Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Tóthfalusi, László; Speidl, Szilvia; Endrényi, László

doi:10.1111/j.1365-2125.2007.02984.x

Cited by 33 publications

(16 citation statements)

References 32 publications

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“…Many such modified-release products employ a multiphasic design that combines both immediate-and extended-release formulation components to achieve a quick onset of action followed by a sustained response (22). The early exposure measure such as partial area has been shown to serve as an excellent tool to characterize the PK and PD relationship (or correlation) during drug development (23). It is to be noted that the use of partial AUC as an early exposure can be truncated at reference T max or at an early time other than T max .…”

Section: Use Of Pauc As Early Exposure Measurementioning

confidence: 99%

Using Partial Area for Evaluation of Bioavailability and Bioequivalence

et al. 2011

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Assessment of bioavailability/bioequivalence generally relies on the comparison of rate and extent of drug absorption between products. Rate of absorption is commonly expressed by peak concentration (C(max)) and time to peak concentration (T(max)), although these parameters are indirect measures of absorption rate. Recognizing the importance of systemic exposure to drug efficacy and safety, FDA recommended that systemic exposure be better used for bioavailability/bioequivalence assessment. Apart from peak exposure and total exposure, FDA also recommended a new metric for early exposure that is considered necessary when a control of input rate is critical to ascertain drug efficacy and/or safety profile. The early exposure can be measured by truncating the area under the curve at T(max) of the reference product (PAUC(r,tmax)) or some designated early time after dosing. The choice of truncation is most appropriately based on PK/PD relationship or efficacy/safety data for the drug under examination. Compared with C(max), PAUC(r,tmax) has higher sensitivity in detecting formulation differences and may be more variable. If the metric is highly variable, the reference-scaling approach can be employed for bioequivalence evaluation. The partial area metric is useful in PK/PD characterization as well as in the evaluation of bioavailability, bioequivalence and/or comparability.

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Section: Use Of Pauc As Early Exposure Measurementioning

confidence: 99%

Using Partial Area for Evaluation of Bioavailability and Bioequivalence

et al. 2011

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“…Unfortunately, deriving a starting dose for phase I studies of anticancer drugs from preclinical animal toxicology and systemic pharmacokinetic data often proves to be the inappropriate conversion of drug doses from animal studies to human studies. The use of models to describe PK/PD data has received more and more attention from academia, industry, and regulatory authorities and is considered an advanced approach for exposure-response analysis (5) and clinical trial simulations (6). In many cases, plasma PK properties have been successfully related to pharmacological effects, thus being used as a surrogate for drug disposition at the site of action.…”

Section: Introductionmentioning

confidence: 99%

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

Zhou

Gallo

2011

AAPS J

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Abstract. Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/ PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two-pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/ PD models will become a standard approach for drug discovery and development.KEY WORDS: anticancer drugs; drug discovery and development; pharmacokinetic/pharmacodynamic model; physiologically based pharmacokinetic model.

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“…For example, partial AUC can be a better predictor of safety than C max when acute tolerance develops to adverse effects (22).…”

Section: Discussionmentioning

confidence: 99%

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

Endrényi

Tóthfalusi

2010

J Pharm Pharm Sci

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-Purpose. To demonstrate that current regulatory requirements for bioequivalence (BE) do not always reflect therapeutic equivalence. To investigate the potential usefulness of an additional metric, the partial AUC. Methods. Pharmacokinetic information was reviewed and evaluated on the pharmacokinetics of modified-release methylphenidate and nifedipine products. Results. In studies of modified-release products of methylphenidate as well as of nifedipine, traditional regulatory criteria found two formulations to be bioequivalent even though their concentration profiles strongly diverged during the period of absorption. An additional metric, partial AUC, discriminated strongly between the concentrations of the drug products. Conclusions. The current regulatory criteria for the acceptance of BE do not always reflect the therapeutic equivalence of modified-release drug products. With some modified-release products, the application of an additional metric, the partial AUC, yields an improved discriminatory representation. __________________________________________________________________________________________

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Exposure–response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

Cited by 33 publications

References 32 publications

Using Partial Area for Evaluation of Bioavailability and Bioequivalence

Using Partial Area for Evaluation of Bioavailability and Bioequivalence

The Pharmacokinetic/Pharmacodynamic Pipeline: Translating Anticancer Drug Pharmacology to the Clinic

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

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