Clin Drug Investig DOI 10.1007/s40261-014-0221-2
ORIGINAL RESEARCH ARTICLE
Pregabalin Controlled-Release Pharmacokinetics in Healthy Volunteers: Analysis of Four Multiple-Dose Randomized Clinical Pharmacology Studies Marci L. Chew • Christine W. Alvey • Anna Plotka • Verne W. Pitman • Tanja Alebic-Kolbah Joseph M. Scavone • Howard N. Bockbrader
•
Ó Springer International Publishing Switzerland 2014
Abstract Background Pregabalin (LyricaÒ) is approved as an immediate-release (IR) formulation for administration twice (BID) or three times (TID) a day depending on indication. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience. Objectives The objectives of this analysis were: (1) to evaluate the pharmacokinetics of pregabalin controlledrelease (CR) administered with food relative to the pregabalin IR formulation administered fasted; (2) to evaluate the pharmacokinetics of a two-tablet dose of pregabalin CR compared with the equivalent one-tablet dose of pregabalin CR; and (3) to determine the safety and tolerability of multiple-dose administration of pregabalin CR and IR. Methods The pharmacokinetic properties of pregabalin CR were determined in four phase I, open-label, multipledose crossover studies (18–24 participants/study). Pregabalin CR (82.5, 165, 330 or 660 mg/day) administered QD was compared with pregabalin IR (75, 150, 300 or 600 mg/day, respectively) administered either BID or TID. Blood samples were collected up to 24 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. Results Eight-four healthy participants (19–55 years of age) received pregabalin. For all pregabalin CR doses, total M. L. Chew (&) C. W. Alvey V. W. Pitman T. Alebic-Kolbah J. M. Scavone Pfizer Inc, Eastern Point Road, Groton, CT 06340, USA e-mail: [email protected] A. Plotka Pfizer Inc, Collegeville, PA, USA H. N. Bockbrader BEP Analyses, Ann Arbor, MI, USA
exposure was equivalent to the corresponding pregabalin IR dose. Relative bioavailability of pregabalin CR was 93–97 % of pregabalin IR, and bioequivalence criteria with respect to the 24-h steady-state exposure (area under the plasma concentration–time curve from 0 to 24 h [AUC24]) were met. Administration of a two-tablet dose of pregabalin CR was bioequivalent to one-tablet pregabalin CR. The relative bioavailability of two-tablet pregabalin CR was 97–102 % of one-tablet pregabalin CR, and bioequivalence criteria with respect to AUC24 and peak plasma concentrations were met. Pregabalin CR pharmacokinetic parameters were dose proportional following administration of 82.5–660 mg/day pregabalin CR. Pregabalin was well tolerated across studies, with no serious or severe adverse events. Conclusion Total daily exposure with multiple-dose pregabalin CR is equivalent to the corresponding pregabalin IR dose.
Key Points Total daily exposure of pregabalin controlled-release (CR) (82.5–660 mg/day) is equivalent to the corresponding pregabalin immediate-release (IR) dose (75–600 mg/day) Total exposure with two tablets of pregabalin CR administered concurrently is equivalent to the corresponding one-tablet pregabalin CR dose Pregabalin CR within the dosing regimen of the present studies is well tolerated in healthy individuals, with most adverse events considered to be mild to moderate in severity
M. L. Chew et al.
1 Introduction Pregabalin (LyricaÒ; Pfizer Inc, New York, NY, USA) is marketed in over 100 countries. In the USA, pregabalin is indicated as adjunctive treatment for partial seizures, for fibromyalgia and for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia and spinal cord injury [1]. In Europe, pregabalin is indicated as adjunctive treatment for partial seizures, for the treatment of peripheral and central neuropathic pain and for generalized anxiety disorder [2]. Pregabalin is approved as an immediate-release (IR) formulation, with a maximum recommended dose of 600 mg/day depending on indication [1, 2]. The pharmacokinetic properties of pregabalin IR have been extensively evaluated in healthy volunteers [3, 4] and in patients with reduced renal function [5], epilepsy [6] or chronic pain [7, 8]. Pregabalin IR is rapidly absorbed when administered fasted, with peak plasma concentrations (Cmax) occurring 0.7–1.5 h after single- (25–300 mg) or multiple-dose (75–900 mg/day) administration but can be taken with or without food [4]. Cmax and area under the plasma concentration–time curve (AUC) values increase linearly with both single- and multiple-dose administration [4]. Furthermore, pregabalin bioavailability is C90 % and is independent of dose [4]. Pregabalin does not bind to plasma proteins and undergoes negligible metabolism [3]. Additionally, pregabalin has no effect on the major cytochrome P450 enzymes [9] and therefore is unlikely to be involved in significant pharmacokinetic drug–drug interactions [1, 10, 11]. Pregabalin is predominantly renally excreted as unchanged drug [3] with an elimination halflife of 6.3 h [4]. Pregabalin IR is administered twice (BID) or three times (TID) a day, depending on indication [1, 2]. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience and could lead to improved patient adherence [12]. To potentially achieve a QD dosing regimen for pregabalin, a controlled-release (CR) formulation, which is administered after a meal, has been developed. Results from initial studies have indicated that pregabalin CR 300 mg administered following a meal is equivalent to pregabalin IR 300 mg with respect to total exposure (Studies 1174 and 1206, Pfizer Inc, data on file). However, since the relative bioavailability of the pregabalin CR 300 mg formulation averages 85–91 % of that of pregabalin IR, the strengths of the pregabalin CR formulations were increased by 10 % for subsequent studies. Therefore, the pregabalin CR formulations used in the studies reported here contain 82.5, 165 or 330 mg of pregabalin per tablet. The pregabalin CR studies reported here sought to (1) evaluate the steady-state pharmacokinetic profile and
bioequivalence of pregabalin CR (82.5, 165, 330 and 660 mg/day) administered QD immediately following an evening meal, relative to the equivalent dose of the pregabalin IR formulation (75, 150, 300 and 600 mg/day) administered fasted BID or TID; (2) evaluate the steadystate pharmacokinetic profile and bioequivalence of a twotablet (administered concurrently) dose of pregabalin CR (2 9 82.5, 2 9 165 mg/day) as compared with the equivalent one-tablet dose of pregabalin CR (1 9 165, 1 9 330 mg/day) (both administered QD immediately following an evening meal); and (3) determine the safety and tolerability of multiple-dose administration of the pregabalin CR and IR formulations. 2 Methods Four studies evaluating the pharmacokinetic properties of pregabalin CR were conducted in healthy volunteers between October 2010 and March 2011. All studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before entering each study. The final protocols and informed consent documentation were reviewed and approved by the Erasme Hospital Ethics Committee, Brussels, Belgium, where the studies were conducted. All studies are registered on ClinicalTrials.gov under the following identifiers: Study 1, NCT01202435 (study sponsor identifier, A0081215); Study 2, NCT01220219 (A0081226); Study 3, NCT01202422 (A0081198); and Study 4, NCT01257516 (A0081216). 2.1 Study Design All studies were phase I, open-label, multiple-dose, randomized, crossover studies with at least a 7-day washout between each period of treatment. Studies 1 and 4 were two-way crossover studies, while Studies 2 and 3 were three-way crossover studies. Participants received either pregabalin CR or pregabalin IR during a 5-day treatment period. The pregabalin CR treatments were administered QD in the evening of days 1–4, and the pregabalin IR formulation was administered either BID or TID, beginning with the evening dose on day 1 and finishing with the final dose in either the morning or the afternoon of day 5. Blood samples were obtained from the evening dose on day 4 onwards for 24 h to provide plasma for pharmacokinetic analysis. Study 1 compared pregabalin CR 82.5 mg/day (1 9 82.5 mg QD) with pregabalin IR 75 mg/day (1 9 25 mg TID). Study 2 compared pregabalin CR
Multiple-Dose Pregabalin Controlled-Release PK
165 mg/day (1 9 165 mg QD and 2 9 82.5 mg QD) with pregabalin IR 150 mg/day (1 9 75 mg BID). Study 3 compared pregabalin CR 330 mg/day (1 9 330 and 2 9 165 mg QD) with pregabalin IR 300 mg/day (1 9 150 mg BID). Study 4 compared pregabalin CR 660 mg/day (2 9 330 mg QD) with pregabalin IR 600 mg/day (1 9 300 mg BID). 2.2 Participants All participants were required to be in good health, which was verified at screening by medical history, physical examination, urine drug test, safety laboratory panel, electrocardiogram and vital signs (blood pressure and pulse rate). Participants aged 18–55 years, with a body mass index (BMI) of 17.5–30.5 kg/m2 and a total body weight of [50 kg, were eligible for entry. Participants were required to abstain from caffeine-containing products for 24 h prior to the start of dosing until collection of the final pharmacokinetic sample of each study period. Key study exclusion criteria included the following: estimated creatinine clearance of \60 ml/min; the use of tobacco or nicotine-containing products in excess of the equivalent of five cigarettes per day; and the use of prohibited medication, including prescription or nonprescription medication (other than contraceptives or hormonereplacement therapy) in the 7 days or 5 half-lives (whichever was longer) prior to receiving the first dose of study medication. Herbal supplements had to be discontinued at least 28 days prior to the first dose of study medication. As an exception, the use of acetaminophen (B1 g/day) was permitted if required.
administration on days 4 and 5, fasting for morning pregabalin IR administration was at least 8 h pre-dose and at least 2 h post-dose; fasting for mid-afternoon pregabalin IR administration was at least 2 h pre- and post-dose; fasting for evening pregabalin IR administration was at least 3 h pre- and post-dose. For both pregabalin formulations, study medication was administered with water and swallowed whole. No dosing titration was used for any dose or formulation. 2.4 Pharmacokinetic Sampling Blood samples were taken throughout each study for determination of plasma pregabalin concentrations. The first sample was taken prior to the evening dose on day 4 (time 0) for all study treatments. In Study 1, blood samples were also drawn at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h after the time 0 dose for pregabalin CR, and at 0.33, 0.67, 1, 1.5, 2, 4, 6, 9, 12, 12.33, 12.67, 13, 13.5, 14, 16, 18, 18.33, 18.67, 19, 19.5, 20, 22 and 24 h after the time 0 dose for pregabalin IR. Participants receiving pregabalin IR were given their day 5 morning and mid-afternoon doses approximately 5 min after the 12 and 18-h blood draws, respectively. In Studies 2, 3 and 4, blood samples were also drawn at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h after the time 0 dose for pregabalin CR, and at 0.33, 0.67, 1, 1.5, 2, 4, 6, 9, 12, 12.33, 12.67, 13, 13.5, 14, 16, 18, 21 and 24 h after the time 0 dose for pregabalin IR. Participants receiving pregabalin IR were given their day 5 morning dose approximately 5 min after the 12-h blood draw.
