
Cmax (mg/mL) 2.59 3.78 68.6 [64.0, 73.6]
tmax (h) 3.17 0.615 515.0 [NA]


AUC1 (mg h/mL) 25.4 26.7 94.9 [92.0, 98.0]
High-fat breakfast (n = 14)
Cmax (mg/mL) 2.60 3.47 74.8 [68.0, 82.2]
tmax (h) 2.29 1.25 183.0 [NA]

a Mean values.

AUC1 (mg h/mL) 25.5 27.3 93.3 [91.4, 95.2]

b Ratio of fed/fasting.
AUC1 = area under the plasma concentration-time curve from time zero to infinity; Cmax = maximum plasma drug concentration; NA = not applicable; tmax = time
to reach the Cmax.

ficant change in the tmax. These increases are not of clinical gabalin concentrations are similar to the whole-blood con-
significance, and no dose adjustment is required when gaba- centrations, indicating that both drugs penetrate red blood
pentin is administered with food.[26] Although both standard cells. Neither gabapentin nor pregabalin is bound to plasma
and high-fat meals decrease the rate of pregabalin absorption, proteins; thus drug-drug interactions with any highly protein-
neither has a significant effect on the extent of absorption. bound agent are not anticipated. The disposition of gaba-
Administration of pregabalin with food reduces the mean Cmax pentin[14,28] and pregabalin[29] in the cerebrospinal fluid (CSF)
values by 25–31% and prolongs the absorption process. The following oral administration is similar. Sparse sampling fol-
mean tmax values increase by »1 hour, ranging from 2.3 hours in lowing single-dose gabapentin administration indicated that
the fasted state to 3.2 hours in the fed state. However, because gabapentin concentrations in the CSF were approximately
only the rate and not the extent of pregabalin bioavailability is 9–14% of the corresponding plasma concentrations. The per-
affected by food, pregabalin can be given without regard to the centage of the gabapentin concentration (CSF/plasma) in-
timing of meals.[20] creased with time after drug administration and following
multiple-dose administration.
1.3 Distribution Following single-dose administration of pregabalin, serial
CSF and plasma samples were obtained at 2, 4, 6, 8 and
According to findings from whole-body autoradiography 24 hours. The percentage of the pregabalin concentration in the
studies in mice, rats and monkeys, the distribution character- CSF ranged from approximately 1% to 30%. The mean plasma
istics of gabapentin and pregabalin are quite similar.[10,27] pregabalin concentrations in the human study peaked at
Likewise, the brain : whole-blood ratio is similar for the two 2 hours (the first sampling time in the study) and decreased by
drugs. In humans, both plasma gabapentin and plasma pre- an apparent first-order process. The mean CSF pregabalin

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
Pregabalin and Gabapentin: PK and PD 665

concentrations peaked much later (at least 8 hours post-dose) subjects with creatinine clearance (CLCR) of 100 mL/minute,
and then decreased at a slower rate relative to that observed for plasma gabapentin clearance was approximately 125 mL/minute,
plasma. Gabapentin and pregabalin steady-state CSF exposure whereas plasma pregabalin clearance was approximately 70 mL/
would be expected to have an attenuated peak-to-trough fluc- minute.[10] For gabapentin, the renal clearance value is similar
tuation relative to that of plasma.[14,28,29] to or slightly greater than the CLCR value. It is not known if
Gabapentin and pregabalin are secreted into milk by lac- gabapentin renal elimination is dependent on a reabsorption
tating rodents, and gabapentin has been found in human breast process; however, cimetidine (a known inhibitor of renal tub-
milk at concentrations similar to those in plasma. Although ular secretion) reduces gabapentin renal clearance by approx-
use of pregabalin in lactating women has not been studied, imately 12%.[18] Therefore, renal tubular secretion is involved in
secretion of pregabalin into human breast milk would be the renal elimination of gabapentin. For pregabalin, the renal
expected.[30,31] clearance value is less than the glomerular filtration rate, which
A slight difference in the apparent volume of distribution indicates that a tubular reabsorption process is involved in
(Vd) values of pregabalin and gabapentin has been observed renal clearance. Whether renal secretion is also involved is not
in humans. The Vd estimates (independent of drug bioavail- known. Elimination half-life parameter estimates for the two
ability) based on population pharmacokinetic analyses of ga- drugs are similar. The reported gabapentin elimination half-life
bapentin and pregabalin are 0.8 and 0.5 L/kg, respectively.[10] estimates range from 5.0 to 7.0 hours and those for pregabalin
For both drugs, the Vd is relatively small and similar to that of average 6.3 hours, indicating that both drugs achieve steady
total body water. This observation is consistent with their high state within 24–48 hours.[23,24]
aqueous solubility, low lipophilicity and lack of significant
tissue binding, as observed in whole-body autoradiography
studies. 1.6 Drug Interactions

