The Use of Toxicokinetic Data in Preclinical Safety Assessment: A Toxicologic Pathologist Perspective

Ploemen, J.H.T.M.; Kramer, Hester; Krajnc, Ernö I.; Martin, Iain

doi:10.1080/01926230701584247

Cited by 19 publications

(13 citation statements)

References 19 publications

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“…Whilst the scope and intent of such guidance are well described since 1994, when it was introduced by the ICH, there has been much less attention to requirements for the analysis and interpretation of the data. In fact, precise details on the design of toxicokinetic studies or the statistical methods for calculating or estimating the endpoints or variables of interest, are not specified [ 13 – 15 ]. Instead, the assessment of exposure often takes places in satellite groups, which may not necessarily present the (same) adverse events or toxicity observed in the main experimental group.…”

Section: Introductionmentioning

confidence: 99%

The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments

Sahota

Danhof

Pasqua

2015

J Pharmacokinet Pharmacodyn

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Current toxicity protocols relate measures of systemic exposure (i.e. AUC, Cmax) as obtained by non-compartmental analysis to observed toxicity. A complicating factor in this practice is the potential bias in the estimates defining safe drug exposure. Moreover, it prevents the assessment of variability. The objective of the current investigation was therefore (a) to demonstrate the feasibility of applying nonlinear mixed effects modelling for the evaluation of toxicokinetics and (b) to assess the bias and accuracy in summary measures of systemic exposure for each method. Here, simulation scenarios were evaluated, which mimic toxicology protocols in rodents. To ensure differences in pharmacokinetic properties are accounted for, hypothetical drugs with varying disposition properties were considered. Data analysis was performed using non-compartmental methods and nonlinear mixed effects modelling. Exposure levels were expressed as area under the concentration versus time curve (AUC), peak concentrations (Cmax) and time above a predefined threshold (TAT). Results were then compared with the reference values to assess the bias and precision of parameter estimates. Higher accuracy and precision were observed for model-based estimates (i.e. AUC, Cmax and TAT), irrespective of group or treatment duration, as compared with non-compartmental analysis. Despite the focus of guidelines on establishing safety thresholds for the evaluation of new molecules in humans, current methods neglect uncertainty, lack of precision and bias in parameter estimates. The use of nonlinear mixed effects modelling for the analysis of toxicokinetics provides insight into variability and should be considered for predicting safe exposure in humans.Electronic supplementary materialThe online version of this article (doi:10.1007/s10928-015-9413-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments

Sahota

Danhof

Pasqua

2015

J Pharmacokinet Pharmacodyn

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“…The doses of ADR used in this study were 4.5 and 9.0 times lower than those used by Chen et al [ 12 ]. Excessive doses in pharmacokinetic studies could influence the pharmacokinetic parameters in the absorption phases [ 17 ]. In this regard, the difference in T max might be due to differences in the amounts of furanocoumarin and non-furanocoumarin components as a result of the ADR preparation method and the dose of the test substance.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous Determination of Three Furanocoumarins by UPLC/MS/MS: Application to Pharmacokinetic Study of Angelica dahurica Radix after Oral Administration to Normal and Experimental Colitis-Induced Rats

2017

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In traditional oriental medicine, Angelica dahurica Radix (ADR) is used in the treatment of gastrointestinal, respiratory, neuromuscular, and dermal disorders. We evaluated the pharmacokinetic profiles of oxypeucedanin, imperatorin, and isoimperatorin, major active ingredients of ADR, in normal and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats. A rapid, sensitive, and validated UPLC/MS/MS method was established for evaluating the pharmacokinetics of three furanocoumarins. After oral administration of ADR (0.5 and 1.0 g/kg), blood samples were collected periodically from the tail vein. In colitis rats, the time to reach the peak concentration (Tmax) of imperatorin and isoimperatorin was significantly delayed (p < 0.05). Lower peak plasma concentrations (Cmax) and longer mean residence times for all furanocoumarins were also observed (p < 0.05) compared with normal rats. There was no significant difference in the area under the plasma concentration–time curve or elimination half-lives. Thus, the delayed Tmax and decreased Cmax, with no influence on the elimination half-life, could be colitis-related changes in the drug-absorption phase. Therefore, the prescription and use of ADR in colitis patients should receive more attention.

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“…Îñîáåííîñòè òîêñèêîêèíåòè÷åñêèõ èññëåäîâàíèé âî ìíîãîì îïðåäåëÿåò èñïîëüçîâàíèå ïðåïàðàòîâ â òîêñè÷åñêèõ äîçàõ, ÷òî îòëè÷àåò èõ îò èññëåäîâàíèé ôàðìàêîêèíåòèêè [15]. Âûñîêèå äîçû ìîãóò èçìåíÿòü ðàñòâîðèìîñòü è âñàñûâàíèå âåùåñòâà â aeåëóäî÷íî-êèøå÷íîì òðàêòå, ïîäàâëÿòü èëè àêòèâèðîâàòü ïðîöåññû ìåòàáîëèçìà, ÷òî ìîaeåò ïðèâåñòè ê èçìåíåíèþ áèîäîñòóïíîñòè ñàìîãî âåùåñòâà èëè åãî ìåòàáîëèòîâ [16,17].…”

Section: òåîðåòè÷åñêèå îñíîâû òîêñèêîêèíåòèêèunclassified

Экспертная Оценка Доклинических Исследований Токсикокинетики Лекарственных Средств (Обзор)

Сюбаев¹,

Енгалычева²,

Горячев³

et al. 2018

Хим.-фарм. ж.

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Представлен анализ данных литературы, отечественных и зарубежных методических документов по доклиническим исследованиям безопасности и токсикокинетики лекарственных средств. Согласно Правилам регистрации и экспертизы лекарственных средств для медицинского применения ЕАЭС в общий технический документ разработчик обязан включать сведения о токсикокинетических исследованиях, которые подлежат оценке при проведении экспертизы результатов доклинических исследований. Сформулированы основные подходы к экспертной оценке результатов токсикокинетических исследований лекарственных средств. Определено основное содержание экспертного анализа, включающего методологическую базу исследований, результаты исследований, характеристику профиля безопасности, экстраполяцию доклинических данных, характеристику факторов риска и прогнозируемого профиля клинической безопасности для пациентов. Включение токсикокинетических исследований в программу доклинического токсикологического изучения имеет принципиальное значение для адекватной экстраполяции экспериментальных данных и прогноза безопасности применения лекарственных средств у человека. Экспертный анализ токсикокинетических данных позволяет оценить корректность интерпретации результатов токсикологических исследований, характеристики профиля токсичности лекарственного средства и риска развития токсических эффектов.

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The Use of Toxicokinetic Data in Preclinical Safety Assessment: A Toxicologic Pathologist Perspective

Cited by 19 publications

References 19 publications

The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments

The impact of composite AUC estimates on the prediction of systemic exposure in toxicology experiments

Simultaneous Determination of Three Furanocoumarins by UPLC/MS/MS: Application to Pharmacokinetic Study of Angelica dahurica Radix after Oral Administration to Normal and Experimental Colitis-Induced Rats

Экспертная Оценка Доклинических Исследований Токсикокинетики Лекарственных Средств (Обзор)

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