2.3 Medication Dosing Schedule
2.5 Sample Handling and Determination of Plasma Pregabalin Concentration
The pregabalin CR formulations were administered as one or two (concurrently administered) tablets QD for 4 days immediately following a 600–750 calorie medium-fat evening meal (with 30–35 % of the total caloric content coming from fat). Evening administration occurred within approximately 5 min of completion of the evening meal. Following administration of the evening study medication, participants abstained from all food and drink (except water) until breakfast the following morning. Study medication was administered at approximately the same time of day for a given participant across each treatment period. The pregabalin IR formulations were administered under fasted conditions BID (every 12 h; Studies 2, 3 and 4) or TID (every 6–6–12 h; Study 1) for 5 days. For BID administration, fasting for morning pregabalin IR administration was at least 8 h pre-dose and at least 2 h postdose; fasting for evening pregabalin IR administration was at least 4 h pre-dose and at least 3 h post-dose. For TID
All blood samples were collected in tubes containing sodium heparin, and the plasma was stored frozen at -20 °C until analysed. Plasma samples were analysed for pregabalin concentrations at WuXi App Tec (Shanghai, China) using a validated, sensitive and specific high-performance liquid chromatography hyphenate chromatography-tandem mass spectrometric method, which is a minor modification of a method validated for lithium heparin plasma [13]. The lower limit of quantification (LLOQ) for pregabalin was 0.0250 lg/ml and the upper limit of quantification (ULOQ) was 10 lg/ml. Clinical specimens with plasma pregabalin concentrations below the LLOQ were reported as below the LLOQ, and those with concentrations above the ULOQ were adequately diluted into calibration range. Assay precision, expressed as the between-day percentage coefficients of variation (% CV) of the mean estimated concentrations of quality control (QC) samples,
M. L. Chew et al.
was B4.9 % across these four studies for low QC (0.0600 lg/ml), medium-low QC (0.600 lg/ml), mediumhigh QC (2.00 lg/ml), high QC (7.50 lg/ml) and dilution QC (20.0 lg/ml) concentrations. The between-day assay accuracy, expressed as the percent relative error for QC concentrations, ranged from -1.2 to ?7.0 % across these four studies for the low QC, medium QC, high QC and dilution QC samples.
exacerbation of previous illnesses; additionally, any clinically significant changes in physical examination findings and abnormal objective test findings were captured and recorded as AEs.
3 Results 3.1 Participants
2.6 Statistical Analyses Pharmacokinetic parameters for pregabalin CR and IR were calculated for each participant for each treatment using noncompartmental analysis of concentration–time data. Concentrations below the LLOQ were treated as zero for the analysis. For both treatments (pregabalin CR and IR), pharmacokinetic parameters were determined for the 0- to 24-h period following the time 0 evening dose. The Cmax, the lowest observed plasma concentration (Cmin) and the time of maximum observed plasma concentration (tmax) were recorded as observed. The AUC from 0 to 24 h (AUC0–24) was calculated using the linear/ log trapezoidal method. The peak–trough ratio (PTR) was calculated according to the formula Cmax/Cmin. In addition, for the pregabalin IR treatments, Cmax and AUC for each dosing interval (time 0 to time s [AUCs]) were determined: evening (0–12 h), morning (12–24 h for BID dosing; 12–18 h for TID dosing) and afternoon (18–24 h for TID dosing). Cmax was recorded as observed and AUCs was calculated using the linear/log trapezoidal method. Natural log-transformed AUC24 and Cmax for 0–24 h were analysed using a mixed-effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Test–Reference) and corresponding 90 % confidence intervals (CI) were obtained from the model. When comparing pregabalin CR doses with pregabalin IR doses, bioequivalence of the Test formulation to the Reference formulation was concluded if the 90 % CIs for AUC24 were contained within 80–125 %. When comparing pregabalin CR doses with other pregabalin CR doses, bioequivalence of the Test formulation to the Reference formulation was concluded if the 90 % CIs for both Cmax and AUC24 were contained within 80–125 %. 2.7 Safety Evaluations Study investigators recorded all observed or volunteered adverse events (AEs), the severity of the events and the relationship to the study treatment. AEs included adverse drug reactions, illnesses with onset during the study and
Eighty-four (64 male, 20 female) participants received pregabalin across the four studies (Table 1). Participants were 19–55 years of age, with a BMI of 18–30 kg/m2 and total body weight 50–103 kg. Compliance with study protocols was generally high, although in Study 3 one participant chewed the pregabalin CR tablets throughout the study in violation of the protocol; therefore, the pharmacokinetic concentration and parameter data for this participant were excluded from the statistical analysis and from all summary plots and tables. 3.2 Pregabalin Pharmacokinetics: Descriptive and Statistical Summary Mean plasma pregabalin concentration–time profiles for each study are presented in Fig. 1. The pregabalin pharmacokinetic parameter values are summarized descriptively in Table 2. Plots of individual and median pharmacokinetic parameter values by treatment are presented in Fig. 2 for AUC24 and Fig. 3 for Cmax. Mean Cmax values for pregabalin CR and evening mean Cmax values for pregabalin IR were similar, while the Table 1 Participant demographics Study 1
Study 2
Study 3
Study 4
N
18
24
24
18
Male, n (%)
14 (77.8)
18 (75.0)
14 (58.3)
18 (100)
Age, years Mean (SD)
37.4 (8.6)
38.3 (10.0)
38.3 (9.9)
31.1 (10.0)
Range
20–54
19–55
22–55
19–50
Race, n (%) White
18 (100)
20 (83.3)
23 (95.8)
17 (94.4)
Black
0
3 (12.5)
1 (4.2)
1 (5.6)
Other
0
1 (4.2)
0
0
Weight, kg Mean (SD)
75.2 (12.4)
78.7 (13.7)
74.5 (14.1)
72.7 (8.7)
Range
50–99
54–103
53–102
55–84
24.5 (2.8) 19–29
25.3 (2.8) 21–30
25.1 (3.3) 19–29
23.2 (2.7) 18–27
BMI, kg/m2 Mean (SD) Range
BMI body mass index, SD standard deviation
10 1x82.5mg CR QD With Food 1x25mg IR TID Fasted
1
0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Study 3 10
1
1x330mg CR QD With Food 2x165mg CR QD With Food 2x150mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Plasma Pregabalin Concentration ( µg/ml)
Study 1
Plasma Pregabalin Concentration (µg/ml)
Plasma Pregabalin Concentration (µg/ml)
Plasma Pregabalin Concentration (µg/ml)
Multiple-Dose Pregabalin Controlled-Release PK
Study 2 10
1
1x165mg CR QD With Food 2x82.5mg CR QD With Food 1x75mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Study 4 10
1
2x330mg CR QD With Food 1x300mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Fig. 1 Mean plasma pregabalin concentration–time profiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
morning mean Cmax values for pregabalin IR BID were higher than for either pregabalin CR or evening pregabalin IR (Table 2). In addition, mean Cmax values for pregabalin CR 82.5 mg QD were generally similar to the mean Cmax values for pregabalin IR 25 mg TID (Table 2). Cmax occurred later for pregabalin CR (median tmax 8–10 h after the evening dose, depending on study) (Table 2) than for pregabalin IR, where the median tmax occurred approximately 0.7–2 h after each dose (Fig. 1). The observed mean Cmin following pregabalin CR administration was 15–25 % lower than that of pregabalin IR administered BID and 35 % lower than that of pregabalin IR administered TID. AUC24 and Cmax values for both pregabalin CR and IR were dose proportional over the range of doses tested (82.5–660 and 75–600 mg, respectively) (Table 2). For both AUC24 and Cmax, variability was low irrespective of dosing regimen or treatment, with % CV values B21 % (Table 2). The range of individual total daily exposures (AUC24) for pregabalin CR (one or two tablets) and
pregabalin IR were comparable at each dose (Fig. 2). For Cmax, the overall range of individual exposures was lower but with overlap for pregabalin CR relative to the respective pregabalin IR dose (Fig. 3). The PTR for pregabalin CR was 13–19 % lower than that of pregabalin IR administered BID, but PTR was 30 % higher than that of pregabalin IR administered TID (Table 2). Results for the comparison of pregabalin CR with pregabalin IR, and for the comparison of two tablets of pregabalin CR with one tablet of pregabalin CR, are summarized in Table 3. The relative bioavailability of pregabalin CR 82.5, 165, 330 and 660 mg given daily after a 600–750 calorie, 30 % fat evening meal was approximately 93–97 % of pregabalin IR (75, 150, 300 and 600 mg/day, respectively), and met bioequivalence criteria with respect to the 24-h steady-state exposures (AUC24), as the 90 % CIs for ratios fell entirely within the 80–125 % range accepted for bioequivalence (Table 3). Ratios of Cmax values were approximately 63–82 % for the
18, 18
IR, 1 9 300 mg, BID
24, 24
IR, 1 9 150 mg, BID
18, 18
23, 22
CR, 2 9 330 mg, QD
23, 22
CR, 1 9 330 mg, QD
24, 24
IR, 1 9 75 mg, BID
CR, 2 9 165 mg, QD
24, 24
CR, 1 9 165 mg, QD
120.00 (13)
115.50 (14)
62.13 (15)
60.06 (18)
59.31 (17)
31.54 (18)
29.35 (17)
29.97 (19)
15.23 (16)
14.69 (18)
AUC24 (lgh/ml) 24-h intervalb
57.85 (12)
N/A
30.27 (15)
N/A
N/A
15.34 (18)
N/A
N/A
7.34 (17)
N/A
Eveningc
62.08 (14)
N/A
31.86 (15)
N/A
N/A
16.20 (18)
N/A
N/A
3.98 (16)
N/A
Morningc
AUCs (lgh/ml)
Parameter summary statisticsa
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
3.90 (16)
N/A
Afternoonc
11.35 (17)
7.75 (12)
6.39 (20)
4.22 (20)
4.11 (16)
3.18 (21)
1.99 (17)
2.03 (20)
1.24 (12)
1.03 (16)
24-h intervalb
9.27 (18)
N/A
4.54 (20)
N/A
N/A
2.38 (20)
N/A
N/A
1.15 (13)
N/A
Eveningc
Cmax (lg/ml)
11.07 (19)
N/A
6.36 (20)
N/A
N/A
3.15 (21)
N/A
N/A
1.20 (15)
N/A
Morningc
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
0.85 (15)
N/A
Afternoonc
2.08 (22)
1.76 (26)
1.11 (21)
0.85 (26)
0.82 (25)
0.59 (25)
0.44 (24)
0.43 (27)
0.31 (24)
0.20 (30)
Cmin (lg/ml)b
4.42 (17) 5.46 (38)
12.7d (0.67–14.00)
5.74 (30)
4.96 (36)
5.01 (29)
9.00 (6.00–12.00)
12.7 (0.67–13.50)
d
10.0 (5.00–11.90)
10.0 (5.00–12.00)
4.58 (41) 5.43 (34)
12.7d (0.67–13.50)
4.75 (37) 8.00 (5.00–11.90)
8.00 (4.00–11.90)
5.16 (28) 3.96 (20)
12.7d (1.00–13.00)
PTRb
8.00 (5.00–10.00)
tmax (h)b
d
c
b
a
Pregabalin IR tmax (12.7 h) occurred during the second (morning) dosing interval, approximately 0.7 h after the morning dose
Pregabalin IR treatments only: parameters assessed over the evening (0–12 h), morning (12–24 h for BID, 12–18 h for TID) and afternoon (18–24 h for TID) dosing intervals
All treatments (pregabalin CR and IR): parameters assessed across the 0–24-h interval
Geometric mean (% coefficient of variation) is presented for all parameters except for tmax, where median (range) is presented
N number of participants in the treatment group, n number of participants included in the analysis, AUC24 area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4, AUCs area under the concentration–time curve for the specified dosing interval, Cmax peak plasma concentration, Cmin lowest observed plasma concentration, tmax time of maximum observed plasma concentration, PTR peak–trough ratio, QD once daily, N/A not applicable, TID three times a day, BID twice a day
4
3
23, 23
CR, 2 9 82.5 mg, QD
17, 17
IR, 1 9 25 mg, TID
2
18, 18
CR, 1 9 82.5 mg, QD
1
N, n
Dose
Study
Table 2 Descriptive summary of pregabalin controlled-release (CR) and immediate-release (IR) pharmacokinetic parameters