1.4 Metabolism Approximately 50–75% of gabapentin doses, ranging from

1800 to 4800 mg/day, are not absorbed.[34] Any agent that
The metabolic profiles of gabapentin and pregabalin are prolongs the transit time of gabapentin in the small intestine
similar. In dogs, both are metabolized to the corresponding could potentially enhance the bioavailability of gabapentin.
N-methyl metabolite.[18] Both compounds undergo negligible Eckhardt et al.[35] demonstrated that the bioavailability of
metabolism in mice and rats; in humans, metabolites account gabapentin increased by 50% when a 600 mg dose was co-
for <1% of the dose.[22,27] An effect of liver disease on the administered with oral morphine. Other agents that decrease
pharmacokinetics of gabapentin and pregabalin has not been small-bowel motility could have a similar effect on the extent of
studied. However, since both compounds undergo negligible gabapentin absorption, although this has not been confirmed
metabolism, their pharmacokinetics are not expected to be clinically. Pregabalin has systemic absorption of ‡90% and
different from those observed in healthy subjects. would not be significantly affected by agents that reduce gas-
trointestinal motility.
1.5 Excretion Neither gabapentin nor pregabalin, at concentrations equal
to or greater than those observed at efficacious dosages, inhibits
With minor exceptions, renal excretion of gabapentin and the major cytochrome P450 (CYP) enzymes (CYP1A2, CYP2A6,
pregabalin is similar and is essentially the only pathway for CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4) that
systemic elimination of the drugs. Gabapentin and pregabalin mediate xenobiotic metabolism in humans. In addition, pre-
plasma clearances are highly correlated with renal function, gabalin has been shown to not induce expression of the CYP
and dosage adjustments are necessary for both drugs in patients enzymes CYP3A4 and CYP1A2 in vitro at concentrations equal
with impaired renal function. Studies in patients undergoing to or greater than those observed at efficacious dosages.[36]
haemodialysis have indicated that a 4-hour treatment lowers Therefore, drug-drug interactions due to inhibition of the me-
the plasma concentrations of gabapentin and pregabalin by tabolism of other agents by gabapentin or pregabalin, or due to
approximately 50%.[32,33] induction of the metabolism of other agents by pregabalin, are
Slight differences between gabapentin and pregabalin in the unlikely. In addition, the pharmacokinetics of these com-
relationship between plasma drug clearance and renal function pounds are not expected to vary as a function of genetic poly-
have been observed. In population pharmacokinetic analyses in morphisms of metabolizing enzymes.[37]

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
666 Bockbrader et al.

Table III. Summary of phase III postherpetic neuralgia trials conducted with either gabapentin or pregabalin
Drug Subjects (n) Dosage (mg/d) Regimen Duration (wk) Reference
Gabapentin 229 3600 TID 8 41
Gabapentin 334 1800, 2400 TID 7 40
Pregabalin 252 75, 150 TID 5 38
Pregabalin 238 150, 300 TID 8 42
Pregabalin 173 300/600a TID 8 39
a
Pregabalin 368 150, 300, 300/600 BID 13 43
a In this study, patients with CLCR between 30 and 60 mL/min received a dosage of 300 mg/d, and patients with CLCR >60 mL/min received a dosage of
600 mg/d.
BID = twice daily; CLCR = creatinine clearance; TID = three times daily.

