SUPPLEMENTAL DIGITAL CONTENT 1
Establishing potency differences between gabapentin and pregabalin
Potency differences between gabapentin and pregabalin were assessed by
comparing the EC50 values obtained from the relationship of average steady
state drug concentrations (Cavg) and placebo-corrected responder ratio (RRatio)
values from the epilepsy trials and placebo-corrected mean endpoint pain scores
from the postherpetic neuralgia trials. The Cavg values were calculated from
AUC/ where AUC (area under the curve) is AUC(0-) for single dose
administration and AUC(0-) following multiple dose administration and  is the
dosing interval. The AUC values were obtained from clinical pharmacology
studies involving gabapentin1, 2 and pregabalin.3
The Cavg values calculated from the various clinical pharmacology
studies are listed in Supplemental Tables 1 and 2. For gabapentin, all AUC
values were obtained following multiple-dose administration given 3 times daily
except for the 1800 mg/day dose since no multiple-dose study investigated 1800
mg/day. The AUC value for this dosing regimen comes from a single-dose study
and is AUC(0-).
1
Supplemental Table 1. Gabapentin Cavg values estimated from the mean AUC
values from the various studies.
945-17
Daily
Dose
600
Doses
/Day
3
Dose
200
AUC
(µg·hr/ml)
19.6
SD/MD
MD
Cavg
2.45
945-12
900
3
300
24.8
MD
3.10
945-17
1200
3
400
33.3
MD
4.16
877-073
1800
3
600
37.8
SD
4.73
945-190
2400
3
800
51.4
MD
6.43
945-190
3600
3
1200
72.4
MD
9.05
Protocol
AUC: area under the curve; SD: single dose; MD: multiple dose
For pregabalin, only the Cavg values following 600 mg/day given twice or
three times daily were calculated from results of a multiple-dose study. The
remaining doses were not investigated in multiple-dose studies. In addition, only
the 25 mg dose was studied in a single-dose study. The mean AUC values for
the 50 and 75 mg doses were estimated from a 100 mg dose, and the mean
AUC value for the 150 mg dose was estimated from a 200 mg dose. It was felt
that estimating the exposure from the closest dose studied in clinical trials was
acceptable since linear pharmacokinetics was observed for pregabalin.
2
Supplemental Table 2. Pregabalin Cavg values estimated from the mean AUC
values.
Protocol
Daily Dose
Doses/Day
Dose
AUC
SD/MD
(µg·hr/ml)
Cavg
(µg/ml)
1008-002
50
2
25
5.63
SD
0.47
1008-002
75
3
25
5.63
SD
0.70
1008-002
150
3
50
11.1
SD
1.38
1008-002
150
2
75
16.6
SD
1.38
1008-002
300
2
150
28.2
SD
2.35
1008-002
600
3
200
41.7
MD
5.22
1008-002
600
2
300
59.0
MD
4.92
AUC: area under the curve; SD: single dose; MD: multiple dose
3
Supplemental Tables 3 and 4 list the RRatio and placebo-corrected
RRatio values from the pivotal efficacy trials for gabapentin4 and pregabalin5-7
along with the Cavg values estimated for each dosing regimen.
Supplemental Table 3. Least square mean RRatio and placebo-corrected
RRatio from the pivotal epilepsy trials with gabapentin.
Study
Dose
Dose/Day
Cavg
RRatio
(µg/ml)
Placebo-Corrected
RRatio
877-210
0
3
0
–0.051
877-210
1200
3
4.16
–0.201
945-5
0
3
0
–0.041
945-5
600
3
2.45
–0.126
–0.085
945-5
1200
3
4.16
–0.117
–0.076
945-5
1800
3
4.73
–0.228
–0.187
945-6
0
3
0
–0.028
945-6
900
3
3.1
–0.154
–0.126
945-6
1200
3
4.16
–0.185
–0.157
945-9/10
0
3
0
–0.033
945-9/10
900
3
3.1
–0.088
–0.055
945-9/10
1200
3
4.16
–0.265
–0.232
4
–0.15
Supplemental Table 4. Least square mean RRatio and placebo-corrected
RRatio from the pivotal epilepsy trials with pregabalin.
Protocol
Dose
Dose/Day
Cavg
RRatio
(µg/ml)
Placebo-Corrected
RRatio
1008-9
0
3
0
0.006
1008-9
600
3
5.22
–0.361
–0.367
1008-9
600
3
4.9
–0.284
-0.29
1008-11
0
3
0
0.009
1008-11
150
3
1.38
–0.115
–0.124
1008-11
600
3
5.22
–0.314
–0.323
1008-34
0
2
0
–0.038
1008-34
50
2
0.47
–0.062
–0.024
1008-34
150
2
1.38
–0.205
–0.167
1008-34
300
2
2.35
–0.278
–0.24
1008-34
600
2
4.92
–0.374
–0.336
The relationship between Cavg and placebo-corrected RRatio was
analyzed using an Emax model. An Emax value of 1, the largest RRatio value
that is feasible, which represents complete seizure control, was assumed.
Supplemental Figure 1 illustrates the relationship between gabapentin and
pregabalin exposure and placebo-corrected RRatio values.
5
Supplemental FIGURE 1. Observed and predicted relationship between
gabapentin and pregabalin exposure and placebo-corrected RRatio values from
phase 3 pivotal efficacy epilepsy trials.
The EC50 values estimated for gabapentin and pregabalin were 23.9 and
9.77 g/mL, respectively. Pregabalin is approximately 2.4 times more potent than
gabapentin based on the expected Cavg EC50s for the daily doses studied in the
epilepsy efficacy trials.