M. L. Chew et al.
Multiple-Dose Pregabalin Controlled-Release PK
Study 2 Plasma pregabalin AUC24 (µg·h/ml)
Plasma pregabalin AUC24 (µg·h/ml)
Study 1
20
15
10
5 A
40
30
20
C
B
D
Treatment group
Treatment group
Study 4
80 70 60 50 40 30 G
H
Plasma pregabalin AUC24 (µg·h/ml)
Plasma pregabalin AUC24 (µg·h/ml)
Study 3 90
F
E
160
140
120
100
80 I
J
Treatment group
Treatment group
Fig. 2 Individual and median pregabalin area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4 (AUC24) values by treatment. Study 1: A, CR, 1 9 82.5 mg, QD; B, IR, 1 9 25 mg, TID. Study 2: C, CR, 2 9 82.5 mg, QD; D, CR, 1 9 165 mg, QD; E, IR, 1 9 75 mg, BID. Study 3: F, CR, 2 9 165 mg, QD; G, CR, 1 9 330 mg, QD; H,
IR, 1 9 150 mg, BID. Study 4: I, CR, 2 9 330 mg, QD; J, IR, 1 9 300 mg, BID. Open circles represent individual participant values. Scatter plot shows median and 25–75 % quartiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
pregabalin CR treatments relative to the respective pregabalin IR treatments. Ratios of both AUC24 and Cmax for the two-tablet pregabalin CR treatments were approximately 97–102 % relative to the respective one-tablet pregabalin CR treatments and met bioequivalence criteria with respect to both parameters (Table 3).
(n = 31, 36.9 %), fatigue (n = 28, 33.3 %), hypersomnia (n = 27, 32.1 %), headache (n = 22, 26.2 %) and somnolence (n = 21, 25.0 %) (Table 4). With pregabalin IR, the most common all-causality AEs across the four studies were dizziness (n = 31, 37.3 %), headache (n = 21, 25.3 %), fatigue (n = 18, 21.7 %), hypersomnia (n = 13, 15.7 %) and somnolence (n = 12, 14.5 %) (Table 4).
3.3 Safety Evaluations Pregabalin was well tolerated in all four studies, with no serious or severe AEs. No participant discontinued owing to an AE. No deaths occurred during these studies. The majority of treatment-related AEs were considered mild or moderate in severity. With pregabalin CR, the most common all-causality AEs across the four studies were dizziness
4 Discussion These findings demonstrate that pregabalin CR (82.5, 165, 330 and 660 mg/day) administered QD immediately following a 600–750 calorie, medium-fat evening meal is equivalent to the pregabalin IR formulation with respect to
M. L. Chew et al.
Study 2 Plasma pregabalin Cmax (µg/ml)
Plasma pregabalin Cmax (µg/ml)
Study 1 2.0
1.5
1.0
0.5 A
B
6
4
2
0 C
D
Treatment group
Study 4 Plasma pregabalin Cmax (µg/ml)
Plasma pregabalin Cmax (µg/ml)
Study 3
10
5
0 F
G
E
Treatment group
H
Treatment group
15
10
5 I
J
Treatment group
Fig. 3 Individual and median pregabalin peak plasma concentration (Cmax) values by treatment. Study 1: A, CR, 1 9 82.5 mg, QD; B, IR, 1 9 25 mg, TID. Study 2: C, CR, 2 9 82.5 mg, QD; D, CR, 1 9 165 mg, QD; E, IR, 1 9 75 mg, BID. Study 3: F, CR, 2 9 165 mg, QD; G, CR, 1 9 330 mg, QD; H, IR, 1 9 150 mg,
BID. Study 4: I, CR, 2 9 330 mg, QD; J, IR, 1 9 300 mg, BID. Open circles represent individual participant values. Scatter plot shows median and 25–75 % quartiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
AUC24. Also, pregabalin CR (two tablets of 82.5 mg or 165 mg) is bioequivalent to one tablet of pregabalin CR (165 mg or 330 mg, respectively) with respect to AUC24 and Cmax. In addition to demonstrating pharmacokinetic equivalence, the safety profiles of pregabalin CR and IR across the dose range were similar to and consistent with that known for pregabalin IR [1, 2]. As expected, slow and sustained absorption occurred with pregabalin CR treatment and peak concentrations were observed approximately 8–10 h following the evening dose. In contrast, absorption occurred more quickly following pregabalin IR administration and peak concentrations were observed at approximately 0.7–2 h after each dose. The observed peak concentrations following pregabalin CR dosing were similar to those observed with evening pregabalin IR administration, but lower than those seen with morning pregabalin IR administration. Pharmacokinetic
parameters for the pregabalin IR formulation were consistent with a decrease in the rate of absorption of pregabalin in the evening relative to morning administration. In all four studies analysed herein, Cmax with pregabalin IR administration was approximately 30 % lower and the median tmax was delayed by 0.8 h with evening administration compared with morning administration, while the geometric mean AUCs was similar for the evening and morning dosing intervals. One possible explanation for this is diurnal variation in gastrointestinal motility [14–17]. Another possible contributing factor is that participants were fasted for at least 8 h prior to the morning dose but only 4 h prior to the evening dose because of logistical constraints. In line with this hypothesis, previous studies with the pregabalin IR formulation have demonstrated a decrease in the rate but not extent of absorption when administered immediately following a meal [4].
Multiple-Dose Pregabalin Controlled-Release PK Table 3 Statistical summary of treatment comparisons for pregabalin immediate-release (IR) and controlled-release (CR) Study
Test
Reference
Parameter
Adjusted geometric means Test
1
CR, 1 9 82.5 mg, QD
IR, 1 9 25 mg, TID
AUC24, lgh/ml Cmax, lg/ml
2
CR, 1 9 165 mg, QD
IR, 1 9 75 mg, BID
CR, 2 9 82.5 mg, QD
IR, 1 9 75 mg, BID
CR, 2 9 82.5 mg, QD
CR, 1 9 165 mg, QD
CR, 2 9 165 mg, QD
IR, 1 9 150 mg, BID
AUC24, lgh/ml Cmax, lg/ml AUC24, lgh/ml Cmax, lg/ml
3
IR, 1 9 150 mg, BID
CR, 2 9 165 mg, QD
CR, 1 9 330 mg, QD
CR, 2 9 330 mg, QD
IR, 1 9 300 mg, BID
14.69
15.30
96.02
1.03
1.25
82.19
92.84,99.30 77.05,87.67
29.35
31.54
93.05
90.47,95.71
1.99
3.18
62.62
59.92,65.43
30.03
31.54
95.21
92.52,97.97
2.03
3.18
63.79
61.00,66.71
30.03 2.03
29.35 1.99
102.31 101.87
99.43,105.28 97.42,106.53
AUC24, lgh/mL
58.75
62.13
94.56
92.05,97.14
4.08
6.39
63.84
60.82,67.00
60.45
62.13
97.30
94.71,99.95
AUC24, lgh/ml Cmax, lg/ml AUC24, lgh/ml Cmax, lg/ml
4
90 % CI for ratio (%)
AUC24, lgh/ml Cmax, lg/ml Cmax, lg/ml
CR, 1 9 330 mg, QD
Reference
Ratio (T/R) of adjusted means (%)
6.39
66.15
63.02,69.42
60.45
97.19
94.56,99.89
4.08
AUC24, lgh/ml Cmax, lg/ml
4.22 58.75 115.5 7.75
4.22 120.0 11.35
96.51
91.87,101.38
96.29
92.35,100.41
68.34
63.76,73.24
T/R test/reference, CI confidence interval, QD once daily, TID three times a day, AUC24 area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4, Cmax peak plasma concentration, BID twice a day
Previous analyses of pregabalin in patients with epilepsy [18], generalized anxiety disorder [19], diabetic peripheral neuropathy [20] or postherpetic neuralgia [21] have shown that similar efficacy is achieved with up to 600 mg/day pregabalin IR taken BID or TID, despite the differences between the concentration–time profiles of pregabalin IR with BID and TID dosing. This could indicate that the different concentration–time profile seen with pregabalin CR administered QD may not have an effect on efficacy of pregabalin CR in these patients. Indeed, pharmacokinetic– pharmacodynamic simulations suggest that, in adults, comparable efficacy can be achieved with administration of pregabalin QD of equivalent total daily exposure (Study PMAR-00109, Pfizer Inc, data on file). Pregabalin CR administered QD could have advantages over pregabalin IR in terms of patient adherence and compliance. Indeed, QD dosing of a wide range of oral medications has been shown to significantly increase adherence rates, compliance and persistence compared with BID, TID or four times daily dosing [12]. In addition, pregabalin CR retains the important features of the pregabalin IR formulation, including good bioavailability [3], low interindividual variability [4], no protein binding or metabolism, primarily renal elimination and lack of significant drug–drug interactions [3]. One consideration for pregabalin CR is the potential impact of potent prokinetic agents such as erythromycin; an ongoing study will demonstrate whether or not erythromycin has any effect on the pharmacokinetic properties of pregabalin CR (Study 1197, Pfizer Inc, manuscript in preparation).