2. Pharmacodynamics 600 mg/day. Model predictions suggested that a pregabalin

dosage of 450 mg/day would produce a pain score reduction
2.1 Neuropathic Pain comparable to the predicted maximum effect of gabapentin.
The treatment effects of the pregabalin 600 mg/day twice-daily
Gabapentin and pregabalin both show dose-response re- regimen were similar to those observed with the three-times-
lationships in the treatment of postherpetic neuralgia and daily regimen. As confirmed by exposure-response modelling,
partial seizures. For both drugs, efficacy increases with in- the exposure-response relationship for the twice-daily regimen
creasing dose; however, differences do exist. Using data from was not statistically different from that for the three-times-daily
six phase III studies,[38-43] a population pharmacokinetic- regimen.[45]
pharmacodynamic model was developed to describe the
relationship between daily gabapentin or pregabalin adminis-
tration and reduction in the pain score of patients experiencing 2.2 Epilepsy
pain associated with postherpetic neuralgia (table III). The
Using seven phase III studies (table IV),[46-51] a population
dosages administered in the two gabapentin studies were 1800,
pharmacokinetic-pharmacodynamic model was developed to
2400 and 3600 mg/day, given three times daily, with a 3- to
describe the relationship between the daily dosage of gabapentin
4-week dose-titration phase. The dosages administered in the
four pregabalin studies were 75, 150, 300 and 600 mg/day, given 0 Pregabalin
three times daily or twice daily, with a 1-week dose-titration Gabapentin

phase. Since daily pain scores were measured as integral, or- −0.5
Change in mean pain score

dinal values on an 11-point numeric rating scale,[44] the pre- −1.0

gabalin and gabapentin dose-response models were developed
to treat the daily pain score as an ordered categorical response. −1.5

For both pregabalin and gabapentin, the observed treatment

−2.0
effects in the mean pain score reductions and model-predicted
values were in good agreement (figure 3). −2.5

The treatment effect in the placebo group varied from study

−3.0
to study, such that three of the six studies showed an approx-
0 1000 2000 3000
imate 0.5-point reduction in the pain score, while the remaining Dosage (mg/d)
three studies showed a greater than 1.0-point reduction. Vari-
Fig. 3. Observed and model-predicted treatment effects of mean pain re-
ability in the placebo effect was comparable between the ga- duction in six trials (two gabapentin and four pregabalin trials, as detailed in
bapentin and pregabalin studies. The pain score reduction with table III) involving patients with postherpetic neuralgia. Each datapoint re-
pregabalin was greater and was achieved at a lower daily dose presents the mean pain score reduction in a treatment group (the 0 mg dose
represents placebo) in a single study. Each shaded area corresponds to 95%
than with gabapentin. While there was a plateau in the maximal
of the predicted interval for the mean pain score reduction with the drug, and
effect of gabapentin at the doses studied, the pain reduction the thick black lines represent the 50th percentile of the predicted mean pain
with pregabalin tended to increase as the dosage increased to score reduction.[38-44]

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
Pregabalin and Gabapentin: PK and PD 667

Table IV. Summary of phase III epilepsy trials conducted with either gabapentin or pregabalin
Drug Subjects (n) Dosage (mg/d) Regimen Duration (wk) Reference
Gabapentin 127 1200 TID 12 46
Gabapentin 306 600, 1200, 1800 TID 12 47
Gabapentin 272 900, 1200 TID 12 48
Gabapentin 87 900, 1200 TID 12 48
Pregabalin 312 600 BID, TID 12 49
Pregabalin 287 150, 600 TID 12 50
Pregabalin 453 50, 150, 300, 600 BID 12 51
BID = twice daily; TID = three times daily.

