SEARCH

SEARCH BY CITATION

Keywords:

  • USL255;
  • Topiramate extended-release formulation;
  • Steady state;
  • Pharmacokinetics;
  • Healthy subjects

Summary

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

Purpose

Compare the pharmacokinetic (PK) profiles of immediate- and extended-release formulations of topiramate (TPM) in healthy subjects following multiple dosing, and evaluate maintenance of topiramate exposures after switching formulations.

Methods

A randomized, open-label, single-center, two-way crossover, multiple-dose study comparing the steady-state PK profile of once-daily extended-release topiramate (USL255) to immediate-release topiramate (TPM-IR) administered twice-daily. The TPM PK profile was evaluated using standard PK parameters (e.g., AUC0–24, Cmax, Cmin) as well as less common PK criteria such as fluctuation index (FI), peak occupancy time (POT), and percent coefficient of variation (%CV). In addition, partial AUC (AUCp) analyses provided comparisons of the AUC profiles over predetermined time intervals between TPM-IR and USL255. Pharmacokinetic equivalence between formulations was defined as containment of the 90% confidence intervals (CIs) of the USL255/TPM-IR geometric least-squares mean (GLSM) ratio within the equivalence limits of 80–125%. The effect of switching between treatments was assessed by evaluating equivalence of PK parameters between the day prior to formulation switch and the day immediately following formulation switch. Maintenance of steady state after switching formulations was also evaluated by comparing the slope between Cmin values at formulation switch and 24 h postswitch. Tolerability was evaluated through adverse event monitoring, vital sign measurements, and clinical laboratory evaluations.

Key Findings

USL255 was well tolerated and provided TPM plasma exposure equivalent to TPM-IR at various time intervals. USL255 also demonstrated a significantly lower Cmax (p < 0.001) and higher Cmin (p < 0.001), longer tmax, lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including Cmin, immediately after transitioning and at steady state.

Significance

As compared with TPM-IR, USL255 provided equivalent plasma exposure with an extended absorption profile. Therefore, USL255 offers a once-daily alternative to twice-daily TPM-IR, with reduced TPM fluctuations.

Immediate-release topiramate (TPM-IR, Topamax; Janssen Pharmaceuticals, Inc., Titusville, NJ, U.S.A.) is approved in many countries for both adjunctive and monotherapy treatment of epilepsy as well as for migraine prophylaxis (Maryanoff et al., 1987; Doose et al., 1996). The recommended total adult TPM-IR dose for adjunctive treatment of partial onset seizures is 200–400 mg/day administered as two divided doses (Topamax Prescribing Information, 2012). TPM-IR displays a linear and dose-proportional pharmacokinetic (PK) profile from 200 to 800 mg with an elimination half-life (t1/2) of 19–25 h (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; Topamax Prescribing Information, 2012).

Maintenance of stable and effective antiepileptic drug (AED) plasma concentrations to prevent seizures is the overall treatment objective for patients with epilepsy. Compliance with the AED prescribed dosage routine is essential for the maintenance of therapeutic plasma concentrations. Unfortunately, noncompliance with AED treatment regimens is common and negatively affects management of epilepsy (Syed & Sajatovic, 2010). Extended-release (ER) AED formulations aim to reduce the frequency of dosing, thereby improving patient compliance (Bialer, 2007). ER formulations can maintain relatively flat drug plasma concentrations during the dosing interval, thereby providing less fluctuation in drug plasma concentrations. These fluctuations in AED plasma concentration may lead to adverse events (AEs) at maximum concentrations (Cmax) or breakthrough seizures at trough concentrations (Cmin) (Bialer, 2007). Because the TPM-IR formulation requires twice-daily dosing in patients with epilepsy, a once-daily formulation might be clinically advantageous if it maintains a more consistent (“flatter”) TPM plasma profile with less fluctuations following multiple dosing, thereby minimizing concentration-related AEs (Bialer, 2007) while consistently maintaining equivalent TPM exposure.

USL255, a once-daily ER formulation of TPM, is currently being developed by Upsher-Smith Laboratories, Inc. (Minneapolis, MN, U.S.A.) for the treatment of epilepsy (Lambrecht et al., 2011a). Single-dose PK data modeled to steady state suggest once-daily USL255 200 mg (USL255 200 mg QD) may provide TPM plasma exposure equivalent to TPM-IR 100 mg dosed every 12 h (TPM-IR 100 mg Q12h) with an improved PK profile (e.g., lower Cmax, higher Cmin, and reduced fluctuation index [FI]) (Lambrecht et al., 2011b).

The objectives of this study were to compare steady-state PK profiles and evaluate the tolerability of USL255 200 mg QD and TPM-IR 100 mg Q12h in healthy subjects. The major PK parameters used to assess rate of absorption (e.g., Cmax and tmax [time to Cmax]) are not ideal in cases of flat concentration-time curves obtained after oral dosing of ER formulations such as USL255 (Lambrecht et al., 2011a). Therefore, multiple PK parameters were evaluated to assess steady-state performance of USL255 compared with TPM-IR in vivo, which included both standard parameters (i.e., AUC0–24 [AUC at steady state], Cmax, Cmin, Cavg [average TPM plasma concentration at steady state], tmax) and less common PK criteria – FI, peak occupancy or plateau time (POT), and percent coefficient of variation of the TPM steady-state plasma concentration (%CV) – that estimate the flatness of the TPM plasma concentration-time curves (Caldwell et al., 1981; Silber et al., 1987; Pollak et al., 1988; Bialer et al., 1998a). In addition, comparative analyses using the metric partial area under the concentration–time curve (AUCp) were conducted on TPM steady-state PK data. Partial AUC analyses evaluate systemic exposure at any sampling time point, which allows for relative comparisons between AUC profiles over a predetermined window of clinical importance to more accurately assess similarity of PK profiles between formulations (Chen et al., 2010).

