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Keywords:

  • USL255;
  • New topiramate extended-release formulation;
  • Pharmacokinetics;
  • Healthy subjects;
  • Food effect

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Purpose:  To compare the pharmacokinetics of USL255, a once-daily extended-release (ER) formulation of topiramate (TPM), with Topamax (immediate-release TPM) in healthy subjects after oral dosing and evaluate the effect of food on USL255 bioavailability and pharmacokinetics.

Methods:  This randomized, single-center, open-label, cross-over design study had three dosing periods separated by 21 days of washout between treatments. Thirty-six volunteers received single doses of USL255 (200 mg) in fasted and fed conditions and two doses of Topamax (100 mg) administered 12 h apart. TPM plasma samples were analyzed by liquid chromatography–mass spectroscopy. Pharmacokinetic parameters were calculated by noncompartmental methods.

Key Findings:  USL255 fasted pharmacokinetic parameters [point estimate (90% confidence interval, CI) compared to Topamax] were: relative bioavailability (F´) 91.2% (84–99%), peak plasma concentration (Cmax) USL255/Topamax-ratio 59% (53–65%), time to reach Cmax (tmax) 19.5 ± 7.2 h, accumulation ratio (Rac) 3.9 ± 1.2, effective half-life (t1/2,eff) 55.7 ± 19.9 h, terminal half-life (t1/2,z) 80.2 ± 14.2 h, and peak-occupancy-time (POT) 12.1 ± 4.0 h. Although the F´ and Cmax were unaffected by food, Rac and t1/2,eff increased to 4.9 ± 0.9, and 72.5 ± 15.4 h, respectively. In contrast to t1/2,z, t1/2,eff reflects absorption rate; therefore, USL255’s t1/2,eff was significantly longer than Topamax’s t1/2,eff (37.1 ± 6.5 h).

Significance:  Although bioequivalent to Topamax in extent of absorption, USL255 had a slower absorption rate as reflected in its lower Cmax and longer tmax, larger POT and longer t1/2,eff, and similar Rac values to that of Topamax (q12 h). This relative flat plasma profile allows for once-daily dosing with diminished fluctuations in TPM plasma levels. In addition, neither USL255’s peak nor extent of plasma exposure of TPM was affected by food.

Topiramate (TPM, Topamax, Jenssen, Ortho, LLC, Gurabo, PR, U.S.A.) is an antiepileptic drug (AED) and central nervous system (CNS) drug that has been approved worldwide since 1995 for the treatment of various kinds of epilepsy as an adjunctive therapy and/or monotherapy as well as for migraine prophylaxis (Maryanoff et al., 1987; Shank et al., 1994; Doose & Streeter, 2002; Bialer et al., 2007).

The pharmacokinetics (PK) of TPM is characterized by linear PK (in a dose range of 100–800 mg), low oral clearance (22–36 ml/min), and a relatively long half-life (19–25 h). Although TPM PK in plasma is linear, TPM clearance from whole blood increases with increasing doses. TPM blood-to-plasma ratio decreases from 8 to 2 as its concentration increases, indicating substantial and saturable binding to erythrocytes (Shank et al., 2005). TPM half-life is reduced when coadministered with enzyme-inducing AEDs such as phenytoin (PHT) and carbamazepine (CBZ) (Doose et al., 1996; Garnett, 2000; Doose & Streeter, 2002; Gidal, 2002; Sachdeo et al., 2002; Bialer et al., 2004; Britzi et al., 2005; Mimrod et al., 2005). The absolute (oral) bioavailability of immediate-release TPM is 81–95% and is not affected by food (Doose et al., 1996). Although TPM is not extensively metabolized when administered as monotherapy (fraction metabolized <30%) (Wu & McKown, 2000; Doose & Streeter, 2002), its metabolism (metabolic clearance) is induced during polytherapy with enzyme-inducing AEDs like carbamazepine (CBZ) or phenytoin (PHT), and, consequently, its fraction metabolized increases (Gidal, 2002; Sachdeo et al., 2002; Bialer et al., 2004; Britzi et al., 2005; Mimrod et al., 2005). This PK change may require TPM dose adjustment when PHT or CBZ therapy is added or discontinued (Sachdeo et al., 2002; Britzi et al., 2005; Mimrod et al., 2005).

