Human pharmacokinetic projection

The binding to plasma or subcellular liver fraction can be taken into account for the prediction of human pharmacokinetic parameters either from preclinical and/or in vitro metabolism data (Obach et al. 1997 Mahmood 2000). Obach (1999) showed by comparison the in vivo investigated clearance values and clearance values projected from in vitro intrinsic clearance data of 29 drugs that the inclusion of blood and liver microsomes binding values gave the best agreement. 

In the following sections, we will illustrate how these principles have been applied. We will highlight the fundamental mathematical models, that with increasing confidence have allowed us to identify compounds projected to exhibit good human pharmacokinetic profiles from simple preclinical data. These mathematical relationships may also provide the basis for a purely in silico prediction of human pharmacokinetics when coupled with robust in silico models of DMPK endpoints. 

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Based on rat neuropharmacokinetic concepts, it has been proposed [37,42,45] that Cb/U may be projected directly from Cp for large animal species (i.e., dog, monkey, and human) in which Cb are rarely measured. For such species, in which serial blood sampling is common for determining plasma pharmacokinetics, compound Cb,u may be extrapolated using its Cp, species-specific /u,p, and rat-derived Cb,u CP/U assuming a fixed ratio across species ... 

According to the EU project entitled Knowledge and Need Assessment on Pharmaceutical Products in Environmental Waters (KNAPPE), ecopharmacovig-ilance deals with APIs monitoring of sources, distribution, fate and biological impact on ecosystems and, ultimately, on human health [5], which environmental levels depend on the amounts sold/consumed, pharmacokinetic behaviour, degradation and wastewater treatment plants (WWTPs) removal efficiency. 

In this project, compound A from a potential lead series was a neutral compound of MW 314 with low aqueous solubility (Systemic clearance, volume and AUC following a 0.5mg/kg intravenous dose to rats were well predicted (within twofold) from scaled microsomal clearance and in silica prediction of pKa, logP and unbound fraction in plasma. Figure 10.3a shows the predicted oral profile compared to the observed data from two rats dosed orally at 2mg/kg. The additional inputs for the oral prediction were the Caco-2 permeability and measured human fed-state simulated intestinal fluid (FeSSIF, 92(tg/mL). The oral pharmacokinetic parameters Tmax. Cmax. AUC and bioavailability were well predicted. Simulation of higher doses of compound A predicted absorption-limited... 

For FTIH trials, all applications should include a summary of projected free plasma concentrations of the new active substance (NAS) in humans and a brief description of any pharmacokinetic modelling programs used to generate the estimates. A comparison with the concentrations obtained in the nonclinical toxicity studies and projected safety margins should be given. In the same section, an estimate of the extent of the intended pharmacological or pharmacodynamic response at the expected plasma concentrations should be included, with a list of the assumptions used in deriving that estimate. 

For saturation of absorption to be used for dose selection, information that the absorption process has been saturated using the intended route of administration is necessary. These data can usually be obtained during well-designed pharmacokinetic studies that evaluate linearity of absorption and dose proportionality using the route and frequency of dosing projected for human clinical studies. 

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