Furthermore, when switching AED formulations, exposure to the drug may be altered (Krauss et al., 2011). This change in exposure may lead to potential problems such as varied treatment response, breakthrough seizures, and/or increased AEs (Crawford et al., 2006). Therefore, this study also evaluated the effects of switching TPM formulations (TPM-IR to USL255; USL255 to TPM-IR) on the maintenance of TPM steady-state plasma concentrations both immediately after the switch and following repeated dosing. The preliminary results of this investigation were reported recently in brief abstracts (Braun et al., 2012; Lambrecht et al., 2012) and the final, more detailed, analyses are presented here.

Methods

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

Study overview

This phase 1 study was designed to compare the steady-state PK profile of USL255 200 mg once-daily (QD) to TPM-IR 100 mg administered every 12 h (Q12h) in healthy subjects. The institutional review board of the participating clinical site approved the study protocol, and subjects provided written informed consent prior to conduct of study procedures.

Study design

Healthy adult subjects (N = 38) were enrolled in a randomized, single-center, open-label, multiple-dose, two-way crossover study consisting of a 12-day up-titration, two 14-day maintenance periods with an immediate crossover between periods, followed by an 8-day down-titration as detailed in Fig. 1. Patients meeting eligibility criteria were randomized 1:1 to receive either USL255 or TPM-IR during up-titration and period 1, and were switched to the alternate formulation (without washout) for period 2, followed by down-titration.

image

Figure 1. Study design: open label, two-way crossover study consisting of a 12-day up-titration period, two 2-week maintenance periods with an immediate crossover on day 15, and an 8-day down-titration period.

Download figure to PowerPoint

USL255 to TPM-IR sequence

USL255 was initiated at 50 mg QD and increased incrementally by 50 mg every 4 days (Days −12 to −1). USL255 was maintained at 200 mg QD for 14 days (period 1; days 1–14). On day 15, subjects were immediately switched to TPM-IR 200 mg/day (100 mg Q12h) and maintained at 200 mg daily for 14 days (period 2; days 15–28). On day 29, TPM-IR was down-titrated to 100 mg/day (50 mg Q12h) for 4 days followed by 4 days at 50 mg/day (25 mg Q12h; days 29–36).

TPM-IR to USL255 sequence

TPM-IR was initiated at 50 mg/day (25 mg Q12h) and increased by 50 mg increments every 4 days (days −12 to −1). TPM-IR was maintained at 200 mg/day (100 mg Q12h) for 14 days (period 1; days 1–14). On day 15, subjects were immediately switched to USL255 200 mg QD and maintained at 200 mg daily for 14 days (period 2; days 15–28). On day 29, USL255 was down-titrated to 100 mg QD for 4 days followed by 4 days at 50 mg QD (days 29–36).

Subjects and study populations

Healthy adult subjects (18–65 years, inclusive) in generally good health, who were willing to abstain from tobacco (90 days before Screening), and alcohol-, caffeine-, and xanthine-containing beverages (48 h prior to admission) were confined to the clinic from study check-in (day −13) until completion of the final study visit on day 37. During this time, subjects were required to avoid prescription and over-the-counter medications.

Subject demographics, baseline characteristics, and safety/tolerability analyses were based on the safety population, defined as all randomized subjects who received ≥1 dose of study drug. PK equivalence population was defined as subjects who completed both periods of the study (periods 1 and 2) and had sufficient plasma samples for accurate estimation of PK parameters collected during both treatment periods.

Pharmacokinetic measures

Blood samples for steady-state PK assessments were collected on days 14, 15, and 28. During the USL255 dosing period, blood samples were drawn within 15 min before dosing (0 h) and 1, 2, 4, 6, 8, 10, 12, 14, 15, 16, 17, 18, 20, 22, and 24 h after dosing. During the TPM-IR dosing period, blood samples were drawn within 15 min before dosing (0 h) and 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 12.5, 13, 13.5, 14, 15, 16, 18, 20, and 24 h after dosing. Additional blood samples for trough plasma concentrations were collected during the up-titration period (days −12, −8, and −4), period 1 (days 1, 5, 7, 12, and 13), and period 2 (days 19, 21, 26, and 27) to evaluate the time to reach steady-state TPM plasma concentrations. Plasma samples were analyzed for TPM using validated high-performance liquid chromatography (HPLC) with tandem mass spectrometry (HPLC MS/MS) method described previously with a lower limit of quantification of 10 ng/ml (Lambrecht et al., 2011a).

Pharmacokinetic analyses

All PK analyses were performed on the defined PK equivalence population, unless otherwise stated. This study was powered to detect a significant difference of 20% in the PK parameters between TPM-IR and USL255 at α = 0.05 and provided sufficient accommodation for dropouts.

