Papers by L Endrenyi
Drug metabolism and disposition: the biological fate of chemicals
The fate of intravenously administered [7-3H]isoproterenol was investigated in cats. Ten minutes ... more The fate of intravenously administered [7-3H]isoproterenol was investigated in cats. Ten minutes after injection the concentration of 3H was highest in the heart, lungs, adrenals, and kidneys, but after 5 hr most of the radioactivity was found in the liver. The concentration of the unchanged drug in the serum declined in a biphasic manner with half-lives of 2.1--2.5 min for the first phase, and 58--77 min for the second phase. The drug was rapidly metabolized to 3-O-methylisoproterenol (MISP) and then conjugated. In 5 hr 44--55% of the administered 3H was excreted in the urine, 2--2.5% as unchanged drug, 21--41% as MISP, and 12--22% as conjugated MISP. Conjugated MISP was also found in the bile. The results indicate that the rate of formation of MISP in cats is much faster than its rate of conjugation and excretion.
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Journal of Toxicology and Environmental Health, 1993
Groups of 12 male Wistar rats, of about 400 g body weight, were dosed with 2, 6, or 15 mg/kg of 1... more Groups of 12 male Wistar rats, of about 400 g body weight, were dosed with 2, 6, or 15 mg/kg of 14C-labeled pyrene, dissolved in acetone, applied to 4 cm2 of a shaved area of the mid back. Three animals in each dose group were killed at 1, 2, 4, and 6 d post-dosing, and their principal organs were removed and analyzed for pyrene and [14C]pyrene equivalents. Urine and feces, as well as the area of skin to which the dose was applied, were also analyzed for [14C]pyrene equivalents. The rate of uptake from the skin was rapid (t1/2 0.5-0.8 d) relative to rate processes for the other organs, and about 50% of the applied dose was excreted over the 6 d of the study. The significant decrease in the fraction of the dose excreted and in the normalized amounts distributed to the various organs and tissues, as the dose increased for all chemical species measured, was strongly suggestive of nonlinear kinetics, as has been observed in previous studies. Levels of pyrene were highest in the liver, kidneys, and fat. Levels of metabolites were also high in the lung. It was evident that the dermal route of uptake was not insignificant for this model polycyclic aromatic hydrocarbon and may represent a significant exposure route for exposed humans.
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Journal of Theoretical Biology, 1986
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Canadian Anaesthetists’ Society Journal, 1984
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OMICS: A Journal of Integrative Biology, 2015
Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and... more Diagnostics spanning a wide range of new biotechnologies, including proteomics, metabolomics, and nanotechnology, are emerging as companion tests to innovative medicines. In this Opinion, we present the rationale for promulgating an "Essential Diagnostics List." Additionally, we explain the ways in which adopting a vision for…
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British Journal of Clinical Pharmacology, 2008
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Pharmaceutical …, 1998
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Clinical Therapeutics, 2011
Advisory committees for the regulatory agencies of the United States (US Food and Drug Administra... more Advisory committees for the regulatory agencies of the United States (US Food and Drug Administration [FDA]) and Canada (Health Canada) recently considered issues associated with the determination of bioequivalence for some multiphasic modified-release (MR) drug products. The FDA has concluded that because of the complicated properties of some multiphasic MR products, additional metrics such as partial AUC are required for their assessment, whereas an advisory panel of Health Canada has decided that the current metrics are adequate and sufficient. The authors agree with the conclusion of the FDA that additional metrics are required. The rationales considered by the advisory committees are discussed and commented upon. It is suggested that without applying an additional metric such as partial AUC, some multiphasic MR drug products might falsely be assumed to be therapeutically equivalent and unexpected clinical effects may occur.
