The Use of ROC Analysis for the Qualitative Prediction of Human Oral Bioavailability from Animal Data

PURPOSE: To develop and evaluate a tool for the qualitative prediction of human oral bioavailability (F(human)) from animal oral bioavailability (F(animal)) data employing ROC analysis and to identify the optimal thresholds for such predictions. METHODS: A dataset of 184 compounds with known F(human) and F(animal) in at least one species (mouse, rat, dog and non-human primates (NHP)) was employed. A binary classification model for F(human) was built by setting a threshold for high/low F(human) at 50%. The thresholds for high/low F(animal) were varied from 0 to 100 to generate the ROC curves. Optimal thresholds were derived from ‘cost analysis’ and the outcomes with respect to false negative and false positive predictions were analyzed against the BDDCS class distributions. RESULTS: We successfully built ROC curves for the combined dataset and per individual species. Optimal F(animal) thresholds were found to be 67% (mouse), 22% (rat), 58% (dog), 35% (NHP) and 47% (combined dataset). No significant trends were observed when sub-categorizing the outcomes by the BDDCS. CONCLUSIONS: F(animal) can predict high/low F(human) with adequate sensitivity and specificity. This methodology and associated thresholds can be employed as part of decisions related to planning necessary studies during development of new drug candidates and lead selection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-013-1193-2) contains supplementary material, which is available to authorized users

Towards bridging translational gap in cardiotoxicity prediction : an application of progressive cardiac risk assessment strategy in TdP risk assessment of moxifloxacin

Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis. A multi-scale mechanistic modeling framework consisting of physiologically based pharmacokinetics (PBPK) simulations of clinically relevant drug exposures combined with Quantitative Systems Toxicology (QST) models of cardiac electro-physiology could bridge this gap. We illustrate this PBPK-QST approach in cardiac risk assessment as exemplified by moxifloxacin, an anti-tuberculosis drug with abundant clinical cardiac safety data. PBPK simulations of moxifloxacin concentrations (systemic circulation and estimated in heart tissue) were linked with in vitro measurements of cardiac ion channel inhibition to predict the magnitude of QT prolongation in healthy individuals. Predictions closely reproduced the clinically observed QT interval prolongation, but no arrhythmia was observed, even at ×10 exposure. However, the same exposure levels in presence of physiological risk factors, e.g., hypokalemia and tachycardia, led to arrhythmic event in simulations, consistent with reported moxifloxacin-related TdP events. Application of a progressive PBPK-QST cardiac risk assessment paradigm starting in early development could guide drug development decisions and later define a clinical “safe space” for post-approval risk management to identify high-risk clinical scenarios

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

In Vitro to in vivo extrapolation of valproic acid hepatotoxicity: A biokinetic and physiologically based toxicokinetic informed approach

Valproic acid (VPA) is used in the management of seizures, bipolar disorder, and migraines however, its use is associated with a number of adverse effects including hepatic steatosis. Whole-body physiologically based toxicokinetic (PBTK) models were developed to simulate the tissue concentrations of VPA in the rat and human. The models were parameterised using physicochemical properties and reverse translation approaches from published data. In order to recover the extended systemic exposure observed in rodent pre-clinical studies, it was necessary to incorporate the enterohepatic recirculation resultant from deconjugation of biliary cleared glucoronidated metabolites in the gut, and the subsequent reabsorption of parent compound. In vitro reporter assays showed activation of the pregnane X receptor (PXR) and peroxisome proliferator activated receptor alpha (PPARa) in response to VPA exposure; both previously identified as molecular initiating events (MIEs) in the hepatic steatosis adverse outcome pathway. Using a steady-state biokinetic model of in vitro distribution, nominal VPA treatment concentrations identified as activating PXR and PPARa in vitro were used to predict the corresponding intracellular concentrations. Using the verified rat and human PBTK models, a reverse-dosimetry approach was employed to determine the oral dose resulting in maximal hepatic concentrations corresponding to the intracellular concentration associated with activating these MIEs in vitro. Doses of 3.7 mg/kg and 1.7 mg/kg in rat and human, respectively, were determined to result in hepatic concentrations associated with activation of MIEs in the steatosis AOP. As might be expected, the MIE activating dose determined in rat, was more than two orders of magnitude lower than the oral LOAEL identified in rat repeat dose toxicity studies (500 mg/kg) linked with histopathological scoring of hepatic steatosis. However, the MIE activating dose in humans, equivalent to ∼125 mg, is well within the therapeutic dosing range. Repeat dosing at therapeutic levels could result in sustained activation of MIEs associated with adverse hepatic outcomes