TPM PK parameters were calculated using noncompartmental methods based on statistical moment theory (Gibaldi & Perrier, 1977, 1982; Yamaoka et al., 1978; Rowland & Tozer, 2010). The area under the TPM steady-state plasma concentration-time curve from time 0 to 24 h (AUC0–24 h) and time 0 to τ (AUC0–τ) as well as various partial AUC (AUCp) values were calculated by using the linear trapezoidal rule. Dosing intervals (τ) evaluated were 12 h (TPM-IR) and 24 h (USL255). Peak steady-state TPM plasma concentrations (Cmax) and the time to Cmax (tmax) were calculated by visual inspection. The POT was calculated by assessing the time span during which the plasma concentrations deviated from Cmax by <20% (Bialer, et al. 1998b). Average TPM plasma concentration during dosing interval at steady state (Cavg) was calculated from the quotient of AUC0–24/τ. FI of TPM plasma concentration was calculated using eqn (1), where trough concentration (Cmin) was determined as the minimum observed concentration after dosing of TPM-IR or USL255 (Caldwell et al., 1981; Silber et al., 1987):

  • display math(1)

The %CV of all TPM steady-state plasma concentrations (Css) within a dosing interval was calculated using eqn (2) (Bialer et al., 1998a):

  • display math(2)

Planned statistical analyses

PK equivalence between USL255 and TPM-IR at steady state was established if the 90% CI for AUC0–24 ratio of geometric least-squares mean (GLSM) was completely contained between the critical limits of 80% and 125%. Cmax was considered equivalent to or lower than TPM-IR if the upper bound of the GLSM ratio 90% CI was <125%. Similarly, USL255 Cmin was considered equivalent to or higher than TPM-IR if the lower bound of the GLSM ratio 90% CI was >80%.

Time to steady-state TPM plasma concentration (Tss) was estimated using the Helmert Contrast Transformation on the trough concentrations (Maganti et al., 2008). Study days included in these analyses were days 5, 7, 12, 13, and 14 in period 1 and days 19, 21, 26, 27, and 28 in period 2. An analysis of variance (ANOVA), with time point as fixed effect and subject as random effect by period and treatment, was performed on log-transformed trough concentrations to determine the earliest day where Cmin was not statistically different (α = 0.05) from all subsequent values in the same period.

Post hoc statistical analyses

Multiple post hoc analyses further evaluated the PK profiles of USL255 and TPM-IR. Partial AUC analyses evaluated the equivalence between USL255 and TPM-IR at various time intervals, including the two TPM dosing intervals (0–12 h; 12–24 h), the USL255 dosing interval (0–24 h), the interval associated with the median USL255 tmax (0–6 h), as well as the 0–18 h interval. Partial AUC (AUCp) values were determined using noncompartmental analysis with actual sampling times used for the calculations. For each AUCp interval, PK equivalence between USL255 and TPM-IR was established if the 90% CI for ratio of GLSM was completely contained between the critical limits of 80% and 125%.

Pharmacokinetic equivalence between USL255 and TPM-IR immediately following formulation switch was established if the 90% CIs for the GLSM day 15 to day 14 ratio for AUC, Cmax, Cmin, and Cavg, were completely contained between the critical limits of 80% and 125%. In addition, the effect of switching TPM formulations on steady-state plasma concentrations was evaluated by comparing predose Cmin values at formulation switch (day 15, 0 h) and 24 h post switch (day 15, +24 h) using ANOVA. Maintenance of steady state was established if the slope estimates for Cmin were not significantly different from zero at the significance level of α = 0.05.

Furthermore, 90% CIs of the steady-state USL255/TPM-IR GLSM ratio for FI, POT, and %CV were evaluated utilizing a paired t-test and differences between USL255 and TPM-IR for Cmax and Cmin after multiple dosing involved one-sided hypothesis testing (α = 0.05) using the following alternative hypotheses:

  • Mean USL255 Cmax < mean TPM-IR Cmax
  • Mean USL255 Cmin > mean TPM-IR Cmin

Safety and tolerability analyses

Vital signs (blood pressure, heart rate, respiration rate), clinical laboratory parameters (hematology, serum chemistry, and urinalysis), and physical examinations were assessed at baseline and throughout the trial. Tolerability and treatment-emergent adverse events (TEAEs) were assessed by the investigator throughout the study. Changes in clinical laboratory parameters and physical examinations from baseline values (screening visit) and final study visit were determined. Sitting blood pressure and heart rate were recorded at screening, up-titration (days −13, −12, −8, −4), period 1 (day 1, 5), period 2 (day 19), and down-titration (day 29, 33). They were also monitored 30 min before dosing as well as 2 and 10 h after dose administration on days 14, 15, and 28. Respiratory rate was measured on day −13 and within 30 min before dosing on days −8, −4, 1, 5, 15, 19, 29, and at the final study visit.

Results

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

Subject demographics and disposition

A total of 38 healthy subjects were randomized and received ≥1 dose of study drug. Two subjects randomized to the TPM-IR to USL255 treatment sequence discontinued during period 1 due to TEAEs; these subjects did not receive USL255 and therefore are not included in the USL255 safety population. All remaining subjects (n = 36) were included in the steady-state PK equivalence population. Overall, demographics of randomized subjects were similar between treatment sequences (Table 1).

