Challenges and opportunities in establishing scientific and regulatory standards for determining therapeutic equivalence of modified-release products: Workshop summary report

Chen, Mei Ling; Shah, Vinod P.; Ganes, Derek; Midha, K. K.; Caro, James; Nambiar, Prabu; Rocci, Mario L.; Thombre, Avinash G.; Abrahamsson, Bertil; Conner, Dale P.; Davit, Barbara M.; Fackler, Paul; Farrell, Christine; Gupta, Suneel; Katz, Russell; Mehta, Mehul; Preskorn, Sheldon; Sanderink, Gérard; Stavchansky, Salomon A; Wang, Yaning; Winkle, Helen; Yu, Lawrence X.

doi:10.1016/j.clinthera.2010.09.014

Cited by 12 publications

(9 citation statements)

References 8 publications

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“…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 t max (0–6 h), and the longer intervals (0–18 h; 0–24 h). Together with the two primary metrics, AUC and C max , AUC p provides a robust assessment of equivalence between formulations (Chen et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, comparative analyses using the metric partial area under the concentration–time curve (AUC p ) 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., ).…”

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confidence: 99%

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

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2013

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“…It was concluded in the workshop that "the current regulatory approaches criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic extended-release formulations." Hence, the experts that attended the workshop did not recommend partial AUC be included for bioequivalence assessment in studies comparing test and reference products which are conventional extended-release formulations (Chen et al 2010a, b, c).…”

Section: Formulations With the Same Release Mechanisms (Monomodal Relmentioning

confidence: 99%

“…An established PK/PD relationship can be applied to identify concentration range associated with a specific pharmacodynamic effect of interest (e.g., onset effect). This approach, by principle, is highly recommended by industry, academia, and regulatory experts because the determined cutoff time points can be more clinically relevant (Chen et al 2010a, b, c). However, no generally agreed approach and criteria across various products have been established at present.…”

Section: Formulations With Combined Fast-release and Slow-release Commentioning

confidence: 99%

FDA Bioequivalence Standards

Yu¹,

Li²

2014

AAPS Advances in the Pharmaceutical Sciences Series

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“…When companies develop MR products, they are required to perform additional placebocontrolled studies of efficacy, even when the amount of drug, as demonstrated by AUC, is substantially similar. 6 Such placebo-controlled studies have been performed for MR formulations of carbamazepine, lamotrigine, levetiracetam, topiramate, oxcarbazepine, and others. 7 The FDA has argued that the differences between a drug that fluctuates between Cmin and Cmax, vs one that has levels that are more consistently maintained at some middle value between the two, could be substantial enough to cause a major change in the ability of the drug to demonstrate an effect.…”

mentioning

confidence: 99%