Although safety and tolerability were objectives of all four studies, it should be noted that no study was powered for the statistical evaluation of AEs. Both pregabalin CR and IR were generally well tolerated across all four studies, with AE profiles consistent with those previously reported for pregabalin IR in patient populations [1, 2]. Clinical trials of pregabalin have shown that the two most common AEs, dizziness and somnolence, typically emerge within the first 1–2 weeks of treatment and resolve 1–2 weeks later, usually without requiring treatment to be discontinued [22]. For the clinical pharmacology studies reported herein, only the overall incidence of AEs has been shown given the short duration of each trial. However, two recently completed 14to 19-week trials of pregabalin CR in patients with epilepsy [23] and fibromyalgia [24] have shown that the AE profile of pregabalin CR is generally comparable to that of pregabalin IR in these patient populations. Additional safety data should soon become available from one other ongoing phase III trial of the pregabalin CR formulation in patients with postherpetic neuralgia (Study 1224, NCT01270828). Other limitations of these studies should also be considered. The study population was limited, as only 7 % of participants were non-white. In addition, the meal types were limited, with calorie content restricted to 600–750 calories with 30–35 % of the total caloric content coming from fat. However, other studies examining the effect of food on the pharmacokinetics of pregabalin CR have shown that, in general, meal content has minimal effect [25] supporting our observations from the present analysis.
M. L. Chew et al. Table 4 All-causality, treatment-emergent adverse events (AEs) occurring in C5 % of treated participantsa Pregabalin CR (mg)
Pregabalin IR (mg)
82.5
165
330
660
Total
75
150
300
600
Total
Participants evaluable for AEs, n
18
24
24
18
84
17
24
24
18
83
Participants with AEs, n (%)
10 (55.6)
22 (91.7)
24 (100.0)
17 (94.4)
73 (86.9)
7 (41.2)
20 (83.3)
24 (100.0)
16 (88.9)
67 (80.7)
Dizziness
0
7 (29.2)
22 (91.7)
2 (11.1)
31 (36.9)
0
8 (33.3)
15 (62.5)
8 (44.4)
31 (37.3)
Fatigue
3 (16.7)
10 (41.7)
6 (25.0)
9 (50.0)
28 (33.3)
2 (11.8)
6 (25.0)
7 (29.2)
3 (16.7)
18 (21.7)
Hypersomnia
1 (5.6)
11 (45.8)
14 (58.3)
1 (5.6)
27 (32.1)
0
3 (12.5)
9 (37.5)
1 (5.6)
13 (15.7)
Headache
3 (16.7)
5 (20.8)
8 (33.3)
6 (33.3)
22 (26.2)
4 (23.5)
2 (8.3)
9 (37.5)
6 (33.3)
21 (25.3)
Somnolence
0
6 (25.0)
13 (54.2)
2 (11.1)
21 (25.0)
0
2 (8.3)
7 (29.2)
3 (16.7)
12 (14.5)
Insomnia
1 (5.6)
6 (25.0)
6 (25.0)
2 (11.1)
15 (17.9)
0
3 (12.5)
2 (8.3)
2 (11.1)
7 (8.4)
Feeling drunk
0
0
2 (8.3)
12 (66.7)
14 (16.9)
0
0
2 (8.3)
7 (38.9)
9 (10.8)
Head discomfort
0
2 (8.3)
6 (25.0)
1 (5.6)
9 (10.7)
0
2 (8.3)
2 (8.3)
5 (27.8)
9 (10.8)
Most common AEs, n (%)
Visual impairment
0
0
2 (8.3)
6 (33.3)
8 (9.5)
0
0
2 (8.3)
3 (16.7)
5 (6.0)
Constipation
0
3 (12.5)
4 (16.7)
1 (5.6)
8 (9.5)
0
0
6 (25.0)
0
6 (7.2)
Change of bowel habit
0
2 (8.3)
4 (16.7)
0
6 (7.1)
0
1 (4.2)
2 (8.3)
1 (5.6)
4 (4.8)
Nasopharyngitis
3 (16.7)
2 (8.3)
1 (4.2)
0
6 (7.1)
2 (11.8)
1 (4.2)
0
0
3 (3.6)
Euphoric mood Nausea
0 0
2 (8.3) 1 (4.2)
2 (8.3) 3 (12.5)
2 (11.1) 2 (11.1)
6 (7.1) 6 (7.1)
0 0
0 0
1 (4.2) 0
0 1 (5.6)
1 (1.2) 1 (1.2)
Diarrhoea
0
2 (8.3)
1 (4.2)
0
3 (3.6)
1 (5.9)
1 (4.2)
2 (8.3)
1 (5.6)
5 (6.0)
CR controlled-release, IR immediate-release a
Based on the total pregabalin CR population
5 Conclusion
Pfizer Inc. Howard N. Bockbrader was an employee of Pfizer Inc at the time these studies were conducted and holds stock in Pfizer Inc.
Total daily exposure of pregabalin CR (82.5–660 mg/day) is equivalent to the corresponding pregabalin IR dose (75–600 mg/day). Total exposure with two tablets of pregabalin CR administered concurrently is bioequivalent to the corresponding one-tablet pregabalin CR dose. Pregabalin CR within the dosing regimen of the present studies is well tolerated in healthy individuals, with most AEs considered to be mild to moderate in severity.
Ethical statement All studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before entering each study. The final protocols and informed consent documentation were reviewed and approved by the Erasme Hospital Ethics Committee, Brussels, Belgium, where the studies were conducted.
Acknowledgments The studies described in this paper were sponsored by Pfizer Inc, who was involved in the study design; the collection, analysis and interpretation of the data; the writing of the report; and the decision to submit the paper for publication. Medical writing support was provided by Lorna Forse, PhD, of Engage Scientific Solutions and funded by Pfizer Inc. Conflict of interest Marci L. Chew, Christine W. Alvey, Anna Plotka, Verne W. Pitman, Tanja Alebic-Kolbah and Joseph M. Scavone are all full-time employees of Pfizer Inc and hold stock in
References 1. Lyrica (pregabalin) [package insert]. New York: Pfizer Inc.; 2013. http://labeling.pfizer.com/ShowLabeling.aspx?id=561. Accessed 18 July 2014. 2. Lyrica EU product information. Sandwich: Pfizer Limited; 2014. http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_ Product_Information/human/000546/WC500046602.pdf. Accessed 18 July 2014.
Multiple-Dose Pregabalin Controlled-Release PK 3. Corrigan BW, Pool WF, Posvar EL, et al. Metabolic disposition of pregabalin in healthy volunteers [abstract PI-68]. Clin Pharmacol Ther. 2001;69:P18. 4. Bockbrader HN, Radulovic LL, Posvar EL, et al. Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol. 2010;50:941–50. 5. Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol. 2003;43:277–83. 6. Bockbrader HN, Burger PJ, Corrigan BW, et al. Population pharmacokinetic (PK) analyses of pregabalin (PGB) in adult patients with refractory partial seizures [abstract 1.265]. Epilepsia. 2001;42(Suppl 7):84. 7. Bockbrader HN, Burger P, Knapp L, Corrigan BW. Population pharmacokinetics of pregabalin in healthy subjects and patients with chronic pain or partial seizures. Epilepsia. 2011;52:248–57. 8. Shoji S, Suzuki M, Tomono Y, et al. Population pharmacokinetics of pregabalin in healthy subjects and patients with postherpetic neuralgia or diabetic peripheral neuropathy. Br J Clin Pharmacol. 2011;72:63–76. 9. Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia. 2004;45(Suppl 6):13–8. 10. Brodie MJ, Wilson EA, Wesche DL, et al. Pregabalin drug interaction studies: lack of effect on the pharmacokinetics of carbamazepine, phenytoin, lamotrigine, and valproate in patients with partial epilepsy. Epilepsia. 2005;46:1407–13. 11. Bockbrader HN, Burger P, Knapp L. Pregabalin effect on steadystate pharmacokinetics of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, and tiagabine. Epilepsia. 2011;52:405–9. 12. Srivastava K, Arora A, Kataria A, et al. Impact of reducing dosing frequency on adherence to oral therapies: a literature review and meta-analysis. Patient Prefer Adherence. 2013;7: 419–34. 13. Alebic-Kolbah T. Pregabalin: development and validation of an LC-MS/MS method for pediatric studies [abstract TP 542]. J Am Soc Mass Spectrom. 2012;23:109. 14. Kellow JE, Borody TJ, Phillips SF, et al. Human interdigestive motility: variations in patterns from esophagus to colon. Gastroenterology. 1986;91:386–95.