Table 1. Subject demographics and characteristics
 Treatment sequenceOverall (N = 38)
USL255 to TPM-IR (N = 19)TPM-IR to USL255 (N = 19)
  1. Data reported as n (%), unless otherwise noted.

  2. a

    Presented as mean (min, max).

Randomized191938
Completed19 (100)17 (89)36 (95)
Age (years)a36 (20, 62)35 (26, 51)36 (20, 62)
Gender   
Male8 (42)11 (58)19 (50)
Female11 (58)8 (42)19 (50)
Race   
White11 (58)12 (63)23 (60)
African American8 (42)6 (32)14 (37)
American Indian/Alaska native01 (5)1 (3)

Pharmacokinetic profile and comparative analyses of USL255 and TPM-IR

Mean TPM plasma concentrations at steady state following multiple dosing of USL255 (200 mg QD) and TPM-IR (100 mg Q12h) are presented in Fig. 2. Mean TPM PK parameters obtained following multiple dosing of USL255 QD and TPM-IR Q12h are presented in Table 2. At steady state, USL255 exhibits a smaller fluctuation in TPM plasma concentration and significantly lower variability in topiramate concentrations (Table 2) over 24 h than TPM-IR.

Table 2. USL255 and TPM-IR steady-state pharmacokinetic parameters
 USL255 QD (N = 36)TPM-IR Q12h (N = 36)Ratio of USL255/TPM-IR GLSM % (90% CI)
  1. Data reported as mean (SD), unless otherwise noted.

  2. CI, confidence interval; CV, coefficient of variation of TPM steady-state plasma levels; FI, fluctuation index; GLSM, geometric least-squares mean; NA, not applicable; NC, not calculated; PE, point estimate; POT, peak occupancy time or plateau time; Q12h, administered every 12 h; QD, administered once daily.

  3. a

    Median (min, max).

  4. b

    p < 0.05 as compared with TPM-IR.

  5. c

    90% CI was not contained within the equivalence limits.

AUC0–24 (mg h/L)158 (32)153 (33)104 (102–105)
AUC0–τ (mg h/L)158 (32)78 (17)NC
Cmin (mg/L)5.3 (1.2)5.0 (1.2)106 (103–109)
Cmax (mg/L)7.9 (1.5)8.4 (1.7)93 (90–97)
Cavg (mg/L)6.6 (1.3)6.5 (1.4)NC
tmax (h)a6.0 (2.0, 17)1.0 (0.5, 14)NC
POT (h)13 (5)b4 (2.3)NA
CV (%)11.9 (2.6)b15.7 (3.1)NA
FI (%)38 (11)53 (12)74 (68–80)c
image

Figure 2. Mean topiramate steady-state plasma concentrations obtained following multiple dosing of USL255 (200 mg QD) and TPM-IR (100 mg Q12h) to 36 subjects.

Download figure to PowerPoint

Steady-state plasma exposure as well as steady-state peak and trough plasma exposure for USL255 were found to be equivalent to TPM-IR, as the GLSM ratio and 90% CIs of the steady-state USL255/TPM-IR AUC, Cmin, and Cmax ratios were completely contained within the 80–125% equivalence limits. In addition, the 90% CIs of the GLSM ratio determined for each AUCp time interval were wholly contained between the 80 and 125% equivalence limits (Table 3).

Table 3. Partial AUC (AUCp) analysis of USL255 and TPM-IR
AUCp interval (h)USL255 QD GLSM (mg h/L) (N = 36)TPM-IR Q12h GLSM (mg h/L) (N = 36)Ratio of USL255/TPM-IR GLSM % (90% CI)
  1. AUCp, area under the concentration–time curve calculated between two specified time points; CI, confidence interval; GLSM, geometric least-squares mean; Q12h, administered every 12 h; QD, administered once daily.

  2. a

    Interval for 0 to median USL255 tmax (6 h).

  3. b

    TPM-IR dosing interval (12 h).

  4. c

    USL255 dosing interval (24 h).

0–6a39.942.294 (92–97)
0–12b81.676.3107 (105–109)
12–24b73.373.3100 (98–102)
0–18120.7115.3105 (103–107)
0–24c155149.6104 (102–105)

Although USL255 and TPM-IR were found to have equivalent extent of systemic exposure (AUC), USL255 demonstrated slower absorption as compared with TPM-IR as reflected by its longer median tmax (6 vs. 1 h) and longer mean POT (13 vs. 4 h), and approximately 26% decreased FI value (Table 2). In fact, one-sided hypothesis testing suggested TPM steady-state plasma fluctuations were reduced with USL255 as compared with TPM-IR, as USL255 demonstrated significantly lower Cmax (p < 0.001) and significantly higher Cmin (p < 0.001). More constant TPM plasma levels were also demonstrated by a lower %CV in TPM steady-state concentrations following administration of USL255. The 11.9% CV (95% CI; 11.0–12.8%) observed with USL255 QD was significantly reduced compared to the 15.7% CV (95% CI; 14.7–16.8%) observed with TPM-IR Q12h (p < 0.05). Furthermore, USL255 achieved steady-state TPM plasma concentrations sooner (day 5) than TPM-IR (day 7). No observable effects on steady-state TPM plasma concentrations were seen after subjects switched TPM formulations. Figure 3 displays the mean TPM concentrations of USL255 and TPM-IR before (day 14; −24 to 0 h) and after formulation switch (day 15; 0 to +24 h).

image

Figure 3. Mean topiramate plasma concentrations during the 48 h surrounding formulation switch (A) TPM-IR to USL255 switch. (B) USL255 to TPM-IR switch.