Recently, a new extended-release (ER) formulation of topiramate USL255, designed for once-daily dosing was developed by Upsher-Smith Laboratories Inc (Halvorsen et al., 2010; Todd et al., 2010). ER formulations are usually designed to reduce dose frequency and maintain relatively constant or flat drug plasma concentrations during the dosing interval. It is unclear whether flat plasma levels of an AED improve antiepileptic efficacy compared to fluctuated plasma concentrations. However, indirect evidence of the benefit of less fluctuation of drug plasma concentrations is provided by the observation that ER formulations minimize concentration-related adverse events. Overall, flexibility, better accumulation ratio, and consistency of plasma levels associated with ER formulations may simplify the management of AED therapy (Bialer, 2007).

The current article analyzes the pharmacokinetics of USL255 in comparison to Topamax following oral dosing to healthy subjects as well as evaluates the effect of food on USL255 bioavailability and pharmacokinetics. The PK evaluation was done utilizing common PK parameters [e.g., area under the curve (AUC), Cmax, tmax, and relative bioavailability – F′) but also less common PK criteria to assess in vivo performance of ER formulations. The less common PK criteria are accumulation ratio (Rac), effective or accumulation half-life (t1/2,eff), peak occupancy or plateau time (POT), and peak-trough fluctuations (Cmax/Cτ) (Pollak et al., 1988; Boxenbaum & Battle, 1995; Bialer et al.,1998). Because the major PK parameters (Cmax and tmax) used to assess rate of absorption are single point parameters (determined by visual inspection), they are not ideal in cases of a flat (plateau) concentration-time curve obtained after oral dosing of TPM-ER formulations. Because of these limitations, USL255 in vivo performance was analyzed by using all of the above PK parameters: AUC, Cmax, tmax, Rac, t1/2,eff, POT, and Cmax/Cτ. The preliminary results of parts of this investigation were reported recently in brief abstracts (Halvorsen et al., 2010; Todd et al., 2010), and the final more detailed analysis is presented here.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Subjects

Thirty-six healthy adult subjects were enrolled in this randomized, single-center, open-label, three-way crossover design study with six possible treatment sequences. Plasma samples were collected for 14 days in each period at the following times after USL255 and Topamax dosing, respectively with a 21-day washout period between treatments: within 1 h pre-dosing (0 h), every 2 h up to 32 h postdose, 36, 48, 72, 96, 120, 168, 216, 264, and 336 h, and at: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 16, 18, 20, 24, 48, 72, 120, 168, 216, 264, and 336 h after the first Topamax dosing. Subjects were confined to the clinic for at least 36 h pre- and 48 h postdose. Subjects received in random sequence: (1) a single dose (200 mg) of USL255 in fasted conditions; (2) a single dose (200 mg) of USL255 in fed conditions (standard high-fat breakfast); and (3) two doses of Topamax (100 mg) administered 12 h apart (q12 h)—first dose administered under fasted conditions. Subjects were required to avoid prescription and over-the-counter medication and be in good general health based on detailed medical history, physical examination, and clinical laboratory evaluation. The investigational review board of the participating clinical site approved the study protocol, and prior to study procedures being conducted, subjects provided written informed consent.

TPM analysis

Plasma samples were analyzed for TPM with high-performance liquid chromatography (HPLC) with MS/MS detection liquid chromatography/mass spectrum/mass spectrum (LC/MS/MS). Briefly, a 100-μL matrix aliquot was fortified with 25 μl of 150 ng/mL internal standard (topiramate-13C6) working solution. Analytes were isolated through supported liquid extraction (SLE) using SLE+ 96-well plates and extracted with 0.8 ml of methylene chloride. The eluate was evaporated under a nitrogen stream at approximately 45°C, and the remaining residue was reconstituted with 200 μl of 60:40 mobile phase A/mobile phase B (MPA/MPB), vol/vol. The final extract was analyzed via HPLC with MS/MS detection. A quadratic, 1/concentration weighted, least squares regression algorithm was used to plot the peak area ratio of the analyte to its internal standard versus concentration. The lower limit of quantification was the lowest nonzero concentration level that was quantified with acceptable accuracy and precision.