15. Kumar D, Wingate D, Ruckebusch Y. Circadian variation in the propagation velocity of the migrating motor complex. Gastroenterology. 1986;91:926–30. 16. Wilson P, Perdikis G, Hinder RA, et al. Prolonged ambulatory antroduodenal manometry in humans. Am J Gastroenterol. 1994;89:1489–95. 17. Soffer EE, Thongsawat S, Ellerbroek S. Prolonged ambulatory duodeno-jejunal manometry in humans: normal values and gender effect. Am J Gastroenterol. 1998;93:1318–23. 18. Beydoun A, Uthman BM, Kugler AR, The Pregabalin 1008-009 Study Group, et al. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology. 2005;64:475–80. 19. Pohl RB, Feltner DE, Fieve RR, Pande AC. Efficacy of pregabalin in the treatment of generalized anxiety disorder: doubleblind, placebo-controlled comparison of BID versus TID dosing. J Clin Psychopharmacol. 2005;25:151–8. 20. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care. 2008;31:1448–54. 21. Frampton JE, Foster RH. Pregabalin: in the treatment of postherpetic neuralgia. Drugs. 2005;65:111–20. 22. Freynhagen R, Serpell M, Emir B, et al. A comprehensive drug safety evaluation of pregabalin in peripheral neuropathic pain. Pain Pract. 2013;. doi:10.1111/papr.12146. 23. French J, Brandt C, Friedman D, et al. Adjunctive use of controlled-release pregabalin in adults with treatment-resistant partial seizures: a double-blind, randomized, placebo-controlled trial. Epilepsia. 2014;. doi:10.1111/epi.12690. 24. Arnold LM, Arsenault P, Huffman C, et al. Once-daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study. Curr Med Res Opin. 2014;. doi:10. 1185/03007995.2014.928275. 25. Chew ML, Plotka A, Alvey CW, et al. Pharmacokinetics of Pregabalin Controlled-Released in Healthy Volunteers: Effect of Food in Five Single-Dose, Randomized, Clinical Pharmacology Studies. Clin Drug Investig. 2014;. doi:10.1007/s40261-0140211-4
ORIGINAL RESEARCH ARTICLE
Pregabalin Controlled-Release Pharmacokinetics in Healthy Volunteers: Analysis of Four Multiple-Dose Randomized Clinical Pharmacology Studies Marci L. Chew • Christine W. Alvey • Anna Plotka • Verne W. Pitman • Tanja Alebic-Kolbah Joseph M. Scavone • Howard N. Bockbrader
•
Ó Springer International Publishing Switzerland 2014
Abstract Background Pregabalin (LyricaÒ) is approved as an immediate-release (IR) formulation for administration twice (BID) or three times (TID) a day depending on indication. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience. Objectives The objectives of this analysis were: (1) to evaluate the pharmacokinetics of pregabalin controlledrelease (CR) administered with food relative to the pregabalin IR formulation administered fasted; (2) to evaluate the pharmacokinetics of a two-tablet dose of pregabalin CR compared with the equivalent one-tablet dose of pregabalin CR; and (3) to determine the safety and tolerability of multiple-dose administration of pregabalin CR and IR. Methods The pharmacokinetic properties of pregabalin CR were determined in four phase I, open-label, multipledose crossover studies (18–24 participants/study). Pregabalin CR (82.5, 165, 330 or 660 mg/day) administered QD was compared with pregabalin IR (75, 150, 300 or 600 mg/day, respectively) administered either BID or TID. Blood samples were collected up to 24 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration–time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. Results Eight-four healthy participants (19–55 years of age) received pregabalin. For all pregabalin CR doses, total M. L. Chew (&) C. W. Alvey V. W. Pitman T. Alebic-Kolbah J. M. Scavone Pfizer Inc, Eastern Point Road, Groton, CT 06340, USA e-mail: [email protected] A. Plotka Pfizer Inc, Collegeville, PA, USA H. N. Bockbrader BEP Analyses, Ann Arbor, MI, USA
exposure was equivalent to the corresponding pregabalin IR dose. Relative bioavailability of pregabalin CR was 93–97 % of pregabalin IR, and bioequivalence criteria with respect to the 24-h steady-state exposure (area under the plasma concentration–time curve from 0 to 24 h [AUC24]) were met. Administration of a two-tablet dose of pregabalin CR was bioequivalent to one-tablet pregabalin CR. The relative bioavailability of two-tablet pregabalin CR was 97–102 % of one-tablet pregabalin CR, and bioequivalence criteria with respect to AUC24 and peak plasma concentrations were met. Pregabalin CR pharmacokinetic parameters were dose proportional following administration of 82.5–660 mg/day pregabalin CR. Pregabalin was well tolerated across studies, with no serious or severe adverse events. Conclusion Total daily exposure with multiple-dose pregabalin CR is equivalent to the corresponding pregabalin IR dose.
Key Points Total daily exposure of pregabalin controlled-release (CR) (82.5–660 mg/day) is equivalent to the corresponding pregabalin immediate-release (IR) dose (75–600 mg/day) Total exposure with two tablets of pregabalin CR administered concurrently is equivalent to the corresponding one-tablet pregabalin CR dose Pregabalin CR within the dosing regimen of the present studies is well tolerated in healthy individuals, with most adverse events considered to be mild to moderate in severity
M. L. Chew et al.
1 Introduction Pregabalin (LyricaÒ; Pfizer Inc, New York, NY, USA) is marketed in over 100 countries. In the USA, pregabalin is indicated as adjunctive treatment for partial seizures, for fibromyalgia and for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia and spinal cord injury [1]. In Europe, pregabalin is indicated as adjunctive treatment for partial seizures, for the treatment of peripheral and central neuropathic pain and for generalized anxiety disorder [2]. Pregabalin is approved as an immediate-release (IR) formulation, with a maximum recommended dose of 600 mg/day depending on indication [1, 2]. The pharmacokinetic properties of pregabalin IR have been extensively evaluated in healthy volunteers [3, 4] and in patients with reduced renal function [5], epilepsy [6] or chronic pain [7, 8]. Pregabalin IR is rapidly absorbed when administered fasted, with peak plasma concentrations (Cmax) occurring 0.7–1.5 h after single- (25–300 mg) or multiple-dose (75–900 mg/day) administration but can be taken with or without food [4]. Cmax and area under the plasma concentration–time curve (AUC) values increase linearly with both single- and multiple-dose administration [4]. Furthermore, pregabalin bioavailability is C90 % and is independent of dose [4]. Pregabalin does not bind to plasma proteins and undergoes negligible metabolism [3]. Additionally, pregabalin has no effect on the major cytochrome P450 enzymes [9] and therefore is unlikely to be involved in significant pharmacokinetic drug–drug interactions [1, 10, 11]. Pregabalin is predominantly renally excreted as unchanged drug [3] with an elimination halflife of 6.3 h [4]. Pregabalin IR is administered twice (BID) or three times (TID) a day, depending on indication [1, 2]. Once daily (QD) dosing may be appropriate for ease of clinical use and patient convenience and could lead to improved patient adherence [12]. To potentially achieve a QD dosing regimen for pregabalin, a controlled-release (CR) formulation, which is administered after a meal, has been developed. Results from initial studies have indicated that pregabalin CR 300 mg administered following a meal is equivalent to pregabalin IR 300 mg with respect to total exposure (Studies 1174 and 1206, Pfizer Inc, data on file). However, since the relative bioavailability of the pregabalin CR 300 mg formulation averages 85–91 % of that of pregabalin IR, the strengths of the pregabalin CR formulations were increased by 10 % for subsequent studies. Therefore, the pregabalin CR formulations used in the studies reported here contain 82.5, 165 or 330 mg of pregabalin per tablet. The pregabalin CR studies reported here sought to (1) evaluate the steady-state pharmacokinetic profile and
bioequivalence of pregabalin CR (82.5, 165, 330 and 660 mg/day) administered QD immediately following an evening meal, relative to the equivalent dose of the pregabalin IR formulation (75, 150, 300 and 600 mg/day) administered fasted BID or TID; (2) evaluate the steadystate pharmacokinetic profile and bioequivalence of a twotablet (administered concurrently) dose of pregabalin CR (2 9 82.5, 2 9 165 mg/day) as compared with the equivalent one-tablet dose of pregabalin CR (1 9 165, 1 9 330 mg/day) (both administered QD immediately following an evening meal); and (3) determine the safety and tolerability of multiple-dose administration of the pregabalin CR and IR formulations. 2 Methods Four studies evaluating the pharmacokinetic properties of pregabalin CR were conducted in healthy volunteers between October 2010 and March 2011. All studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before entering each study. The final protocols and informed consent documentation were reviewed and approved by the Erasme Hospital Ethics Committee, Brussels, Belgium, where the studies were conducted. All studies are registered on ClinicalTrials.gov under the following identifiers: Study 1, NCT01202435 (study sponsor identifier, A0081215); Study 2, NCT01220219 (A0081226); Study 3, NCT01202422 (A0081198); and Study 4, NCT01257516 (A0081216). 2.1 Study Design All studies were phase I, open-label, multiple-dose, randomized, crossover studies with at least a 7-day washout between each period of treatment. Studies 1 and 4 were two-way crossover studies, while Studies 2 and 3 were three-way crossover studies. Participants received either pregabalin CR or pregabalin IR during a 5-day treatment period. The pregabalin CR treatments were administered QD in the evening of days 1–4, and the pregabalin IR formulation was administered either BID or TID, beginning with the evening dose on day 1 and finishing with the final dose in either the morning or the afternoon of day 5. Blood samples were obtained from the evening dose on day 4 onwards for 24 h to provide plasma for pharmacokinetic analysis. Study 1 compared pregabalin CR 82.5 mg/day (1 9 82.5 mg QD) with pregabalin IR 75 mg/day (1 9 25 mg TID). Study 2 compared pregabalin CR
Multiple-Dose Pregabalin Controlled-Release PK
165 mg/day (1 9 165 mg QD and 2 9 82.5 mg QD) with pregabalin IR 150 mg/day (1 9 75 mg BID). Study 3 compared pregabalin CR 330 mg/day (1 9 330 and 2 9 165 mg QD) with pregabalin IR 300 mg/day (1 9 150 mg BID). Study 4 compared pregabalin CR 660 mg/day (2 9 330 mg QD) with pregabalin IR 600 mg/day (1 9 300 mg BID). 2.2 Participants All participants were required to be in good health, which was verified at screening by medical history, physical examination, urine drug test, safety laboratory panel, electrocardiogram and vital signs (blood pressure and pulse rate). Participants aged 18–55 years, with a body mass index (BMI) of 17.5–30.5 kg/m2 and a total body weight of [50 kg, were eligible for entry. Participants were required to abstain from caffeine-containing products for 24 h prior to the start of dosing until collection of the final pharmacokinetic sample of each study period. Key study exclusion criteria included the following: estimated creatinine clearance of \60 ml/min; the use of tobacco or nicotine-containing products in excess of the equivalent of five cigarettes per day; and the use of prohibited medication, including prescription or nonprescription medication (other than contraceptives or hormonereplacement therapy) in the 7 days or 5 half-lives (whichever was longer) prior to receiving the first dose of study medication. Herbal supplements had to be discontinued at least 28 days prior to the first dose of study medication. As an exception, the use of acetaminophen (B1 g/day) was permitted if required.