Download figure to PowerPoint

As summarized in Table 4, the USL255 and TPM-IR PK were immediately equivalent after formulation switch. The 90% CIs for the steady-state GLSM ratios for AUC, Cmin, Cmax, and Cavg for the day prior to formulation switch (day 14) and the day immediately following formulation switch (day 15) were all contained within the 80–125% equivalence limits. Furthermore, no statistically significant differences in trough TPM plasma concentration were identified during formulation transition. Slope estimates from predose concentrations on the day of switch (day 15) versus 24 h postswitch were not significantly different from zero for either formulation switch (data not shown).

Table 4. Pharmacokinetic parameters for USL255 and TPM-IR on day before (day 14) and day of (day 15) formulation switch
 USL255 to TPM-IRTPM-IR to USL255
GLSMRatio of GLSMa (90% CI)GLSMRatio of GLSMa (90% CI)
USL255 Day 14 (n = 19)TPM-IR Day 15 (n = 19)TPM-IR Day 14 (n = 17)USL255 Day 15 (n = 17)
  1. AUCp, area under the concentration–time curve calculated between two specified time points; CI, confidence interval; FI, fluctuation index; GLSM, geometric least-squares mean; Q12h, administered every 12 h; QD, administered once daily.

  2. a

    GLSM ratio of day 15 to day 14.

AUC0–24 h (mg h/L)15215099 (97–102)147148101 (98–104)
Cmin (mg/L)5.054.9598 (93–103)4.894.95101 (99–104)
Cmax (mg/L)7.628.14107 (102–112)8.207.4090 (86–95)
Cavg (mg/L)6.326.39101 (98–104)6.256.1899 (96–102)
FI (%)3949126 (110–144)523873 (67–80)

Safety and tolerability

Overall, 34 (89.5%) of 38 total subjects experienced ≥1 TEAE, most of which were deemed related to study drug. All TEAEs were mild in intensity, and there were no deaths or serious adverse events. Two subjects, however, discontinued study drug due to intolerable AEs (postural dizziness and diarrhea) after treatment with TPM-IR. Within each phase of the study (up-titration, down-titration, and maintenance), a similar percentage of subjects experienced TEAEs for both USL255 and TPM-IR. As expected, the percentage of subjects who experienced TEAEs during the two down-titration steps was less than the percentage of subjects who experienced TEAEs during the three up-titration steps (USL255 32–53%; TPM-IR 37–63%).

The highest percentage of subjects experiencing TEAEs occurred during the maintenance phase for both USL255 (61%) and TPM-IR (66%). TEAEs experienced by more than two subjects during the steady-state maintenance phase (200 mg/day) are shown in Table 5. The most commonly experienced TEAEs (≥10% subjects) were diarrhea, headache, and paresthesia, with similar incidences in both treatment groups. Subjects receiving TPM-IR reported more cognitive disorders and memory impairment than those receiving USL255. Postural dizziness and contusion were the only TEAEs reported exclusively in the USL255 treatment group. Postural dizziness (i.e., vertigo) is a known adverse event reported with TPM-IR. Two of the three incidences of contusion were associated with known causes (physical exercise and blood draw); the third reported case of contusion had no known cause.

Table 5. Summary of treatment-emergent adverse events (TEAEs) with an incidence in more than two subjects of the safety population in either treatment group during maintenance dosage (200 mg/day)
 USL255 (N = 36)TPM-IR (N = 38)
  1. Data are presented as n (%).

  2. TEAE, treatment-emergent adverse event.

  3. a

    Data presented as n.

Subjects with ≥1 TEAE22 (61)25 (66)
Total number of TEAEsa8376
Nervous system disorders  
Headache5 (14)3 (7.9)
Paresthesia4 (11)6 (16)
Postural dizziness3 (8.3)0
Cognitive disorder1 (2.8)3 (7.9)
Memory impairment03 (7.9)
Gastrointestinal disorders  
Diarrhea6 (17)7 (18)
Respiratory, thoracic, and mediastinal disorders  
Epistaxis3 (8.3)2 (5.3)
Metabolism and nutrition  
Loss of/decreased appetite03 (7.9)
Injury, poisoning, and procedural complications  
Contusion3 (8.3)0

Overall, mean hematology and serum chemistry results were within the reference ranges at the time points assessed, and the mean values observed after dosing were similar to those observed at baseline. No apparent treatment-related differences were observed in vital sign measurements or physical examination findings.

Discussion

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

The primary objective of this study was to evaluate the steady-state PK profile of USL255 and determine its equivalence to TPM-IR. Standard steady-state PK parameters (AUC, Cmax, Cmin, Cavg) demonstrated that USL255 provided equivalent TPM plasma exposure with an extended absorption profile when compared to TPM-IR. Additional PK parameters (POT, FI, %CV) provided even greater insight into the in vivo performance of USL255.

