Evaluation of Prediction Accuracy for Volume of Distribution in Rat and Human Using In Vitro, In Vivo, PBPK and QSAR Methods

• Published in: Journal of pharmaceutical sciences 2021-04, Vol.110 (4), p.1799-1823
• Main Authors: Mathew, Shibin, Tess, David, Burchett, Woodrow, Chang, George, Woody, Nathaniel, Keefer, Christopher, Orozco, Christine, Lin, Jian, Jordan, Samantha, Yamazaki, Shinji, Jones, Rhys, Di, Li
• Format: Article
• Language: English
• Subjects: Absorption, distribution, metabolism, and excretion (ADME); Distribution; Interspecies (dose) scaling; Log partition coefficient (s) (log P/log PC); Partition coefficient(s); Pharmacokinetics; Physiologically based pharmacokinetic (PBPK) modeling; Protein binding; Quantitative structure–activity relationship(s) (QSAR); Tissue partition
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2020.12.005

Volume of distribution at steady state (Vss) is an important pharmacokinetic parameter of a drug candidate. In this study, Vss prediction accuracy was evaluated by using: (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (fu,t) method with adipose and muscle also provided high Vss prediction accuracy. Overall, the high performing methods for human Vss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The fu,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful Vss prediction involves strategic integration of in silico, in vitro and in vivo approaches.