administration on days 4 and 5, fasting for morning pregabalin IR administration was at least 8 h pre-dose and at least 2 h post-dose; fasting for mid-afternoon pregabalin IR administration was at least 2 h pre- and post-dose; fasting for evening pregabalin IR administration was at least 3 h pre- and post-dose. For both pregabalin formulations, study medication was administered with water and swallowed whole. No dosing titration was used for any dose or formulation. 2.4 Pharmacokinetic Sampling Blood samples were taken throughout each study for determination of plasma pregabalin concentrations. The first sample was taken prior to the evening dose on day 4 (time 0) for all study treatments. In Study 1, blood samples were also drawn at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h after the time 0 dose for pregabalin CR, and at 0.33, 0.67, 1, 1.5, 2, 4, 6, 9, 12, 12.33, 12.67, 13, 13.5, 14, 16, 18, 18.33, 18.67, 19, 19.5, 20, 22 and 24 h after the time 0 dose for pregabalin IR. Participants receiving pregabalin IR were given their day 5 morning and mid-afternoon doses approximately 5 min after the 12 and 18-h blood draws, respectively. In Studies 2, 3 and 4, blood samples were also drawn at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18 and 24 h after the time 0 dose for pregabalin CR, and at 0.33, 0.67, 1, 1.5, 2, 4, 6, 9, 12, 12.33, 12.67, 13, 13.5, 14, 16, 18, 21 and 24 h after the time 0 dose for pregabalin IR. Participants receiving pregabalin IR were given their day 5 morning dose approximately 5 min after the 12-h blood draw.
2.3 Medication Dosing Schedule
2.5 Sample Handling and Determination of Plasma Pregabalin Concentration
The pregabalin CR formulations were administered as one or two (concurrently administered) tablets QD for 4 days immediately following a 600–750 calorie medium-fat evening meal (with 30–35 % of the total caloric content coming from fat). Evening administration occurred within approximately 5 min of completion of the evening meal. Following administration of the evening study medication, participants abstained from all food and drink (except water) until breakfast the following morning. Study medication was administered at approximately the same time of day for a given participant across each treatment period. The pregabalin IR formulations were administered under fasted conditions BID (every 12 h; Studies 2, 3 and 4) or TID (every 6–6–12 h; Study 1) for 5 days. For BID administration, fasting for morning pregabalin IR administration was at least 8 h pre-dose and at least 2 h postdose; fasting for evening pregabalin IR administration was at least 4 h pre-dose and at least 3 h post-dose. For TID
All blood samples were collected in tubes containing sodium heparin, and the plasma was stored frozen at -20 °C until analysed. Plasma samples were analysed for pregabalin concentrations at WuXi App Tec (Shanghai, China) using a validated, sensitive and specific high-performance liquid chromatography hyphenate chromatography-tandem mass spectrometric method, which is a minor modification of a method validated for lithium heparin plasma [13]. The lower limit of quantification (LLOQ) for pregabalin was 0.0250 lg/ml and the upper limit of quantification (ULOQ) was 10 lg/ml. Clinical specimens with plasma pregabalin concentrations below the LLOQ were reported as below the LLOQ, and those with concentrations above the ULOQ were adequately diluted into calibration range. Assay precision, expressed as the between-day percentage coefficients of variation (% CV) of the mean estimated concentrations of quality control (QC) samples,
M. L. Chew et al.
was B4.9 % across these four studies for low QC (0.0600 lg/ml), medium-low QC (0.600 lg/ml), mediumhigh QC (2.00 lg/ml), high QC (7.50 lg/ml) and dilution QC (20.0 lg/ml) concentrations. The between-day assay accuracy, expressed as the percent relative error for QC concentrations, ranged from -1.2 to ?7.0 % across these four studies for the low QC, medium QC, high QC and dilution QC samples.
exacerbation of previous illnesses; additionally, any clinically significant changes in physical examination findings and abnormal objective test findings were captured and recorded as AEs.
3 Results 3.1 Participants
2.6 Statistical Analyses Pharmacokinetic parameters for pregabalin CR and IR were calculated for each participant for each treatment using noncompartmental analysis of concentration–time data. Concentrations below the LLOQ were treated as zero for the analysis. For both treatments (pregabalin CR and IR), pharmacokinetic parameters were determined for the 0- to 24-h period following the time 0 evening dose. The Cmax, the lowest observed plasma concentration (Cmin) and the time of maximum observed plasma concentration (tmax) were recorded as observed. The AUC from 0 to 24 h (AUC0–24) was calculated using the linear/ log trapezoidal method. The peak–trough ratio (PTR) was calculated according to the formula Cmax/Cmin. In addition, for the pregabalin IR treatments, Cmax and AUC for each dosing interval (time 0 to time s [AUCs]) were determined: evening (0–12 h), morning (12–24 h for BID dosing; 12–18 h for TID dosing) and afternoon (18–24 h for TID dosing). Cmax was recorded as observed and AUCs was calculated using the linear/log trapezoidal method. Natural log-transformed AUC24 and Cmax for 0–24 h were analysed using a mixed-effect model with sequence, period and treatment as fixed effects and participant within sequence as a random effect. Estimates of the adjusted mean differences (Test–Reference) and corresponding 90 % confidence intervals (CI) were obtained from the model. When comparing pregabalin CR doses with pregabalin IR doses, bioequivalence of the Test formulation to the Reference formulation was concluded if the 90 % CIs for AUC24 were contained within 80–125 %. When comparing pregabalin CR doses with other pregabalin CR doses, bioequivalence of the Test formulation to the Reference formulation was concluded if the 90 % CIs for both Cmax and AUC24 were contained within 80–125 %. 2.7 Safety Evaluations Study investigators recorded all observed or volunteered adverse events (AEs), the severity of the events and the relationship to the study treatment. AEs included adverse drug reactions, illnesses with onset during the study and
Eighty-four (64 male, 20 female) participants received pregabalin across the four studies (Table 1). Participants were 19–55 years of age, with a BMI of 18–30 kg/m2 and total body weight 50–103 kg. Compliance with study protocols was generally high, although in Study 3 one participant chewed the pregabalin CR tablets throughout the study in violation of the protocol; therefore, the pharmacokinetic concentration and parameter data for this participant were excluded from the statistical analysis and from all summary plots and tables. 3.2 Pregabalin Pharmacokinetics: Descriptive and Statistical Summary Mean plasma pregabalin concentration–time profiles for each study are presented in Fig. 1. The pregabalin pharmacokinetic parameter values are summarized descriptively in Table 2. Plots of individual and median pharmacokinetic parameter values by treatment are presented in Fig. 2 for AUC24 and Fig. 3 for Cmax. Mean Cmax values for pregabalin CR and evening mean Cmax values for pregabalin IR were similar, while the Table 1 Participant demographics Study 1
Study 2
Study 3
Study 4
N
18
24
24
18
Male, n (%)
14 (77.8)
18 (75.0)
14 (58.3)
18 (100)
Age, years Mean (SD)
37.4 (8.6)
38.3 (10.0)
38.3 (9.9)
31.1 (10.0)
Range
20–54
19–55
22–55
19–50
Race, n (%) White
18 (100)
20 (83.3)
23 (95.8)
17 (94.4)
Black
0
3 (12.5)
1 (4.2)
1 (5.6)
Other
0
1 (4.2)
0
0
Weight, kg Mean (SD)
75.2 (12.4)
78.7 (13.7)
74.5 (14.1)
72.7 (8.7)
Range
50–99
54–103
53–102
55–84
24.5 (2.8) 19–29
25.3 (2.8) 21–30
25.1 (3.3) 19–29
23.2 (2.7) 18–27
BMI, kg/m2 Mean (SD) Range
BMI body mass index, SD standard deviation
10 1x82.5mg CR QD With Food 1x25mg IR TID Fasted
1
0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Study 3 10
1
1x330mg CR QD With Food 2x165mg CR QD With Food 2x150mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Plasma Pregabalin Concentration ( µg/ml)
Study 1
Plasma Pregabalin Concentration (µg/ml)
Plasma Pregabalin Concentration (µg/ml)
Plasma Pregabalin Concentration (µg/ml)
Multiple-Dose Pregabalin Controlled-Release PK
Study 2 10
1
1x165mg CR QD With Food 2x82.5mg CR QD With Food 1x75mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Study 4 10
1
2x330mg CR QD With Food 1x300mg IR BID Fasted 0.1 0
4
8
12
16
20
24
Nominal Time Post-Dose (hr)
Fig. 1 Mean plasma pregabalin concentration–time profiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