Due to concerns that traditional PK metrics such as Cmax and tmax may not fully correspond to therapeutic equivalence for a modified-release formulation, additional analyses using the metric AUCp were conducted to further evaluate the similarity of the steady-state PK profiles between USL255 QD and TPM-IR Q12h. As depicted in Table 3, all USL255/TPM-IR AUCp GLSM ratios were within the acceptable 90% CI values for pharmacokinetic equivalence. Therefore, these data suggest the topiramate exposure was equivalent between formulations across the two TPM-IR dosing intervals (0–12 h; 12–24 h), the interval associated with the median steady state USL255 tmax (0–6 h), and the longer intervals (0–18 h; 0–24 h). Together with the two primary metrics, AUC and Cmax, AUCp provides a robust assessment of equivalence between formulations (Chen et al., 2010).

Differences in the shape of the topiramate plasma concentration-time curve and/or tmax of USL255 QD and TPM-IR Q12h should not result in differences in pharmacodynamic responses. Sensitivity to differences in the shape of the PK curve depends on the rapidity of onset and where clinical doses fall on the dose-response (or concentration-response) curve (Chen et al., 2010). Overall, if a drug does not have rapid therapeutic effects and is not dosed on the steep part of the dose–response curve, differences in the rate of drug release and/or shape of the PK curve should not result in clinical differences. The time to Cmax and/or shape of the plasma concentration-time curve is critical for drugs with a rapid onset of effect (minutes to hours), such as medications for pain relief (e.g., hydromorphone) or sleep aids (e.g., zolpidem). However, for drugs that take days to weeks to elicit efficacy, such as TPM, changes in efficacy/effectiveness due to the differences in tmax or shape of the plasma concentration-time profile is highly unlikely. In addition, clinical dosages of TPM (200–400 mg/day) do not fall within the steep portion of the PK-PD dose–response curve. This is demonstrated clinically by the lack of increased efficacy at doses above 400 mg/day (Faught et al., 1996; Privitera et al., 1996) as well as by modeling the TPM exposure–response relationships for monotherapy and adjunctive treatment of epilepsy (Girgis et al., 2010). Therefore, because TPM does not have a rapid therapeutic effect and is not dosed on the steep part of the PK-PD response curve, differences in rate of drug release and/or shape of the PK curve should not result in clinical differences.

Steady-state PK parameters obtained in the current study were compared with data obtained in a previous single-dose study (Lambrecht et al., 2011a). Systemic exposure of TPM provided by a single 200 mg dose of USL255 (170 mg h/L) was comparable to the TPM systemic exposure after USL255 200 mg was administered once-daily for 14 days (158 mg h/L). In addition, the calculated USL255 POT values after a single dose and at steady state were not different (12 and 13 h, respectively). Similarly, no differences in systemic exposure or POT were observed with TPM-IR 100 mg Q12h after single- and multiple-dose administration. Predicted values for steady-state Cmax and Cmin were calculated from the product of the mean single-dose Cmax or Cmin values and the accumulation ratio (Rac) for both USL255 and TPM-IR. Rac was estimated by the single-dose AUC0–inf/AUC0–τ quotient as depicted in eqn (3). Keff is the disposition rate constant, and the effective half-life (t1/2,eff) is equal to the quotient ln2/Keff as depicted in eqn (4) (Kwan et al., 1984; Boxenbaum and Battle, 1995; Sahin & Benet, 2008).

  • display math(3)
  • display math(4)

The predicted USL255 200 mg values (9.2 mg/L [Cmin] and 10.8 mg/L [Cmax]) were higher than observed values (5.3 mg/L [Cmin] and 7.9 mg/L [Cmax]). Predicted Cmin and Cmax values for TPM-IR 100 mg Q12h were also higher than observed values (data not shown). Unlike Cmax and Cmin, which are difficult to accurately predict for drugs with a flat PK profile like USL255, USL255 200 mg Cavg values were nearly identical (predicted = 6.6 mg/L; observed = 6.3 mg/L). Cavg is a more robust PK parameter than the empirical, single-point parameters of Cmax and Cmin. This, coupled with the fact these studies were conducted in different subject groups, may help explain why predicted Cmax and Cmin were higher than the actual observed values. In addition, steady-state tmax is shorter than the tmax after a single-dose administration. This is not unexpected as single-dose tmax is a function of the absorption and elimination rate constants, whereas steady-state tmax is also affected by τ. Consequently, the steady-state tmax is shorter than the single-dose tmax as the numerator of the single-dose tmax is multiplied by a repetitive-dosing factor smaller than 1 (Gibaldi & Perrier, 1977). As such, these data suggest a linear PK profile of TPM at the clinically relevant dose range, when given either as an IR or ER formulation. This is supported by the ability of robust PK parameters (e.g., AUC0–24, Cavg, POT) calculated after a single-dose study to accurately predict TPM steady-state PK parameters after multiple dosing.