The quantification range of the LC/MS/MS assay was 0.01–10 mg/L using 500 μL of plasma. The interassay precision (% coefficient of variation) throughout the quantification range was between 7.03 and 10.4% and the interassay accuracy (% nominal) was in the range of −0.178 and −1.63% at the above quantification range.

Pharmacokinetic and statistical analysis

Pharmacokinetic analysis was conducted by noncompartmental methods based on statistical moment theory (Yamaoka et al., 1978; Gibaldi & Perrier, 1982; Rowland & Tozer, 2010). The following individual pharmacokinetic parameters were calculated: Peak concentration (Cmax) and the time to reach Cmax (tmax) were determined by visual inspection. Trough concentrations (Cτ) were recorded at 12 or 24 h after dosing of Topamax, or USL255, respectively. The plateau time or peak occupancy time (POT) was calculated by assessing the time span during which the plasma concentrations deviate from the Cmax by <20% (Pollak et al., 1988; Bialer et al., 1998). The area under the plasma concentration-versus-time curve (AUC) to 12 h (Topamax) or 24 h (USL255) and to the last measured concentration (at 336 h) was estimated by the linear trapezoidal method (AUC0–12, AUC0–24 or AUC0–336). The AUC from 0 to infinity (AUC0–∞) was estimated by AUC0–336 + C336/λz, where C336 is the monitored concentration at 336 h after dosing and λz is the terminal slope of the linear fit of the log TPM plasma concentration versus time curve. USL255 relative bioavailability (F´) compared to Topamax was calculated from their AUC0–∞ arithmetic mean ratio.

The terminal half-life (t1/2,z) was calculated from the quotient ln2/λz. Since AUC0–∞ = AUCss [AUC within a dosing interval (τ) at steady-state], the accumulation ratio (Rac) was estimated by the quotient of AUC0–∞/AUC0–12 (normalized to 100 mg dose) for Topamax or AUC0–∞/AUC0–24 for USL255, where Keff is the disposition rate constant. In linear systems with monoexponential disposition and bolus input, Keff is equal to the elimination rate constant (K). The effective half-life (t1/2,eff) was calculated from eqns 1 and 2 (Kwan et al., 1984; Boxenbaum & Battle, 1995; Sahin & Benet, 2008).

  • image(1)
  • image(2)

The following pharmacokinetic parameters of TPM were comparatively evaluated after USL255 administration in the presence (fed) and absence (fasted) of food and for Topamax: Cmax, tmax, POT, AUC0–336, AUC0–∞, Rac, t1/2,z, and t1/2,eff.

Statistical analysis

Comparative statistics across groups were conducted by one-way analysis of variance (ANOVA) on AUC and dose-normalized Cmax and AUC values to explore for differences between USL255 (fasted) and Topamax (fasted) and between USL255 administered under fed and fasted conditions. Ratio of the geometric least squares mean (LSM) for AUC0–336, AUC0–∞, and Cmax were calculated for USL255/Topamax. The 90% confidence intervals (90% CIs) for these ratios were calculated. Bioequivalence between USL255 (fasted) and Topamax or between USL255 (fed) and USL255 (fasted) was defined as 90% CIs for the AUC or Cmax ratios within the acceptable range of 80–125%. ANOVA with fixed factors (sequence, period, and treatment) and random factor (subject nested in sequence) was performed on the natural log transformed AUC and Cmax values. Median tmax was compared between US255 (fasted) and Topamax (fasted) and between USL255 administered under fasted and fed conditions.

Safety evaluations

Safety was assessed based on adverse event (AE ) monitoring, vital signs monitoring, physical examination, electrocardiography (ECG), and clinical laboratory results. Clinical laboratory parameters (hematology, serum chemistry, and urinalysis) were measured at screening and final study visit. Incidence and severity of treatment-emergent adverse events (TEAEs) were recorded from screening to final study visit.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Study procedures

Thirty-six healthy adult subjects (mean age 37.5 years) were randomized in the study and one subject was discontinued after two phases and did not receive Topamax. One subject had inadequate plasma samples in the USL255 fasted group and was not included in the analysis. Demographic and baseline characteristics are summarized in Table 1.

Table 1.   Subject disposition and demographics—safety population
 USL255 200 mg (fasted and fed) QD N = 36IR TPM 100 mg q12 h × 2 N = 35
  1. q12 h, every 12 h; QD, once-daily.

