Volker W. Steinijans

Sample size determination for bioequivalence assessment using a multiplicative model

In bioequivalence studies Cmax and AUCserve as the primary pharmacokinetic characteristics of rate and extent of absorption. Based on pharmacokinetic relationships and on empirical evidence, the distribution of these characteristics corresponds to a multiplicative model, which implies a logarithmic normal distribution in the case of a parametric analysis. Hence, consideration is given to exact and approximate formulas of sample sizes in the case of a multiplicative model.

Bioequivalence studies in drug development

Bioequivalence studies in drug development , Bioequivalence studies in drug development , کتابخانه دیجیتال جندی شاپور اهواز

The U.S. draft guidance regarding population and individual bioequivalence approaches: comments by a research‐based pharmaceutical company

Generally, the motivation for switching from average bioequivalence to population and/or individual bio-equivalence is well recognized in the light of certain limitations of the concept of average bioequivalence. However, this switch still results in unresolved issues which should be addressed before the regulatory guidance is finalized.

Clinical pharmacokinetics of urapidil.

SummaryUrapidil is a selective α1adrenoceptor antagonist with central antihypertensive action which is increasingly used in the treatment of hypertension. Urapidil is readily absorbed, is subject to moderate first-pass metabolism and is eliminated primarily as metabolites of much lower antihypertensive activity than the parent drug.The influences of age, renal and hepatic disease on the disposition of urapidil are reviewed. Studies on the relationship between pharmacodynamics and pharmacokinetics show that the optimum use of urapidil in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

International Harmonization of Regulatory Requirements for Average Bioequivalence and Current Issues in Individual Bioequivalence

International harmonization of regulatory requirements for average bioequivalence has made major progress during the last years, particularly with regard to the bioequivalence range and statistical analysis. The multiplicative model and hence the logarithmic transformation of the primary extent and rate characteristics AUC and Cmax and—consistent with this—the bioequivalence range of (0.80, 1.25) are now accepted by all major health authorities including the European Committee for Proprietary Medicinal Products (CPMP), the United States Food and Drug Administration (FDA), and the Canadian Health Protection Branch (HPB). Such a consensus is missing for the concept of individual bioequivalence. The selection of an appropriate methodology and suitable operative procedures for assessing individual bioequivalence must be addressed in the future by biostatisticians, biopharmaceutical scientists, and regulatory authorities.

METRICS TO CHARACTERIZE CONCENTRATION-TIME PROFILES IN SINGLE- AND MULTIPLE-DOSE BIOEQUIVALENCE STUDIES

In bioequivalence assessment, pharmacokinetic characteristics of concentration-time curves have traditionally been associated with rate and extent of absorption. In the actual context of bioequivalence, however, the similarity of the shapes rather than that of the absorption rates is essential. As a consequence, the following definition of bioequivalence was proposed during Bio-International ‘94 as a more appropriate one: “Two medicinal products are considered bioequivalent if their concentration-time profiles are so similar that they are unlikely to produce clinically relevant differences in therapeutic and/or adverse effects.” In order to quantify the similarity of concentration-time profiles, suitable shape characteristics (metrics) and appropriate bioequivalence acceptance limits (bioequivalence ranges) are needed. Whereas the majority of recent investigations dealt with indirect measures of rate of absorption and their sensitivity to simulated changes in the absorption rate, future research should focus on the similarity of the concentration-time curves rather than that of absorption rates.

Individual bioequivalence—a european perspective

Regulatory requirements for average bioequivalence have been internationally harmonized, which is by no means the case for the more recent concept of individual bioequivalence. The main reason for introducing more complex replicate designs and bioequivalence criteria are the highly variable drugs, for which the setting of suitable bioequivalence ranges poses a major problem and scaling of the bioequivalence criteria by the intrasubject variability has been suggested. The shortcoming of the present two-treatment, two-period (2 x 2) crossover design to detect subject-by-formulation interaction provides a second argument in favor of the more complex replicate designs. A unified approach of proposed statistical procedures for the replicate design has been given by Schall. However, the availability of these methods and understanding of them seems to be limited to a small working group, so a broader international awareness of the problems and potentional solutions is desirable.

Modified-Release Dosage Forms: Acceptance Criteria and Statistics for Bioequivalence

Statistical methods to assess bioequivalence of a test and a reference formulation for modified-release products are the same as for immediate-release products, the only difference being the selection of a suitable rate characteristic. The statistical methods are reviewed with emphasis on the distribution of bioequivalence characteristics, the appropriate choice of the equivalence range, and sample size determination.

Some Conceptual Issues in the Evaluation of Average, Population, and Individual Bioequivalence:

New approaches to population bioequivalence (PBE) and individual bioequivalence (IBE) have been motivated by the limitations of average bioequivalence (ABE) to handle unequal variances and subject-by-formulation interaction. The criteria for PBE and IBE described in the Food and Drug Administration draft guidance employ aggregate criteria that combine information on differences in bioavailability between formulation means, and differences in bioavailability variation of formulations between and within subjects. Examples from replicate design studies have demonstrated that the trade-off in means offered by the scaled aggregate criterion may result in clinically unacceptable decisions in favor of IBE, although ABE does not hold. Concerning the statistical methods, there are at least three conceptual issues that are still unresolved. First, aggregate hypotheses on the logarithmic scale have no obvious translation into the original scale. Second, scaling corresponds to a modification of the bioequivalence acceptance limits, and is an issue independent of IBE, PBE, and ABE, but is handled differently for IBE and PBE than for ABE. Third, the proposed criteria do not mandate hierarchical testing (first means, then variances, lastly subject-by-formulation interaction). If, despite major clinical reservations, IBE is further pursued, statistical research should focus on disaggregate criteria that allow exact stepwise procedures for evaluating untransformed parameters.