A population exposure–response (PK-PD) model for TPM has recently been developed, which includes data from a total of 11 clinical studies in both adults and pediatrics for both monotherapy and adjunctive treatment of epilepsy (Girgis et al., 2010). For monotherapy, steady-state Cmin was related to the time-to-first-seizure; as an adjunctive therapy, both percent reduction in seizure frequency from baseline and responder rate (defined as a ≥50% seizure reduction of baseline seizure frequency) were related to steady-state minimum TPM concentrations. Because therapeutic effects of TPM, in both monotherapy and adjunctive treatment of epilepsy, are related to TPM Cmin, subtherapeutic concentrations of TPM could lead to lack of efficacy. The results from this study demonstrate that steady-state Cmin after administration of USL255 QD was slightly higher (5.3 mg/L) than Cmin values achieved after TPM-IR Q12h (5.0 mg/L). In addition, when the effects of switching between formulations were evaluated, no significant difference in minimum TPM concentrations was identified in the 24 h after the switch. This indicates switching from TPM-IR to USL255 provides immediate maintenance of minimum therapeutic concentrations and equivalent exposure. Together, these data provide evidence that at equivalent daily doses, USL255 QD will consistently maintain TPM concentrations at, or above, minimum concentrations provided by TPM-IR Q12h.

USL255, administered as once-daily doses of 200 mg for 14 days, was generally well tolerated. All observed TEAEs were mild in intensity and were consistent with those generally seen with TPM-IR. Furthermore, the proportion of subjects and the incidences of TEAEs were similar between the two formulations.

The current study demonstrates that USL255 is pharmacokinetically equivalent to TPM-IR in systemic exposure, yet displays an improved TPM PK profile (e.g., lower Cmax, higher Cmin) with decreased fluctuations in TPM steady-state plasma concentrations. Coupled with the ability to maintain steady-state TPM concentrations after switching from TPM-IR and the PK results of a previous single dose study (Lambrecht et al., 2011a), these data suggest USL255 may offer a once-daily alternative to TPM-IR.

Acknowledgments

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

The authors express their appreciation to Larry Lambrecht, Pharm.D., for his contributions to the development of USL255 and Annie Clark, Pharm.D., Ph.D., for her editorial assistance. This text was sponsored by Upsher-Smith Laboratories, Inc., which included funding the services of professional medical writers (Jacqueline Benjamin, Ph.D. and Regina Switzer, Ph.D.).