  2. aSubject discontinued due to ongoing back pain and a need for the use of concomitant medications with the potential to confound safety results.

Randomized, n (%)36 (100)36 (100)
Completed, n (%)36 (100)35 (97.2)
Discontinued, n (%)0 (0)1 (2.8)a
Gender, n (%)  
 Male18 (50)18 (50)
 Female18 (50)17 (48.6)
Mean age (years)  
 Range (min, max)37.5 (20–62)37.5 (20–62)
Race, n (%)  
 White32 (88.9)31 (88.6)
 African American3 (8.3)3 (8.6)
 Asian1 (2.8)1 (2.9)

Pharmacokinetic data

The mean values of TPM plasma concentration-time curves following a single dose (200 mg) of USL255 (fasted) and two doses of Topamax (100 mg; q12 h) are illustrated in Fig. 1. The mean values of TPM plasma concentration-time curves following single dose (200 mg) of USL255 under fasted and fed conditions are illustrated in Fig. 2.

image

Figure 1.   Mean topiramate (TPM) plasma concentration obtained following a single dose (200 mg) of USL255 (fasted) and two doses of Topamax (100 mg; q12 h).

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image

Figure 2.   Mean topiramate (TPM) plasma concentrations obtained following a single dose (200 mg) of USL255 at fasted and fed conditions.

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The mean pharmacokinetic parameters of TPM obtained following the administration of USL255 and Topamax are presented in Table 2. USL255 was found to be bioequivalent to Topamax at fasted and fed conditions. The geometric mean point estimate (PE) of the USL255/Topamax-AUC0–∞ ratio was 91%; 90% CI = 84–99% (fasted) and 89%; 90% CI = 82–97% (fed). The PE of the geometric mean ratios and their 90% CI values were within the acceptable range and thus met the bioequivalence limits of 80–125%. The geometric mean PE of the USL255(fed)/USL255(fasted)-AUC0–∞ ratio was 97%; 90% CI = 90–104% and geometric mean PE of the USL255(fed)/USL255(fasted)-Cmax ratio was 99%; 90% CI = 89–109%.

Table 2.   Mean ± SD PK parameters of topiramate obtained following a single dose of USL255 (200 mg) with or without food and Topamax (100 mg q12 h)
PK ParameterUSL255 (fasted) N = 35USL255 (fed) N = 36Topamax N = 35
  1. aFor Topamax: inline image

  2. bFor Topamax-Experimental Cmax and Cτ values obtained following the first dose (100 mg) normalized to 200 mg.

  3. cPeak occupancy time or plateau time—the time span in which TPM plasma concentrations deviate from Cmax by <20%.

  4. dPE -Point estimate calculated from the ratio of the geometric least square mean (LSM) for the USL255/Topamax ratio for the AUC0–336, AUC0-∞ and Cmax. The 90% confidence intervals (90% CIs) for these ratios were calculated by using mean square (MS) error (residual) from the ANOVA.

AUC0–τ (mg*h/L)48.1 ± 16.935.3 ± 9.219.1 ± 4.3
AUC0–336 h (mg*h/L)170.1 ± 44.7166.1 ± 43.5183.1 ± 39.0a
AUC0–∞ (mg*h/L)173.7 ± 43.9169.5 ± 43.8186.9 ± 39.7a
Relative Bioavailability F’ (%)92.1 ± 13.091.0 ± 16.0Reference
Accumulation Ratio (Rac)3.9 ± 1.24.9 ± 0.95.0 ± 0.8
Cmax (mg/L)2.8 ± 0.82.7 ± 0.84.6 ± 1.2b
Cmin = Cτ (mg/L)2.4 ± 0.72.5 ± 0.82.6 ± 0.6b
τ = 24 hτ = 24 hτ = 12 h
Cmax/Cτ1.2 ± 0.11.1 ± 0.11.7 ± 0.3
tmax (h)   
 Mean19.5 ± 7.222.7 ± 4.31.4 ± 1.1
 Median20241
Effective half-life t1/2,eff (h)55.7 ± 19.972.5 ± 15.437.1 ± 6.5
Terminal half-life t1/2,z (h)80.2 ± 14.278.6 ± 10.982.8 ± 14.4
POTc (h)12.1 ± 4.08.0 ± 3.32.6 ± 1.9
USL255-Topamax AUC0–336 h ratio (%) PE (90% CI)d91.1 (84–99)87.9 (81–96)Reference
USL255-Topamax AUC0–∞ ratio (%) PE (90% CI)d91.2 (84–99)89.0 (82–97)Reference
USL255 (fed)-(fast) AUC0–∞ ratio (%) PE (90% CI)dReference97 (90–104)
USL255-Topamax Cmax ratio (%) PE (90% CI)d59 (53–65)58 (52–63)Reference
USL255 (fed)-(fast) Cmax ratio (%) PE (90% CI)dReference99 (89–109)