morning mean Cmax values for pregabalin IR BID were higher than for either pregabalin CR or evening pregabalin IR (Table 2). In addition, mean Cmax values for pregabalin CR 82.5 mg QD were generally similar to the mean Cmax values for pregabalin IR 25 mg TID (Table 2). Cmax occurred later for pregabalin CR (median tmax 8–10 h after the evening dose, depending on study) (Table 2) than for pregabalin IR, where the median tmax occurred approximately 0.7–2 h after each dose (Fig. 1). The observed mean Cmin following pregabalin CR administration was 15–25 % lower than that of pregabalin IR administered BID and 35 % lower than that of pregabalin IR administered TID. AUC24 and Cmax values for both pregabalin CR and IR were dose proportional over the range of doses tested (82.5–660 and 75–600 mg, respectively) (Table 2). For both AUC24 and Cmax, variability was low irrespective of dosing regimen or treatment, with % CV values B21 % (Table 2). The range of individual total daily exposures (AUC24) for pregabalin CR (one or two tablets) and
pregabalin IR were comparable at each dose (Fig. 2). For Cmax, the overall range of individual exposures was lower but with overlap for pregabalin CR relative to the respective pregabalin IR dose (Fig. 3). The PTR for pregabalin CR was 13–19 % lower than that of pregabalin IR administered BID, but PTR was 30 % higher than that of pregabalin IR administered TID (Table 2). Results for the comparison of pregabalin CR with pregabalin IR, and for the comparison of two tablets of pregabalin CR with one tablet of pregabalin CR, are summarized in Table 3. The relative bioavailability of pregabalin CR 82.5, 165, 330 and 660 mg given daily after a 600–750 calorie, 30 % fat evening meal was approximately 93–97 % of pregabalin IR (75, 150, 300 and 600 mg/day, respectively), and met bioequivalence criteria with respect to the 24-h steady-state exposures (AUC24), as the 90 % CIs for ratios fell entirely within the 80–125 % range accepted for bioequivalence (Table 3). Ratios of Cmax values were approximately 63–82 % for the
18, 18
IR, 1 9 300 mg, BID
24, 24
IR, 1 9 150 mg, BID
18, 18
23, 22
CR, 2 9 330 mg, QD
23, 22
CR, 1 9 330 mg, QD
24, 24
IR, 1 9 75 mg, BID
CR, 2 9 165 mg, QD
24, 24
CR, 1 9 165 mg, QD
120.00 (13)
115.50 (14)
62.13 (15)
60.06 (18)
59.31 (17)
31.54 (18)
29.35 (17)
29.97 (19)
15.23 (16)
14.69 (18)
AUC24 (lgh/ml) 24-h intervalb
57.85 (12)
N/A
30.27 (15)
N/A
N/A
15.34 (18)
N/A
N/A
7.34 (17)
N/A
Eveningc
62.08 (14)
N/A
31.86 (15)
N/A
N/A
16.20 (18)
N/A
N/A
3.98 (16)
N/A
Morningc
AUCs (lgh/ml)
Parameter summary statisticsa
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
3.90 (16)
N/A
Afternoonc
11.35 (17)
7.75 (12)
6.39 (20)
4.22 (20)
4.11 (16)
3.18 (21)
1.99 (17)
2.03 (20)
1.24 (12)
1.03 (16)
24-h intervalb
9.27 (18)
N/A
4.54 (20)
N/A
N/A
2.38 (20)
N/A
N/A
1.15 (13)
N/A
Eveningc
Cmax (lg/ml)
11.07 (19)
N/A
6.36 (20)
N/A
N/A
3.15 (21)
N/A
N/A
1.20 (15)
N/A
Morningc
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
0.85 (15)
N/A
Afternoonc
2.08 (22)
1.76 (26)
1.11 (21)
0.85 (26)
0.82 (25)
0.59 (25)
0.44 (24)
0.43 (27)
0.31 (24)
0.20 (30)
Cmin (lg/ml)b
4.42 (17) 5.46 (38)
12.7d (0.67–14.00)
5.74 (30)
4.96 (36)
5.01 (29)
9.00 (6.00–12.00)
12.7 (0.67–13.50)
d
10.0 (5.00–11.90)
10.0 (5.00–12.00)
4.58 (41) 5.43 (34)
12.7d (0.67–13.50)
4.75 (37) 8.00 (5.00–11.90)
8.00 (4.00–11.90)
5.16 (28) 3.96 (20)
12.7d (1.00–13.00)
PTRb
8.00 (5.00–10.00)
tmax (h)b
d
c
b
a
Pregabalin IR tmax (12.7 h) occurred during the second (morning) dosing interval, approximately 0.7 h after the morning dose
Pregabalin IR treatments only: parameters assessed over the evening (0–12 h), morning (12–24 h for BID, 12–18 h for TID) and afternoon (18–24 h for TID) dosing intervals
All treatments (pregabalin CR and IR): parameters assessed across the 0–24-h interval
Geometric mean (% coefficient of variation) is presented for all parameters except for tmax, where median (range) is presented
N number of participants in the treatment group, n number of participants included in the analysis, AUC24 area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4, AUCs area under the concentration–time curve for the specified dosing interval, Cmax peak plasma concentration, Cmin lowest observed plasma concentration, tmax time of maximum observed plasma concentration, PTR peak–trough ratio, QD once daily, N/A not applicable, TID three times a day, BID twice a day
4
3
23, 23
CR, 2 9 82.5 mg, QD
17, 17
IR, 1 9 25 mg, TID
2
18, 18
CR, 1 9 82.5 mg, QD
1
N, n
Dose
Study
Table 2 Descriptive summary of pregabalin controlled-release (CR) and immediate-release (IR) pharmacokinetic parameters
M. L. Chew et al.
Multiple-Dose Pregabalin Controlled-Release PK
Study 2 Plasma pregabalin AUC24 (µg·h/ml)
Plasma pregabalin AUC24 (µg·h/ml)
Study 1
20
15
10
5 A
40
30
20
C
B
D
Treatment group
Treatment group
Study 4
80 70 60 50 40 30 G
H
Plasma pregabalin AUC24 (µg·h/ml)
Plasma pregabalin AUC24 (µg·h/ml)
Study 3 90
F
E
160
140
120
100
80 I
J
Treatment group
Treatment group
Fig. 2 Individual and median pregabalin area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4 (AUC24) values by treatment. Study 1: A, CR, 1 9 82.5 mg, QD; B, IR, 1 9 25 mg, TID. Study 2: C, CR, 2 9 82.5 mg, QD; D, CR, 1 9 165 mg, QD; E, IR, 1 9 75 mg, BID. Study 3: F, CR, 2 9 165 mg, QD; G, CR, 1 9 330 mg, QD; H,
IR, 1 9 150 mg, BID. Study 4: I, CR, 2 9 330 mg, QD; J, IR, 1 9 300 mg, BID. Open circles represent individual participant values. Scatter plot shows median and 25–75 % quartiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
pregabalin CR treatments relative to the respective pregabalin IR treatments. Ratios of both AUC24 and Cmax for the two-tablet pregabalin CR treatments were approximately 97–102 % relative to the respective one-tablet pregabalin CR treatments and met bioequivalence criteria with respect to both parameters (Table 3).
(n = 31, 36.9 %), fatigue (n = 28, 33.3 %), hypersomnia (n = 27, 32.1 %), headache (n = 22, 26.2 %) and somnolence (n = 21, 25.0 %) (Table 4). With pregabalin IR, the most common all-causality AEs across the four studies were dizziness (n = 31, 37.3 %), headache (n = 21, 25.3 %), fatigue (n = 18, 21.7 %), hypersomnia (n = 13, 15.7 %) and somnolence (n = 12, 14.5 %) (Table 4).
3.3 Safety Evaluations Pregabalin was well tolerated in all four studies, with no serious or severe AEs. No participant discontinued owing to an AE. No deaths occurred during these studies. The majority of treatment-related AEs were considered mild or moderate in severity. With pregabalin CR, the most common all-causality AEs across the four studies were dizziness
4 Discussion These findings demonstrate that pregabalin CR (82.5, 165, 330 and 660 mg/day) administered QD immediately following a 600–750 calorie, medium-fat evening meal is equivalent to the pregabalin IR formulation with respect to
M. L. Chew et al.
Study 2 Plasma pregabalin Cmax (µg/ml)
Plasma pregabalin Cmax (µg/ml)
Study 1 2.0
1.5
1.0
0.5 A
B
6
4
2
0 C
D
Treatment group
Study 4 Plasma pregabalin Cmax (µg/ml)
Plasma pregabalin Cmax (µg/ml)
Study 3
10
5
0 F
G
E
Treatment group
H
Treatment group
15
10
5 I
J
Treatment group
Fig. 3 Individual and median pregabalin peak plasma concentration (Cmax) values by treatment. Study 1: A, CR, 1 9 82.5 mg, QD; B, IR, 1 9 25 mg, TID. Study 2: C, CR, 2 9 82.5 mg, QD; D, CR, 1 9 165 mg, QD; E, IR, 1 9 75 mg, BID. Study 3: F, CR, 2 9 165 mg, QD; G, CR, 1 9 330 mg, QD; H, IR, 1 9 150 mg,
BID. Study 4: I, CR, 2 9 330 mg, QD; J, IR, 1 9 300 mg, BID. Open circles represent individual participant values. Scatter plot shows median and 25–75 % quartiles. CR controlled-release, QD once daily, IR immediate-release, TID three times a day, BID twice a day
AUC24. Also, pregabalin CR (two tablets of 82.5 mg or 165 mg) is bioequivalent to one tablet of pregabalin CR (165 mg or 330 mg, respectively) with respect to AUC24 and Cmax. In addition to demonstrating pharmacokinetic equivalence, the safety profiles of pregabalin CR and IR across the dose range were similar to and consistent with that known for pregabalin IR [1, 2]. As expected, slow and sustained absorption occurred with pregabalin CR treatment and peak concentrations were observed approximately 8–10 h following the evening dose. In contrast, absorption occurred more quickly following pregabalin IR administration and peak concentrations were observed at approximately 0.7–2 h after each dose. The observed peak concentrations following pregabalin CR dosing were similar to those observed with evening pregabalin IR administration, but lower than those seen with morning pregabalin IR administration. Pharmacokinetic
parameters for the pregabalin IR formulation were consistent with a decrease in the rate of absorption of pregabalin in the evening relative to morning administration. In all four studies analysed herein, Cmax with pregabalin IR administration was approximately 30 % lower and the median tmax was delayed by 0.8 h with evening administration compared with morning administration, while the geometric mean AUCs was similar for the evening and morning dosing intervals. One possible explanation for this is diurnal variation in gastrointestinal motility [14–17]. Another possible contributing factor is that participants were fasted for at least 8 h prior to the morning dose but only 4 h prior to the evening dose because of logistical constraints. In line with this hypothesis, previous studies with the pregabalin IR formulation have demonstrated a decrease in the rate but not extent of absorption when administered immediately following a meal [4].
