Comparative steady‐state pharmacokinetic evaluation of immediate‐release topiramate and USL255, a once‐daily extended‐release topiramate formulation

Abstract

SUMMARYPurpose: 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, twoway 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., AUC 0-24 , C max , C min ) 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 (AUC p ) 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 C min 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 C max (p < 0.001) and higher C min (p < 0.001), longer t max , lower %CV, and 26% decreased FI, as compared with TPM-IR. Further, switching between TPM-IR and USL255 did not affect TPM concentrations, including C min , 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.

Topiramate Extended-Release Options: A Focus on Efficacy and Safety in Epilepsy and Comorbidities

“…Patients were assessed over two 14-day maintenance periods, a crossover period, and 12-day titration period. 18 Although QXR and TPM-IR demonstrated equivalent steady-state, peak and trough exposures, QXR took more time to reach peak concentrations compared with TPM-IR (6 vs 1 h, respectively). QXR also had greater plateau time than TPM-IR (13 vs 4 h, respectively).…”

“…Source: Adapted with permission from John Wiley & Sons. 18 Wang et al 5 associated with both an increased ethinyl estradiol clearance and an 18% to 30% decreased ethinyl estradiol AUC. 26 Therefore, it would be prudent to use oral contraceptive pills having a higher estrogen content while on TPM 21 ⩾200 mg/ day and/or to use a different form of contraception.…”

“…The conversion from TPM-IR to TPM-ER is one to one. 18 Multiple studies have shown that pharmacokinetics (PK) parameters between TPM-IR vs TKR and TPM-IR vs QXR are similar with equivalent plasma exposure (see Table 2, and Figures 1 and 2). Figures 1 and 2 demonstrate decreased concentration fluctuations and less frequent concentration peaks and troughs over 24 hours when using TKR or QXR compared with TPM-IR 100 mg twice a day.…”

“…These data came from PWE undergoing formulation change studies. 18,19 A randomized, open-label, single-centered, multiple-dose study assessed 38 patients receiving TPM-IR 100 mg administered every 12 hours or QXR 200 mg once daily. Patients were assessed over two 14-day maintenance periods, a crossover period, and 12-day titration period.…”

Efficacy of once-daily extended-release topiramate (USL255): A subgroup analysis based on the level of treatment resistance

“…USL255 [5]. In phase I studies, USL255 displayed equivalent drug exposure to TPM-IR, with a smoother concentration-time curve and an improved steady-state PK profile (e.g., reduced fluctuation index, significantly decreased maximum plasma concentrations) [6,7]. The recent PREVAIL phase III study demonstrated that USL255 significantly improved seizure control in adults with drug-resistant partial-onset seizures (POSs) taking one to three concomitant AEDs [8].…”