or pregabalin and the reduction in the seizure frequency 3. Discussion and Conclusions
in refractory patients with partial seizures. The dosages
administered in the four gabapentin studies were 600, 900, 1200 Comparison of the pharmacokinetic and pharmacodynamic
and 1800 mg/day, given three times daily; the dosages ad- properties of gabapentin and pregabalin indicates several sim-
ministered in the three pregabalin studies were 50, 150, 300 and ilarities in negligible protein binding, no adjustment required
600 mg/day, given three times daily or twice daily. The observed for dosing with food, negligible metabolism in humans, a strong
median percentage changes in the seizure frequency from correlation between plasma clearance and renal function, sim-
baseline for gabapentin and pregabalin are shown in figure 4. ilar elimination half-life estimates with attainment of steady
Comparison of the dose-response relationships for both drugs state within 24–48 hours, and no inhibition of enzyme systems
revealed two important distinctions: (i) pregabalin was 2.5 times that are responsible for drug metabolism in humans.
more potent than gabapentin, as measured by the dosage that
reduced the seizure frequency by ‡50%; and (ii) pregabalin was 40 Pregabalin
Gabapentin
more effective than gabapentin on the basis of the magnitude of
the reduction in the seizure frequency. The curve describing the
20
seizure frequency from baseline

dose-response relationship for gabapentin was relatively flat,

Mean percentage change in

partly because of the saturable absorption process described

above. As the daily dosage increases, the fraction that is ab- 0

sorbed decreases. Accordingly, the slope of the dose-response

relationship at dosages greater than 1800 mg/day (the highest
−20
dose studied in phase III trials) is expected to remain shallow.
Unlike gabapentin, pregabalin shows a steep dose-response
relationship, which is, in part, due to its greater potency and −40

linear pharmacokinetics.
−60
2.3 Adverse Effects 0 300 600 900 1200 1500 1800
Dosage (mg/d)
Pregabalin and gabapentin are generally well tolerated.
Fig. 4. Observed and model-predicted seizure frequency (mean percentage
Dizziness is the most commonly reported adverse effect of change from baseline) vs dose (gabapentin: 0–1800 mg/d, pregabalin:
pregabalin, followed by somnolence, which is the most fre- 0–600 mg/d) in patients with refractory partial seizures, as detailed in table IV.
quent reason for treatment discontinuation (4%). Other ad- Pregabalin (50–600 mg/d) and gabapentin (600–1800 mg/d) showed a dose-
related decrease in the seizure frequency in patients with refractory partial
verse effects include dry mouth, oedema and blurred vision. seizures. Each datapoint represents the mean percentage change in the
Dizziness and somnolence are the most commonly reported seizure frequency from a treatment group (the 0 mg dose represents placebo)
adverse effects of gabapentin, occurring in >20% of patients. in a single study. Each shaded area corresponds to 95% of the predicted
interval for the reduction in the seizure frequency with the drug – that is, the
Confusion and peripheral oedema have also been reported.
model-predicted 10th–90th percentiles for the median percentage change in
The adverse effects of both drugs are dose dependent and the seizure frequency from baseline for gabapentin and pregabalin. The thick
reversible.[52] black lines represent the 50th percentile of each predicted reduction.[46-51]

ª 2010 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2010; 49 (10)
668 Bockbrader et al.

Small differences in the chemical structure of the first- and 11. Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport me-
chanism in the intestinal absorption of gabapentin is the underlying cause of
second-generation a2d-binding anticonvulsant compounds are
the lack of proportionality between increasing dose and drug levels in plasma.
clearly important and differentiate the pharmacokinetic and Pharm Res 1993 Feb; 10 (2): 276-81
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neuralgia and epilepsy than gabapentin. The differences in 15. Piyapolrungroj N, Li C, Bockbrader H, et al. Mucosal uptake of gabapentin
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Several of the studies discussed in this paper were funded by Pfizer Inc. 23 (4): 441-8
Howard N. Bockbrader, PhD, David Wesche, MD, PhD, Raymond 19. Bockbrader HN, Radulovic LL, Strand JC, et al. Regional differences in
Miller, PhD, Sunny Chapel, PhD, Nancy Janiczek, PhD and Paula Burger, the colonic absorption of pregabalin [abstract no. CI-1008]. Pharm Sci 2000;
BS, were employees of Pfizer Inc. and owned stock in Pfizer Inc. during the 2: 2080
development of this paper. Editorial and administrative assistance was 20. Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics
provided by Thomas G. Hedberg, PhD, of UBC Scientific Solutions, and of pregabalin in healthy volunteers. J Clin Pharmacol 2010 Aug; 50 (8):
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was funded by Pfizer Inc.
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daily pregabalin for treating pain and related sleep interference in postherpetic E-mail: [email protected]

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