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Statistics in Medicine, 2000
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Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Société canadienne des sciences pharmaceutiques, 2012
To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and ... more To provide tables of sample sizes which are required, by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), for the design of bioequivalence (BE) studies involving highly variable drugs. To elucidate the complicated features of the relationship between sample size and within-subject variation. 3- and 4-period studies were simulated with various sample sizes. They were evaluated, at various variations and various true ratios of the two geometric means (GMR), by the approaches of scaled average BE and by average BE with expanding limits. The sample sizes required for yielding 80% and 90% statistical powers were determined. Because of the complicated regulatory expectations, the features of the required sample sizes are also complicated. When the true GMR = 1.0 then, without additional constraints, the sample size is independent of the intrasubject variation. When the true GMR is increased or decreased from 1.0 then the required sample sizes rise at ab...
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Journal of Pharmaceutical Sciences, 1997
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Journal of pharmacokinetics and pharmacodynamics, 2003
Following the oral administration of drugs, the plasma concentration generally reaches, in princi... more Following the oral administration of drugs, the plasma concentration generally reaches, in principle, a single, well-defined peak (Cmax) at the time of Tmax. A complication for the direct estimation of Cmax and Tmax is that measurements of concentrations are recorded only at discrete time points. Theoretical equations characterizing the population distribution of Cmax and Tmax are derived in relationship to the pharmacokinetic model, its parameters, their variabilities, and experimental errors. These equations can be solved by numerical integration. The resulting means, variances and other summary statistics of Cmax and Tmax are evaluated under various conditions involving single and multiple drug administrations. Results gained by the proposed numerical method agree closely with results gained by Monte-Carlo simulations. It is argued that the numerical method could be useful to study the statistical properties of the investigated measures and could, in some cases, provide a viable ...
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Pharmaceutical research, 2003
To provide a rational procedure for establishing regulatory bioequivalence (BE) limits that can b... more To provide a rational procedure for establishing regulatory bioequivalence (BE) limits that can be applied in determinations of scaled average BE for highly-variable (HV) drugs and drug products. Two-period crossover BE investigations with either 24 or 36 subjects were simulated with assumptions of a coefficient of variation of 10, 20, 30, or 40%. The decline in the fraction of accepted studies was recorded as the ratio of geometric means (GMR) for the two formulations was raised from 1.00 to 1.45. Acceptance of BE was evaluated by scaled average BE, assuming various BE limits, and, for comparison, by unscaled average BE. A procedure for calculating exact confidence limits in two-period studies is presented, and an approximate method, based on the linearization of the regulatory model, is applied. A mixed model is proposed for average BE. Accordingly, at low variabilities, the BE limit is constant, +/-BELo, generally log(1.25). Beyond a logarithmic, limiting, "switching" v...
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Pharmaceutical Research, 2001
Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-v... more Purpose. To establish procedures for the effective evaluation of bioequivalence (BE) for highly-variable drugs and drug products (HVD/P).
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Paraplegia, 1987
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Pharmaceutical Research, 2000
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TECHNOLOGY GOVERNANCE by L Endrenyi
The current paradigm of drug development can detect only the most common Adverse Drug Reactions (... more The current paradigm of drug development can detect only the most common Adverse Drug Reactions (ADRs) during clinical trials. One reason is that new drug candidates are tested in as few as 500 and rarely >5000 individuals in clinical trials. Once a drug is set free for use outside the realm of controlled clinical trials, novel ADR signals begin to emerge as the diversity and size of the population exposed to the drug increase to many thousands and millions.
Could the existing pharmacovigilance paradigm be improved to detect a broader range of ADRs, including those that are uncommon, and well in advance of deploying new drugs in clinical practice?
https://www.liebertpub.com/doi/10.1089/omi.2019.0013
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Papers by L Endrenyi
TECHNOLOGY GOVERNANCE by L Endrenyi
Could the existing pharmacovigilance paradigm be improved to detect a broader range of ADRs, including those that are uncommon, and well in advance of deploying new drugs in clinical practice?
https://www.liebertpub.com/doi/10.1089/omi.2019.0013
Could the existing pharmacovigilance paradigm be improved to detect a broader range of ADRs, including those that are uncommon, and well in advance of deploying new drugs in clinical practice?
https://www.liebertpub.com/doi/10.1089/omi.2019.0013