Do Regulatory Bioequivalence Requirements Adequately Reflect the Therapeutic Equivalence of Modified-Release Drug Products?

Endrényi, László; Tóthfalusi, László

doi:10.18433/j32g6p

Cited by 23 publications

(16 citation statements)

References 14 publications

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“…Although bioequivalence of a newly formulated ER product to the original IR product is ideal, it is not a prerequisite for FDA approval. Indeed, there have been discussions at the FDA regarding modified‐release products regarding whether standard bioequivalence measures are optimal, as significant deviations in concentration profiles in the absorption phase have been observed even when an ER drug has met the traditional criteria for bioequivalence to an IR counterpart (Endrenyi & Tothfalusi, 2010). A more robust measure of bioequivalence may be the determination of partial AUC (and associated 90% CIs), especially for modified‐release products.…”

Section: Pharmacokinetic Considerations For Antiepileptic Drugsmentioning

confidence: 99%

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

Leppik

Hovinga

2012

Epilepsia

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SUMMARYMany antiepileptic drugs (AEDs) have short half-lives with large fluctuations in peak-to-trough plasma concentrations. Consequences of these pharmacokinetic (PK) properties may include adverse events (AEs) and breakthrough seizures, potentially leading to poor adherence. To address these challenges, newer formulations of these AEDs have been developed using unique extended-release (ER) technologies. These technologies extend the dosing interval such that dosing frequency can be minimized, which may improve patient adherence. Available ER formulations have the potential to minimize the spikes in maximum plasma concentrations (C max ) at steady-state that often contribute to AEs during treatment with immediate-release (IR) products. In so doing, tolerability advantages may lead to increased AED effectiveness by improving adherence and allowing higher doses if clinically indicated. Direct PK comparison studies of IR and ER formulations (e.g., carbamazepine, divalproate sodium, lamotrigine, oxcarbazepine, levetiracetam, and phenytoin) have found that dose-normalized ER formulations may or may not be bioequivalent to their IR counterparts, but most ER formulations have a lower fluctuation index ([C max -C min ]/C avg ) compared with the IR versions. This results in flatter concentration-time plots. Not all ER preparations improve the various PK parameters to the same extent, and PK nuances may impact the effectiveness, tolerability, and adherence rates of various ER formulations.

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Section: Pharmacokinetic Considerations For Antiepileptic Drugsmentioning

confidence: 99%

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

Leppik

Hovinga

2012

Epilepsia

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“…The addition of partial AUC as a metric of comparison substantially enhances the probability that determination of the BE of these MR formulations ensures their therapeutic equivalence (57). Thus, partial AUC has been usefully applied as a metric for the evaluation of BE of some multiphasic MR formulations.…”

Section: Partial Auc For Some Multiphasic Mr Productsmentioning

confidence: 99%

Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations

Endrényi

Tóthfalusi

2012

AAPS J

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Abstract. Metrics are discussed which are used for the evaluation of bioequivalence of modifiedrelease formulations. In order to ensure the therapeutic equivalence of the compared drug products, it would be important to contrast measures which are additional to area under the curve (AUC) and C max . For delayed-release products, the assessment of lag times is informative. For extended-release dosage forms, comparisons of the half-value duration and the midpoint duration time are useful. For some modified-release formulations with complicated, multiphasic concentration profiles, the comparison of partial AUCs is important. In determinations of the bioequivalence of extended-release dosage forms, investigations performed under steady-state conditions rather than after single dosing can yield enhanced probability of therapeutic equivalence, especially with substantial accumulation of the drug products. In steady-state investigations of bioequivalence, evaluation of the trough concentration and of the peak trough fluctuation is informative.

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“…The single-dose bioequivalence study design is preferred for quality control because single-dose studies are the most sensitive for detecting differences. For modified-release products, single-dose C max often (but not always) has higher kinetic sensitivity and better statistical responsiveness and provides better quality control (23). However, steady-state C max may be clinically more important, particularly with high accumulation.…”

Section: Measures For the Determination Of Bioequivalence Of Modifiedmentioning

confidence: 99%

“…A 2-day workshop was held on October [22][23]2011 in Washington, DC and focused on best practices in the application of biopharmaceutics in oral drug product development, along with new evolving bioequivalence approaches. Entitled "Facilitating Oral Product Development and Reducing Regulatory Burden through Novel Approaches to Assess Opinions expressed in this report are those of the authors (BMD and AGA) and do not necessarily reflect the views or policies of the FDA or AEMPS.…”

Section: Introductionmentioning

confidence: 99%

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

Polli

Cook

Davit

et al. 2012

AAPS J

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Abstract. This summary workshop report highlights presentations and over-arching themes from an October 2011 workshop. Discussions focused on best practices in the application of biopharmaceutics in oral drug product development and evolving bioequivalence approaches. Best practices leverage biopharmaceutic data and other drug, formulation, and patient/disease data to identify drug development challenges in yielding a successfully performing product. Quality by design and product developability paradigms were discussed. Development tools include early development strategies to identify critical absorption factors and oral absorption modeling. An ongoing theme was the desire to comprehensively and systematically assess risk of product failure via the quality target product profile and root cause and risk analysis. However, a parallel need is reduced timelines and fewer resources. Several presentations discussed applying Biopharmaceutics Classification System (BCS) and in vitro-in vivo correlations in development and in post-development and discussed both resource savings and best scientific practices. The workshop also focused on evolving bioequivalence approaches, with emphasis on highly variable products (HVDP), as well as specialized modified-release products. In USA, two bioequivalence approaches for HVDP are the reference-scaled average bioequivalence approach and the two-stage group-sequential design. An adaptive sequential design approach is also acceptable in Canada. In European Union, two approaches for HVDP are a two-stage design and an approach to widen C max acceptance limits. For some specialized modified-release products, FDA now requests partial area under the curve. Rationale and limitations of such metrics were discussed (e.g., zolpidem and methylphenidate). A common theme was the benefit of the scientific and regulatory community developing, validating, and harmonizing newer bioequivalence methodologies (e.g., BCS-based waivers and HVDP trial designs).

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Do Regulatory Bioequivalence Requirements Adequately Reflect the Therapeutic Equivalence of Modified-Release Drug Products?

Cited by 23 publications

References 14 publications

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

Extended‐release antiepileptic drugs: A comparison of pharmacokinetic parameters relative to original immediate‐release formulations

Metrics for the Evaluation of Bioequivalence of Modified-Release Formulations

Summary Workshop Report: Facilitating Oral Product Development and Reducing Regulatory Burden Through Novel Approaches to Assess Bioavailability/Bioequivalence

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