USL255 had a slower absorption rate compared to Topamax as reflected by its later median tmax (20 vs. 1 h) and mean POT (12.1 ± 4.0 vs. 2.6 ± 1.9 h) and smaller Cmax values (by ∼40%) as well as diminished peak-trough fluctuations (USL255-Cmax/C24 h vs. Topamax-Cmax/C12 h) in TPM plasma concentrations. The geometric mean of the USL255/Topamax Cmax ratio was 59%; 90% CI = 53–65% (fasted) and 58%; 90% CI = 52–63% (fed). Therefore, the significantly slower absorption rate of USL255 did not harm its extent of absorption. Although USL255 and Topamax exhibited similar mean TPM-terminal half-life (t1/2,z) values of 80.2 ± 14.2 and 82.8 ± 14.4 h, respectively, their effective half-lives (t1/2,eff) were markedly different. Unlike t1/2,z, t1/2,eff is affected by the drug release from the formulation so if the absorption rate is slower or extended (i.e., ER), the t1/2,eff is longer. Consequently, the mean USL255-t1/2,eff was almost twice as long as that of Topamax (55.7 vs. 37.1 h) and was longer under fed condition than under fasted conditions.

A total of 28 of the 36 subjects in the overall safety population experienced ≥1 TEAE during at least one of the three treatment periods. The overall incidence and severity of TEAEs are reported in Table 3. Most TEAEs were treatment-related and mild in severity with no serious AEs, or intolerable AEs that lead to discontinuation. The most frequently reported TEAEs were classified as either nervous system or gastrointestinal disorders. Common TEAEs included dizziness, nausea, and paraesthesia. Dizziness, the most common TEAE, occurred in a higher percentage of subjects receiving Topamax (37.1%) than USL255 (25.0%). No treatment-related differences were observed in clinical laboratory results, vital sign measurements, or physical examination findings.

Table 3.   Incidence and severity of TEAEs
 USL255 200 mg QD (fasted) N = 36USL255 200 mg QD (fed) N = 36Topamax 100 mg q12 h N = 35
  1. q12 h, every 12 h; QD, once-daily; TEAEs, treatment-emergent adverse events.

  2. Data are presented as n (%).

Subjects with ≥1 TEAE15 (41.7)15 (41.7)20 (57.1)
Relationship of TEAE to study medication   
 Unrelated1 (2.8)1 (2.8)3 (8.6)
 Related14 (38.9)14 (38.9)17 (48.6)
Severity of TEAE   
 Mild13 (36.1)14 (38.9)18 (51.4)
 Moderate2 (5.6)1 (2.8)2 (5.7)
 Severe0 (0)0 (0)0 (0)

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

A key objective of this study was to investigate the pharmacokinetics and bioequivalence of USL255, a new once-daily TPM-ER formulation as compared to Topamax. USL255 was found to be bioequivalent to Topamax in its extent of absorption; however, it had a slower (extended) rate of absorption as reflected by its later tmax and longer t1/2,eff values. A mean tmax value of 20 h after single dose indicates that TPM absorption continues throughout the 24 h dosing interval at fasted and fed conditions. The plateau time or POT of USL255 was 3–4 times longer than that of Topamax. USL255 predicted that accumulation ratio (Rac = 3.9 ± 1.2) following once-daily dosing was similar to that obtained following twice-daily dosing of Topamax (Rac = 5.0 ± 0.8). This coupled with the fact that the mean peak-trough ratio (Cmax/Cτ) for USL255 (τ = 24 h) was smaller (1.2 ± 0.1) than that of Topamax (τ = 12 h) (1.7 ± 0.3), shows that TPM peak plasma exposure and plasma peak-trough fluctuations will be less than those obtained following twice-daily dosing of Topamax.

