Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs

A database containing maximum daily doses of 1841 marketed oral drugs was used to examine the influence of physicochemical properties on dose and hepatotoxicity (drug induced liver injury, DILI). Drugs in the highest ∼20% dose range had significantly reduced mean lipophilicity and molecular weight, increased fractional surface area, increased % of acids, and decreased % of bases versus drugs in the lower ∼60% dose range. Drugs in the ∼20-40% dose range had intermediate mean properties, similar to the mean values for the full drug set. Drugs that are both large and highly lipophilic almost invariably do not have doses in the upper ∼20% range. The results show that oral druglike physicochemical properties are different according to these dose ranges, and this is consistent with maintenance of acceptable safety profiles as efficacious exposure increases. Verified DILI annotations from a compilation of >1000 approved drugs (Chen, M.; et al. Drug Discov. Today, 2016, 21, 648 ) were used. The drugs classified as "No DILI" ( n = 163) had significantly lower dose and lipophilicity, and higher Fsp3 (fraction of carbon atoms that are sp³ hybridized) versus the "Most DILI" ( n = 163) drugs. The percentages of acids were reduced and bases increased in the "No DILI" versus the "Most DILI" groups. Drugs classified as "Less DILI" or "Ambiguous DILI" had intermediate mean values of dose, lipophilicity, Fsp3, and % acids and bases. The impact of lipophilicity and Fsp3 on DILI increases in the upper 20% versus the lower 80% dose range, and a simple decision tree model predicted "No DILI" versus "Most DILI" outcomes with 82% accuracy. The model correctly classified 19 of 22 drugs (86%) that failed in development due to human hepatotoxicity. Because many oral drugs lacking DILI annotations are predicted to be "Most DILI", the model is best used preclinically in conjunction with experimental DILI mitigation.