The potency difference between gabapentin and pregabalin was also
estimated from the postherpetic neuralgia clinical studies.8-12 Tables 5 and 6
6
contain the daily doses, Cavg values, least square mean endpoint pain scores,
and placebo-corrected mean endpoint pain scores.
Supplemental Table 5. Least square mean endpoint pain score and placebocorrected endpoint mean pain score from pivotal postherpetic neuralgia trials with
gabapentin.
Protocol
Dose
Doses/Day
Cavg
Mean
Placebo-
(µg/ml)
Endpoint
Corrected Mean
Pain Score
Endpoint Pain
Score
945-211
0
3
0
6
945-211
3600
3
9.05
4.2
945-295
0
3
0
5.3
945-295
1800
3
4.73
4.3
–1.07
945-295
2400
3
6.42
4.2
–1.18
945-306
0
3
0
5.48
945-306
2400
3
6.42
3.85
7
–1.67
–1.63
Supplemental Table 6. Least square mean endpoint pain score and placebocorrected endpoint mean pain score from the pivotal postherpetic neuralgia trials
with pregabalin.
Protocol
1008-30
1008-45
1008-127
1008-196
1008-132
Dose
Doses/Day
Cavg
Mean
Placebo-Corrected
(µg/ml)
Endpoint
Mean Endpoint
Pain Score
Pain Score
0
3
0
5.59
75
3
0.47
5.46
–0.13
150
3
1.38
5.52
–0.07
0
3
0
6.33
150
3
1.38
5.14
–1.19
300
3
2.77
4.76
–1.57
0
3
0
5.29
600
3
5.22
3.6
0
2
0
6.14
150
2
1.38
5.26
–0.88
300
2
2.35
5.07
–1.07
600
2
4.92
4.35
–1.79
0
2
0
6.23
150
2
1.38
5.05
–1.18
300
2
2.35
4.9
–1.33
600
2
4.92
4.21
–2.02
8
–1.69
The relationship between Cavg and placebo-corrected mean endpoint
pain score was analyzed using an Emax model. Supplemental Figure 2 illustrates
the relationship between gabapentin or pregabalin exposure and placebocorrected mean endpoint pain score values.
Supplemental FIGURE 2. Observed and predicted relationship between
gabapentin and pregabalin exposure and placebo-corrected mean endpoint pain
score values from phase 3 post-herpetic neuralgia efficacy trials.
The EC50 values estimated for gabapentin and pregabalin were 11.7 and
4.21 g/mL, respectively. In the treatment of postherpetic neuralgia, pregabalin
9
appears to be approximately 2.8 times more potent than gabapentin based on
the EC50 values. The more conservative potency value of 2.4 from the epilepsy
indication was used in the simulations since it is similar to the differences
observed for gabapentin and pregabalin in inhibiting 3H-gabapentin binding to pig
brain α2δ type 1 receptors. The Ki values for gabapentin and pregabalin in this
model were 75 nM and 42 nM, respectively, indicating that pregabalin is
approximately 2 times more potent than gabapentin in this in vitro model.
In the reported simulations, the exposure resulting from the combined
administration of gabapentin and pregabalin was estimated by reducing the
predicted gabapentin concentrations by a potency difference of 2.4-fold, and the
total estimated exposure for plasma gabapentin and pregabalin concentrations
were shown as pregabalin-equivalent concentrations.
REFERENCES
1.
Bockbrader HN. Clinical Pharmacokinetics of Gabapentin. Drugs of
Today. 1995;31:613-619.
2.
Bockbrader HN, Breslin EM, Underwood BA, et al. Multiple-dose, doseproportionality study of Neurontin (gabapentin) in healthy volunteers
(Abstract). Epilepsia. 1996;37 (suppl 5):159.
3.
Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics
of pregabalin in healthy volunteers. J Clin Pharmacol. 2010;50:941-950.
4.
McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy.
Clin Ther. 2003;25:1382-1406.
10
5.
French JA, Kugler AR, Robbins JL, et al. Dose-response trial of pregabalin
adjunctive therapy in patients with partial seizures. Neurology.
2003;60:1631−1637.
6.
Arroyo S, Anhut H, Kugler AR, et al. Pregabalin add-on treatment: a
randomized, double-blind, placebo-controlled, dose-response study in
adults with partial seizures. Epilepsia. 2004;45:20-27.
7.
Beydoun A, Uthman BM, Kugler AR, et al. Safety and efficacy of two
pregabalin regimens for add-on treatment of partial epilepsy. Neurology.
2005;64:475-480.
8.
Rice AS, Maton S. Gabapentin in postherpetic neuralgia: a randomised,
double blind, placebo controlled study. Pain. 2001;94:215-224.
9.
Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of
postherpetic neuralgia: a randomized controlled trial. JAMA.
1998;280:1837-1842.
10.
Sabatowski R, Galvez R, Cherry DA, et al. Pregabalin reduces pain and
improves sleep and mood disturbances in patients with post-herpetic
neuralgia: results of a randomised, placebo-controlled clinical trial. Pain.
2004;109:26-35.
11.
Dworkin RH, Corbin AE, Young JP, Jr., et al. Pregabalin for the treatment
of postherpetic neuralgia: a randomized, placebo-controlled trial.
Neurology. 2003;60:1274-1283.
12.
van Seventer R, Feister HA, Young JP, Jr., et al. Efficacy and tolerability
of twice-daily pregabalin for treating pain and related sleep interference in
11
postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin.
2006;22:375-384.
12