Multiple-Dose Pregabalin Controlled-Release PK Table 3 Statistical summary of treatment comparisons for pregabalin immediate-release (IR) and controlled-release (CR) Study
Test
Reference
Parameter
Adjusted geometric means Test
1
CR, 1 9 82.5 mg, QD
IR, 1 9 25 mg, TID
AUC24, lgh/ml Cmax, lg/ml
2
CR, 1 9 165 mg, QD
IR, 1 9 75 mg, BID
CR, 2 9 82.5 mg, QD
IR, 1 9 75 mg, BID
CR, 2 9 82.5 mg, QD
CR, 1 9 165 mg, QD
CR, 2 9 165 mg, QD
IR, 1 9 150 mg, BID
AUC24, lgh/ml Cmax, lg/ml AUC24, lgh/ml Cmax, lg/ml
3
IR, 1 9 150 mg, BID
CR, 2 9 165 mg, QD
CR, 1 9 330 mg, QD
CR, 2 9 330 mg, QD
IR, 1 9 300 mg, BID
14.69
15.30
96.02
1.03
1.25
82.19
92.84,99.30 77.05,87.67
29.35
31.54
93.05
90.47,95.71
1.99
3.18
62.62
59.92,65.43
30.03
31.54
95.21
92.52,97.97
2.03
3.18
63.79
61.00,66.71
30.03 2.03
29.35 1.99
102.31 101.87
99.43,105.28 97.42,106.53
AUC24, lgh/mL
58.75
62.13
94.56
92.05,97.14
4.08
6.39
63.84
60.82,67.00
60.45
62.13
97.30
94.71,99.95
AUC24, lgh/ml Cmax, lg/ml AUC24, lgh/ml Cmax, lg/ml
4
90 % CI for ratio (%)
AUC24, lgh/ml Cmax, lg/ml Cmax, lg/ml
CR, 1 9 330 mg, QD
Reference
Ratio (T/R) of adjusted means (%)
6.39
66.15
63.02,69.42
60.45
97.19
94.56,99.89
4.08
AUC24, lgh/ml Cmax, lg/ml
4.22 58.75 115.5 7.75
4.22 120.0 11.35
96.51
91.87,101.38
96.29
92.35,100.41
68.34
63.76,73.24
T/R test/reference, CI confidence interval, QD once daily, TID three times a day, AUC24 area under the plasma concentration–time curve for the 24-h period following the evening dose on day 4, Cmax peak plasma concentration, BID twice a day
Previous analyses of pregabalin in patients with epilepsy [18], generalized anxiety disorder [19], diabetic peripheral neuropathy [20] or postherpetic neuralgia [21] have shown that similar efficacy is achieved with up to 600 mg/day pregabalin IR taken BID or TID, despite the differences between the concentration–time profiles of pregabalin IR with BID and TID dosing. This could indicate that the different concentration–time profile seen with pregabalin CR administered QD may not have an effect on efficacy of pregabalin CR in these patients. Indeed, pharmacokinetic– pharmacodynamic simulations suggest that, in adults, comparable efficacy can be achieved with administration of pregabalin QD of equivalent total daily exposure (Study PMAR-00109, Pfizer Inc, data on file). Pregabalin CR administered QD could have advantages over pregabalin IR in terms of patient adherence and compliance. Indeed, QD dosing of a wide range of oral medications has been shown to significantly increase adherence rates, compliance and persistence compared with BID, TID or four times daily dosing [12]. In addition, pregabalin CR retains the important features of the pregabalin IR formulation, including good bioavailability [3], low interindividual variability [4], no protein binding or metabolism, primarily renal elimination and lack of significant drug–drug interactions [3]. One consideration for pregabalin CR is the potential impact of potent prokinetic agents such as erythromycin; an ongoing study will demonstrate whether or not erythromycin has any effect on the pharmacokinetic properties of pregabalin CR (Study 1197, Pfizer Inc, manuscript in preparation).
Although safety and tolerability were objectives of all four studies, it should be noted that no study was powered for the statistical evaluation of AEs. Both pregabalin CR and IR were generally well tolerated across all four studies, with AE profiles consistent with those previously reported for pregabalin IR in patient populations [1, 2]. Clinical trials of pregabalin have shown that the two most common AEs, dizziness and somnolence, typically emerge within the first 1–2 weeks of treatment and resolve 1–2 weeks later, usually without requiring treatment to be discontinued [22]. For the clinical pharmacology studies reported herein, only the overall incidence of AEs has been shown given the short duration of each trial. However, two recently completed 14to 19-week trials of pregabalin CR in patients with epilepsy [23] and fibromyalgia [24] have shown that the AE profile of pregabalin CR is generally comparable to that of pregabalin IR in these patient populations. Additional safety data should soon become available from one other ongoing phase III trial of the pregabalin CR formulation in patients with postherpetic neuralgia (Study 1224, NCT01270828). Other limitations of these studies should also be considered. The study population was limited, as only 7 % of participants were non-white. In addition, the meal types were limited, with calorie content restricted to 600–750 calories with 30–35 % of the total caloric content coming from fat. However, other studies examining the effect of food on the pharmacokinetics of pregabalin CR have shown that, in general, meal content has minimal effect [25] supporting our observations from the present analysis.
M. L. Chew et al. Table 4 All-causality, treatment-emergent adverse events (AEs) occurring in C5 % of treated participantsa Pregabalin CR (mg)
Pregabalin IR (mg)
82.5
165
330
660
Total
75
150
300
600
Total
Participants evaluable for AEs, n
18
24
24
18
84
17
24
24
18
83
Participants with AEs, n (%)
10 (55.6)
22 (91.7)
24 (100.0)
17 (94.4)
73 (86.9)
7 (41.2)
20 (83.3)
24 (100.0)
16 (88.9)
67 (80.7)
Dizziness
0
7 (29.2)
22 (91.7)
2 (11.1)
31 (36.9)
0
8 (33.3)
15 (62.5)
8 (44.4)
31 (37.3)
Fatigue
3 (16.7)
10 (41.7)
6 (25.0)
9 (50.0)
28 (33.3)
2 (11.8)
6 (25.0)
7 (29.2)
3 (16.7)
18 (21.7)
Hypersomnia
1 (5.6)
11 (45.8)
14 (58.3)
1 (5.6)
27 (32.1)
0
3 (12.5)
9 (37.5)
1 (5.6)
13 (15.7)
Headache
3 (16.7)
5 (20.8)
8 (33.3)
6 (33.3)
22 (26.2)
4 (23.5)
2 (8.3)
9 (37.5)
6 (33.3)
21 (25.3)
Somnolence
0
6 (25.0)
13 (54.2)
2 (11.1)
21 (25.0)
0
2 (8.3)
7 (29.2)
3 (16.7)
12 (14.5)
Insomnia
1 (5.6)
6 (25.0)
6 (25.0)
2 (11.1)
15 (17.9)
0
3 (12.5)
2 (8.3)
2 (11.1)
7 (8.4)
Feeling drunk
0
0
2 (8.3)
12 (66.7)
14 (16.9)
0
0
2 (8.3)
7 (38.9)
9 (10.8)
Head discomfort
0
2 (8.3)
6 (25.0)
1 (5.6)
9 (10.7)
0
2 (8.3)
2 (8.3)
5 (27.8)
9 (10.8)
Most common AEs, n (%)
Visual impairment
0
0
2 (8.3)
6 (33.3)
8 (9.5)
0
0
2 (8.3)
3 (16.7)
5 (6.0)
Constipation
0
3 (12.5)
4 (16.7)
1 (5.6)
8 (9.5)
0
0
6 (25.0)
0
6 (7.2)
Change of bowel habit
0
2 (8.3)
4 (16.7)
0
6 (7.1)
0
1 (4.2)
2 (8.3)
1 (5.6)
4 (4.8)
Nasopharyngitis
3 (16.7)
2 (8.3)
1 (4.2)
0
6 (7.1)
2 (11.8)
1 (4.2)
0
0
3 (3.6)
Euphoric mood Nausea
0 0
2 (8.3) 1 (4.2)
2 (8.3) 3 (12.5)
2 (11.1) 2 (11.1)
6 (7.1) 6 (7.1)
0 0
0 0
1 (4.2) 0
0 1 (5.6)
1 (1.2) 1 (1.2)
Diarrhoea
0
2 (8.3)
1 (4.2)
0
3 (3.6)
1 (5.9)
1 (4.2)
2 (8.3)
1 (5.6)
5 (6.0)
CR controlled-release, IR immediate-release a
Based on the total pregabalin CR population
5 Conclusion
Pfizer Inc. Howard N. Bockbrader was an employee of Pfizer Inc at the time these studies were conducted and holds stock in Pfizer Inc.
Total daily exposure of pregabalin CR (82.5–660 mg/day) is equivalent to the corresponding pregabalin IR dose (75–600 mg/day). Total exposure with two tablets of pregabalin CR administered concurrently is bioequivalent to the corresponding one-tablet pregabalin CR dose. Pregabalin CR within the dosing regimen of the present studies is well tolerated in healthy individuals, with most AEs considered to be mild to moderate in severity.
Ethical statement All studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. All participants provided written informed consent before entering each study. The final protocols and informed consent documentation were reviewed and approved by the Erasme Hospital Ethics Committee, Brussels, Belgium, where the studies were conducted.
Acknowledgments The studies described in this paper were sponsored by Pfizer Inc, who was involved in the study design; the collection, analysis and interpretation of the data; the writing of the report; and the decision to submit the paper for publication. Medical writing support was provided by Lorna Forse, PhD, of Engage Scientific Solutions and funded by Pfizer Inc. Conflict of interest Marci L. Chew, Christine W. Alvey, Anna Plotka, Verne W. Pitman, Tanja Alebic-Kolbah and Joseph M. Scavone are all full-time employees of Pfizer Inc and hold stock in
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