Guidance on safety evaluation of sources of nutrients and bioavailability of nutrient from the sources

Whenever new substances are proposed for use as sources of nutrients in food supplements, foods for the general population or foods for specific groups, EFSA is requested by the European Commission to perform an assessment of their safety and of the bioavailability of the nutrient from the proposed source. This guidance describes the scientific data required to allow an evaluation of the safety of the source within the established framework for risk assessment of food additives and novel food ingredients and the bioavailability of the nutrient from this source. This document is arranged in five main sections: one on technical data aimed at characterising the proposed source and at identifying potential hazards resulting from its manufacture and stability in food; one on existing authorisations and evaluation, providing an overview of previous assessments on the proposed source and their conclusions; one on proposed uses and exposure assessment section, allowing an estimate of the dietary exposure to the source and the nutrient based on the proposed uses and use levels; one on toxicological data, describing approaches which can be used to identify (in conjunction with data on manufacture and composition) and to characterise hazards of the source and any relevant breakdown products; the final section on bioavailability focuses on determining the extent to which the nutrient from the proposed source is available for use by the body in comparison with one or more forms of the same nutrient that are already permitted for use on the positive lists. This guidance document should replace the previous guidance issued by the Scientific Committee for Food and published in 2001

Predictive Performance of Physiologically Based Pharmacokinetic Modelling of Beta-Lactam Antibiotic Concentrations in Adipose, Bone and Muscle Tissues.

Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable as-sociated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentra-tions of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazi-dime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evalu-ated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underpre-diction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predic-tions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be over -predicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue con-centrations and the associated need for more accurate models.SIGNIFICANCE STATEMENTClinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentra-tions. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.Physiologically based pharmacokinetic (PBPK) models consist of compartments representing different tissues. As most models are only verified based on plasma concentrations, it is unclear how reliable as-sociated tissue profiles are. This study aimed to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in different tissues and assess the impact of using effect site concentrations for evaluation of target attainment. Adipose, bone, and muscle concentra-tions of five beta-lactams (piperacillin, cefazolin, cefuroxime, ceftazi-dime, and meropenem) in healthy adults were collected from literature and compared with PBPK predictions. Model performance was evalu-ated with average fold errors (AFEs) and absolute AFEs (AAFEs) between predicted and observed concentrations. In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 unbound interstitial fluid (uISF) concentrations. Concurrent plasma concentrations, used as baseline verification of the models, were fairly accurate (AFE: 1.14, AAFE: 1.50). Predicted total tissue concentrations were less accurate (AFE: 0.68, AAFE: 1.89). A slight trend for underpre-diction was observed but none of the studies had AFE or AAFE values outside threefold. Similarly, predictions of microdialysis-derived uISF concentrations were less accurate than plasma concentration predic-tions (AFE: 1.52, AAFE: 2.32). uISF concentrations tended to be over -predicted and two studies had AFEs and AAFEs outside threefold. Pharmacodynamic simulations in our case showed only a limited impact of using uISF concentrations instead of unbound plasma concentrations on target attainment rates. The results of this study illustrate the limitations of current PBPK models to predict tissue con-centrations and the associated need for more accurate models.SIGNIFICANCE STATEMENTClinical inaccessibility of local effect site concentrations precipitates a need for predictive methods for the estimation of tissue concentra-tions. This is the first study in which the accuracy of PBPK-predicted tissue concentrations of beta-lactam antibiotics in humans were assessed. Predicted tissue concentrations were found to be less accurate than concurrent predicted plasma concentrations. When using PBPK models to predict tissue concentrations, this potential relative loss of accuracy should be acknowledged when clinical tissue concentrations are unavailable to verify predictions.A

Animal versus human oral drug bioavailability: Do they correlate?

AbstractOral bioavailability is a key consideration in development of drug products, and the use of preclinical species in predicting bioavailability in human has long been debated. In order to clarify whether any correlation between human and animal bioavailability exist, an extensive analysis of the published literature data was conducted. Due to the complex nature of bioavailability calculations inclusion criteria were applied to ensure integrity of the data. A database of 184 compounds was assembled. Linear regression for the reported compounds indicated no strong or predictive correlations to human data for all species, individually and combined.The lack of correlation in this extended dataset highlights that animal bioavailability is not quantitatively predictive of bioavailability in human. Although qualitative (high/low bioavailability) indications might be possible, models taking into account species-specific factors that may affect bioavailability are recommended for developing quantitative prediction

Accuracy of PBPK-predicted tissue concentrations: a case study of beta-lactam antibiotics in fat, bone and muscle

Background: A core concept of physiologically based pharmacokinetics (PBPK) is the modelling of tissues as distinct PK compartments. As most drug targets are located outside the bloodstream and sampling of tissue concentrations is generally not feasible, PBPK models could potentially bridge the gap between plasma and effect-site PK. In perfusion-limited compartments such as adipose, bone and muscle, concentrations are predicted using equations relying on tissue composition, drug physicochemistry and blood binding as input. These equations were mainly developed and validated using animal tissue concentrations. While these models are able to predict the volume of distribution in humans reasonably well, the accuracy of predicted tissue concentration profiles is unclear. Aim: This work aims to assess the accuracy of PBPK-predicted beta-lactam antibiotic concentrations in adipose, bone and muscle tissues. Methods: Observed concentrations from the literature were compared to PBPK predictions for five beta-lactam antibiotics (piperacillin, cefazolin, cefuroxime, ceftazidime and meropenem). Observed data stemmed from healthy adults subjects and included plasma concentrations, total tissue concentrations obtained from tissue homogenates and unbound interstitial fluid (uISF) concentrations sampled using microdialysis. PBPK predictions were performed using the Simcyp® simulator (V20). A PBPK model for piperacillin was developed and validated using plasma concentrations in healthy volunteers. For the other four beta-lactam antibiotics, published PBPK models were used. All five models used the Rodgers & Rowland method to predict tissue-to-plasma partition coefficients. Total tissue concentrations were converted to microdialysis (uISF) concentrations by assuming an equilibrium with unbound plasma concentrations at distribution steady-state (free drug hypothesis). Differences between predicted and measured concentrations in plasma and tissues were quantified as average fold errors (AFEs) and absolute AFEs (AAFEs). Model performance was deemed adequate when AFE and AAFE values were within twofold (0.5-2). Results: In total, 26 studies were included, 14 of which reported total tissue concentrations and 12 uISF concentrations. All but one study reported plasma concentrations, which were captured reasonably well by the PBPK simulations: most studies (88%) had AFE and AAFE values within twofold and the overall AFE and AAFE values were 1.14 and 1.50, respectively. Predicted total tissue concentrations were less accurate, with only half of the simulated studies passing the AFE and AAFE criteria. None of the studies had AFE and AAFEs outside threefold (0.33-3.00). Overall AFE and AAFE were 0.68 and 1.89 respectively, indicating that the PBPK models tended to underpredict total tissue concentrations. Similarly, half of the simulated uISF concentration-time profiles did not pass the model performance criteria. Two uISF studies had AFE and AAFE values outside threefold. The overall AFE and AAFE were 1.52 and 2.32, indicating that the models tended to overpredict the uISF concentration profiles. Conclusion: PBPK predicted tissue concentrations were generally within threefold of observed values but were less accurate than predicted plasma concentrations. This calls for caution when using PBPK models validated using plasma data to predict tissue concentrations