The concentration-time curves of drugs are usually best described by a multiexponential function that yields more than one half-life to describe the drug plasma profile (Sahin & Benet, 2008); therefore, there is no single half-life that can adequately predict appropriate dosing interval and drug accumulation following multiple dosing for most drugs. For TPM, like many other drugs, the only half-life reported to date is the terminal half-life (t1/2,z). In the current study due to longer sampling times (up to 336 h) and lower limit of quantification of the assay (10 ng/mL), TPM-t1/2,z was found to be longer (80 vs. 20–30 h) than the values previously reported in the literature (Doose et al., 1996; Doose & Streeter, 2002; Bialer et al., 2004; Britzi et al., 2005; Shank et al., 2005). However, for many drugs, particularly for those with a relatively long half-life such as TPM, t1/2,z may only represent a small fraction of TPM total body clearance or elimination. Consequently, it has minimal effect on the extent of accumulation (Rac) of TPM obtained following multiple (bid) dosing. Effective half-life (t1/2,eff) in contrast to t1/2,z estimates drug accumulation utilizing Rac and, therefore, it is a function of the elimination and absorption rates and the dosing interval, as opposed to being only a drug-related parameter (Sahin & Benet, 2008).

In our study, USL255-mean t1/2,eff (56–73 h) was shorter than its mean t1/2,z (80 h) and was three times longer than the previously reported t1/2,eff for eslicarbazepine following eslicarbazepine acetate (ESL) once daily oral dosing (Almeida et al., 2009). This TPM long t1/2,eff enables USL255 to be dosed once daily with less plasma fluctuations compared to in the case of ESL. Effective half-life is more clinically relevant than t1/2,z, since it provides a better prediction about TPM accumulation in a patient following multiple dosing of USL255.

Although 100 mg of Topamax was administered 12 h after the first dosing, assuming linear PK, Topamax experimental AUC0–∞ obtained after the two, 100-mg doses is equal to the AUC0–∞ that would have been obtained after a single 200-mg Topamax dose, as detailed in eqns 3–5.

After the first Topamax dose, the AUC can be divided into two parts; experimental AUC0–12 plus AUC12–∞ that is nested (included) in the experiential AUC0–∞ obtained after the second Topamax dose (eqn 3).

  • image(3)

The AUC0–∞ after the second Topamax dose is depicted in eqn 4.

  • image(4)

The experimental total AUC0–∞ obtained after the two Topamax doses is equal to the AUC of two single doses (100 mg) of Topamax as depicted in eqn 5.

  • image(5)

In contrast to t1/2z, which is calculated from a few terminal plasma concentrations, t1/2,eff is calculated utilizing all experimental plasma concentrations and is the half-life that reflects drug accumulation. Therefore t1/2,eff is more clinically relevant than t1/2z and is appropriately referred to as accumulation half-life (Boxenbaum & Battle, 1995). In addition, t1/2,eff is a more robust PK parameter (than t1/2z) calculated by numeric model-independent methods and thus may be utilized in cases of unknown, complex absorption, and disposition processes like in the case of ER formulations. The parameters examined in this study (e.g., Cmax/Cτ, t1/2,eff, POT, Rac) provide greater insight into the in vivo performance of ER products than the single-points parameters Cmax and tmax, which can be misleading in cases of flat plasma curves obtained following administration of ER formulations.

In conclusion, the current study documents the PK profile of a new TPM-ER formulation (USL255) and demonstrates a similar extent of absorption to Topamax while having a significantly slower absorption rate that enables once-daily dosing.

Acknowledgment

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

Dr. Meir Bialer is a consultant to Upsher-Smith. In addition, he has received in the last 3 years speakers’ or consultancy fees from BIAL, BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Lundbeck, Rekah, Sepracor, Tombotech, and UCB Pharma. Dr. Meir Bialer has been involved in the design and development of new antiepileptics and CNS drugs as well as new formulations of existing drugs.

Disclosure

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References

None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Acknowledgment
  7. Disclosure
  8. References
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