Disclosure

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

Dr. Meir Bialer is a consultant to Upsher-Smith Laboratories, Inc. In addition, within the last 3 years, he has received speakers or consultancy fees from BIAL, BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, 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. Drs. Braun and Halvorsen are employees of Upsher-Smith Laboratories, Inc. T. Shekh-Ahmad has no conflict of interest to disclose. We, the authors, 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. Acknowledgments
  7. Disclosure
  8. References
  • Bialer M. (2007) Extended-release formulations for the treatment of epilepsy. CNS Drugs 21:765774.
  • Bialer M, Yacobi A, Moros D, Levitt B, Houle JM, Munsaka MS. (1998a) Criteria to assess in vivo performance and bioequivalence of generic controlled-release formulations of carbamazepine. Epilepsia 39:513519.
  • Bialer M, Arcavi L, Sussan S, Volosov A, Yacobi A, Moros D, Levitt B, Laor A. (1998b) Existing and new criteria for bioequivalence evaluation of new controlled release (CR) products of carbamazepine. Epilepsy Res 32:371378.
  • Bialer M, Doose DR, Murthy B, Curtin C, Wang SS, Twyman RE, Schwabe S. (2004) Pharmacokinetic interactions of topiramate. Clin Pharmacokinet 43:763780.
  • Boxenbaum H, Battle M. (1995) Effective half-life in clinical pharmacology. J Clin Pharmacol 35:763766.
  • Braun TL, Lambrecht LJ, Todd WM, Halvorsen MB. (2012) Steady-state pharmacokinetic profiles of extended- and immediate-release topiramate [AAN Abstract 6.111]. Presented at the 64th Annual Meeting of the American Academy of Neurology; April 21–28, 2012; New Orleans, LA.
  • Britzi M, Perucca E, Soback S, Levy RH, Fattore C, Crema F, Gatti G, Doose DR, Maryanoff BE, Bialer M. (2005) Pharmacokinetic and metabolic investigation of topiramate disposition in healthy subjects in the absence and in the presence of enzyme induction by carbamazepine. Epilepsia 46:378384.
  • Caldwell HC, Westlake WJ, Shriver RC, Bumbier EE. (1981) Steady state lithium blood level fluctuations in man following administration of lithium carbonate conventional and controlled -release dosage form. J Clin Pharmacol 21:106109.
  • Chen M-L, Shah VP, Ganes D, MIhha KK, Caro J, Nambiar P, Rocci ML Jr, Avinash GT, Abrahmsson B, Conner D, David B, Fackler P, Farrel C, Gupta S, Katz R, Metha M, Preskorn SH, Sanderink G, Stavchansky S, Temple R, Wang W, Winkle H, Yu L. (2010) Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: workshop summary report. Clin Ther 32:17041712.
  • Crawford P, Feely M, Guberman A, Kramer G. (2006) Are there potential problems with generic substitution of antiepileptic drugs? A review of issues. Seizure 15:165176.
  • Doose DR, Streeter AJ. (2002) Topiramate – chemistry, biotransformation, and pharmacokinetics. In Levy RH, Mattson RH, Meldrum BS, Perucca E (Eds) Antiepileptic drugs. 5th ed. Lippincott, Williams & Williams, Philadelphia, PA, pp. 727734.
  • Doose DR, Walker SA, Gisclon LG, Nayak RK. (1996) Single-dose pharmacokinetics and effect of food on the bioavailability of topiramate, a novel antiepileptic drug. J Clin Pharmacol 36:884891.
  • Faught E, Wilder BJ, Ramsay RE, Reife RA, Kramer LD, Pledger GW, Karim RM. (1996) Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600–mg daily dosages. Topiramate YD Study Group. Neurology 46:16841690.
  • Garnett WR. (2000) Clinical pharmacology of topiramate: a review. Epilepsia 41(Suppl. 1):S61S65.
  • Gibaldi M, Perrier D. (1977) Pharmacokinetics. Marcel Dekker, New York, NY, pp. 110113.
  • Gibaldi M, Perrier D. (1982) Pharmacokinetics. 2nd ed. Marcel Dekker, New York, NY.
  • Gidal BE. (2002) Topiramate – drug interactions. In Levy RH, Mattson RH, Meldrum BS, Perucca E (Eds) Antiepileptic drugs. 5th ed. Lippincott, Williams & Williams, Philadelphia, PA, pp. 735739.
  • Girgis IG, Nandy P, Nye JS, Ford L, Mohanty S, Wang S, Ochalski S, Erdekens M, Cox E. (2010) Pharmacokinetic-pharmacodynamic assessment of topiramate dosing regimens for children with epilepsy 2 to <10 years of age. Epilepsia 5:19541962.
  • Janssen Pharmaceuticals, Inc. (2012) Topamax® [Prescribing Information]. Janssen Pharmaceuticals, Inc. Titusville, NJ.
  • Krauss GL, Caffo B, Chang YT, Hendrix CW, Chuang K. (2011) Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol 70:221228.
  • Kwan KC, Bohidar NR, Hwang SS. (1984) Estimation of an effective half-life. In Benet LZ, Levy G, Ferraiolo B (Eds) Pharmacokinetics: A modern view. Plenum Press, New York, pp. 147162.
  • Lambrecht LJ, Shekh-Ahmad T, Todd WM, Halvorsen MB, Bialer M. (2011a) Comparative pharmacokinetic analysis of USL255, a new once-daily extended-release formulation of topiramate. Epilepsia 52:18771883.
  • Lambrecht LJ, Todd WM, Carrithers J, Halvorsen MB. (2011b) Development and optimization of extended-release formulations of topiramate [AAN abstract 1.116]. Presented at the 63rd Annual Meeting of the American Academy of Neurology; April 9–16, 2011; Honolulu, HI.
  • Lambrecht LJ, Braun TL, Todd WM, Halvorsen MB. (2012) Switching between immediate- and extended-release formulations does not affect the steady-state pharmacokinetic profile of topiramate [AAN abstract P06.112]. Presented at the 64th Annual Meeting of the American Academy of Neurology; April 21–28, 2012; New Orleans, LA.
  • Maganti L, Panebianco DL, Maes AL. (2008) Evaluation of methods for estimating time to steady state with examples from Phase 1 studies. AAPS J 10:141147.
  • Maryanoff BE, Nortey SO, Gardocki JF, Shank RP, Dodgson SP. (1987) Anticonvulsant O-alkyl sulfamates. 2,3:4,5-Bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate and related compounds. J Med Chem 30:880887.
  • Mimrod D, Specchio LM, Britzi M, Perucca E, Specchio N, La Neve A, Soback S, Levy RH, Gatti G, Doose DR, Maryanoff BE, Bialer M. (2005) A comparative study of the effect of carbamazepine and valproic acid on the pharmacokinetics and metabolic profile of topiramate at steady state in patients with epilepsy. Epilepsia 46:10461054.
  • Pollak PT, Freeman DJ, Carruthers SG. (1988) Mean apical concentration and duration in the comparative bioavailability of slowly absorbed and eliminated drug preparations. J Pharm Sci 77:477480.
  • Privitera M, Fncham R, Penry J, Reife R, Kramer L, Pledger G, Karim R. (1996) Topiramate placebo-controlled dose ranging trial in refractory partial epilepsy using 600-, 800-, and 1,000-mg daily dosages. Neurology 46:16781683.
  • Rowland M, Tozer T. (2010) Clinical pharmacokinetics and pharmacodynamics. 4th ed. Lippincott, Williams & Williams, Philadelphia, PA.
  • Sachdeo RC, Sachdeo SK, Levy RH, Streeter AJ, Bishop FE, Kunze KL, Mather GG, Roskos LK, Shen DD, Thummel KE, Trager WF, Curtin CR, Doose DR, Gisclon LG, Bialer M. (2002) Topiramate and phenytoin pharmacokinetics during repetitive monotherapy and combination therapy to epileptic patients. Epilepsia 43:691696.
  • Sahin S, Benet LZ. (2008) The operational multiple dosing half-life: a key to defining drug accumulation in patients and to designing extended release dosage forms. Pharm Res 25:28692877.
  • Silber BM, Bialer M, Yacobi A. (1987) Pharmacokinetic/pharmacodynamic basis of controlled drug delivery. In Robinson JR, Lee VH (Eds) Controlled drug delivery. 2nd ed. Marcel Dekker, New York, pp. 213252.
  • Syed TU, Sajatovic M. (2010) Extended-release lamotrigine in the treatment of patients with epilepsy. Expert Opin Pharmacother 11:15791585.
  • Yamaoka K, Nakagawa T, Uno T. (1978) Statistical moments in pharmacokinetics. J Pharmacokinet Biopharm 6:547558.