Search

Physiology-based pharmacokinetic and toxicokinetic (PBPK/TK) models allow us to simulate the concentration of xenobiotica in the plasma and different tissues of an organism. PBPK/TK models are therefore routinely used in many fields of life sciences to simulate the physiological concentration of exogenous compounds in plasma and tissues. The application of PBTK models in ecotoxicology, however, is currently hampered by the limited availability of models for focal species. Here, we present a best practice workflow that describes how to build PBTK models for novel species. To this end, we extrapolated eight previously established rabbit models for several drugs to six additional mammalian species (human, beagle, rat, monkey, mouse, and minipig). We used established PBTK models for these species to account for the species-specific physiology. The parameter sensitivity in the resulting 56 PBTK models was systematically assessed to rank the relevance of the parameters on overall model performance. Interestingly, more than 80% of the 609 considered model parameters showed a negligible sensitivity throughout all models. Only approximately 5% of all parameters had a high sensitivity in at least one of the PBTK models. This approach allowed us to rank the relevance of the various parameters on overall model performance. We used this information to formulate a best practice guideline for the efficient development of PBTK models for novel animal species. We believe that the workflow proposed in this study will significantly support the development of PBTK models for new animal species in the future.

Objectives: To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of micafungin in septic patients at the plasma and peritoneal sites. Methods: From healthy (n = 8) and septic piglet group (n = 16), total micafungin concentrations were subject to a population PK analysis using Monolix®. Data from 16 septic humans patients from others studies was used to compare micafungin PK between septic piglets and septic patients. Results: Sepsis induced in piglets slightly alters the total clearance and the volume of distribution, while inter-compartment clearance is increased (from 3.88 to 5.74 L/h) as well as the penetration into peritoneal cavity (from 61 to 90%). In septic human patients, PK parameters are similar except for the Vd, which is corrected by an allometric factor based on the body weight of each species. Micafungin penetration into peritoneal cavity of humans is lower than in septic piglets (40 versus 90%). Conclusions: The sepsis induced in the porcine model alters the PK of micafungin comparable to that in humans. In addition, micafungin PK is similar between these two species at the plasma level taking into account the allometric relationship of the body weight of these species on the central volume of distribution. The porcine septic plasma model would be able to predict the micafungin PK in the septic patients. However, further studies on peritoneal penetration are necessary to characterize this inter-species difference. [ABSTRACT FROM AUTHOR]

Transfer of knowledge along the different phases of drug development is a fundamental process in pharmaceutical research. In particular, cross-species extrapolation between different laboratory animals and further on to first-in-human trials is challenging because of the uncertain comparability of physiological processes. Physiologically based pharmacokinetic ( PBPK) modeling allows translation of mechanistic knowledge from one species to another by specifically considering physiological and biochemical differences in between. We here evaluated different knowledge-driven approaches for cross-species extrapolation by systematically incorporating specific model parameter domains of a target species into the PBPK model of a reference species. Altogether, 15 knowledge-driven approaches were applied to murine and human PBPK models of 10 exemplary drugs resulting in 300 different extrapolations. Statistical analysis of the quality of the different extrapolations revealed not only species-specific physiology as the key determinant in cross-species extrapolation but also identified a synergistic effect when considering both kinetic rate constants and gene expression profiles of relevant enzymes and transporters. Moreover, we show that considering species-specific physiology, plasma protein binding, enzyme and transport kinetics, as well as tissue-specific gene expression profiles in PBPK modeling increases accuracy of cross-species extrapolations and thus supports first-in-human trials based on prior preclinical knowledge. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:191-206, 2015 [ABSTRACT FROM AUTHOR]

Internal dose metrics, as computed with pharmacokinetic models, are increasingly used as a means for extrapolating animal toxicological data to humans and to extrapolate across routes of administration. These internal dose metrics are thought to provide a more scientific means of comparing toxicological effects across animal species. The use of internal dose metrics is based on the universal assumption that toxic effects are equal across species if and only if the concentration of the toxic moieties in the target tissue is equal across species. Herein it is shown that this assumption is inconsistent with empirical toxicological data. It is shown that measurement of internal dose metrics in chronological time, as is done for AUC (Area under the concentration curve) and rate of metabolite production per kg of target tissue, does not produce equal toxic effects across species. A consequence of this observation is that the application of pharmacokinetics in risk assessments for such important chemicals as trichloroethylene, vinyl chloride, perchloroethylene, and perchlorate may need reassessment. [ABSTRACT FROM AUTHOR]

For a particular chemical, one can treat the chemical-by-chemical variation in rel-ative doses for equal toxicity in experimental animals and humans as a characteriza-tion of the likelihoods of extrapolation factors of different magnitudes. An emerging approach to noncancer risk assessment is to use such empirical distributions in place of fixed Uncertainty Factors. This paper discusses dividing the overall variation into two sub-distributions representing pharmacokinetic (PK) and pharmacodynamic (PD) contributions to the variation among chemicals in the animal-to-human toxi-cologically equivalent dose. If a physiologically based pharmacokinetic model (PBPK model) is used to derive a compound specific adjustment factor (CSAF) for the phar-macokinetic component, the deconvolution of the PK and PD components allows one to remove the PK component (to be replaced with the CSAF), while retaining the uncertainty in pharmacodynamics that PBPK models do not address. One must then add back the uncertainty in the PBPK determination of the CSAF (which may be considerable). A candidate criterion for whether one can use an uncertain PBPK model is whether the generic uncertainty about cross-species pharmacokinetics (re-flected in the PK component of the overall empirical distribution) is larger than the chemical-specific uncertainty in the determination of kinetically equivalent doses in experimental animals and humans. [ABSTRACT FROM AUTHOR]